Paclitaxel conjugate compounds and pharmaceutical compositions thereof

Abstract

Provided herein are peptide-paclitaxel conjugate compounds comprising paclitaxel conjugated to an oligo-arginine peptide via a disulfide linker, wherein the disulfide linker is attached to the paclitaxel at the C2' hydroxyl position; pharmaceutical compositions thereof; methods of making thereof; and methods of using thereof for treating or preventing a proliferative, dermatological, or ophthalmic disease or disorder.

Description

Cross-references to related applications

[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. Technical Field

[0002] This article provides peptide-paclitaxel conjugates and their pharmaceutical compositions. Background Technology

[0003] Despite significant progress over the years, cancer remains a global health problem. It is one of the leading causes of death worldwide. In 2018, there were 18.1 million new cancer cases and 9.5 million cancer-related deaths globally. By 2040, the number of new cancer cases is projected to rise to 29.5 million annually, and cancer-related deaths to 16.4 million. See National Cancer Institute (USA) 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 worldwide are diagnosed with this cancer each year. Liver cancer is also a leading cause of cancer death worldwide, causing more than 700,000 deaths annually.

[0005] Ovarian cancer is the fifth leading cause of cancer death among women, with an estimated 22,000 women diagnosed and 15,500 dying in the United States.

[0006] Stomach cancer is the fourth most common cancer worldwide and the second leading cause of cancer death. 40% of stomach cancer deaths involve liver metastasis, while 53%–60% involve peritoneal spread. Systemic chemotherapy provides a median survival of 7 months; however, in cases of 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 approximately 49,700 deaths each year, making it the second leading cause of cancer death. At diagnosis, about 10% of patients have peritoneal dissemination, which is the second leading cause of death for those with colorectal cancer. The median overall survival for patients with colorectal cancer and peritoneal dissemination is 24 months.

[0008] Currently, no chemotherapy agents are explicitly approved for intraperitoneal (IP) chemotherapy. All current clinical studies of IP chemotherapy are conducted using drugs designed for intravenous (IV) administration through off-label use.

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

[0010] As of 2021, an estimated 2.2 billion people worldwide were affected by eye conditions. Nearly half of these cases were preventable or had not yet been resolved through treatment. As reported by Ono et al., 2010, Am. J. Public Health 100(9):1784-1788, in 2013, the global burden of eye disease was estimated to account for 4.0% of the total global disease burden.

[0011] There is a need for additional therapies to treat proliferative, skin, or ophthalmic diseases and conditions. There is also a need for new therapies that are effective for intraperitoneal administration to treat proliferative, skin, or ophthalmic diseases and disorders. Summary of the Invention

[0012] In one aspect, this document provides a pharmaceutical composition comprising a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 1 to 20. In some embodiments, n is 8. In some embodiments, the compound is a compound of formula (II). Or a pharmaceutically acceptable salt. In some embodiments, the compound is an acetate.

[0013] In some embodiments, the pharmaceutical composition is a formulation that further comprises mannitol. In some embodiments, mannitol accounts for 2.5 wt% of the formulation. In some embodiments, the formulation is substantially free of surfactants. The formulation may be aqueous or lyophilized.

[0014] In another aspect, this document provides an aqueous pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: (I), where n is an integer selected from 1 to 20, 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 a compound of formula (II). Or a pharmaceutically acceptable salt. In some embodiments, the compound is an acetate. In some embodiments, the aqueous pharmaceutical composition further comprises mannitol. In some embodiments, mannitol accounts for 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. 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.

[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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is not 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is about or greater 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 4.5, and the concentration of the compound (e.g., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is about or greater 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 4.0, and the concentration of the compound (e.g., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is about or greater 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 3.5, and the concentration of the compound (e.g., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is about or greater 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 3.0, and the concentration of the compound (e.g., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is about or greater 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, this document provides an aqueous pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: (I), where n is an integer selected from 1 to 20, 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 a compound of formula (II). Or a pharmaceutically acceptable salt. In some embodiments, the compound is an acetate. In some embodiments, the aqueous pharmaceutical composition further comprises mannitol. In some embodiments, mannitol comprises 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 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 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.

[0019] In some embodiments, the concentration of the compound (e.g., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 25 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 50 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 75 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 100 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 150 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 200 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 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., a compound of formula (I) or (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. Attached Figure Description

[0020] Figure 1A shows the results of 24 hours after in a buffer system containing the compound of formula (II) at different pH values ​​(1 mg / mL). The solution samples have pH values ​​of 3, 4, 5, 6, 7, 8, and 9 from left to right.

[0021] Figure 1B is a graph showing the solution (10 mg / mL) of compound (II) in buffer systems with different pH values ​​after 24 hours. The solution samples have pH values ​​of 3, 4, 5, 6, 7, 8 and 9 from left to right.

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

[0023] Figure 1D is a graph showing the solution (200 mg / mL) of compound (II) in buffer systems with different pH values ​​after 24 hours. The solution samples have pH values ​​of 3, 4, 5, 6, 7, 8 and 9 from left to right.

[0024] Figure 1E is a graph of prepared solutions (5 mg / mL) of the compound of formula (II) in WFI at different pH values. The solution samples have pH values ​​of 3, 4, 5, 6, 7, 8 and 9 from left to right.

[0025] Figure 1F shows the results of 24 hours after in a buffer system containing the compound of formula (II) at different pH values ​​(5 mg / mL). The solution samples have pH values ​​of 3, 4, 5, 6, 7, 8, and 9 from left to right.

[0026] Figure 2 is a graph showing the relationship between the degradation level of compound (II) and pH.

[0027] Figure 3 shows the relationship between the degradation level of compound (II) and storage days under different pH conditions.

[0028] Figure 4 shows the relationship between the degradation level of compound (II) and storage days under different initial concentrations. Detailed Implementation

[0029] This document describes pharmaceutical compositions containing peptide-paclitaxel conjugates or pharmaceutically acceptable salts thereof. This application is based, in part, on the unexpected finding that aqueous pharmaceutical compositions containing peptide-paclitaxel conjugates of formula (I) (particularly compounds of formula (II)) or pharmaceutically acceptable salts thereof exhibit significant solubility and stability under one or more of the following conditions: 1) low pH (e.g., not exceeding about pH 5.5); 2) high concentration (e.g., at least about 25 mg / mL); and 3) in mannitol-containing formulations. Therefore, this application provides pharmaceutical compositions (including specific formulations) suitable for the paclitaxel-peptide conjugates or pharmaceutically acceptable salts thereof described herein. definition

[0030] Unless otherwise defined, all technical terms, symbols, and other scientific terms used herein are intended to have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains. In some instances, terms with their commonly understood meanings are defined herein for clarity and / or ease of reference. The techniques and procedures described or mentioned herein are generally well understood by one of ordinary skill in the art and are typically employed by one of ordinary skill in the use of conventional methods. Procedures involving the use of commercially available kits and reagents are typically performed according to manufacturer-defined protocols and conditions, unless otherwise stated.

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

[0032] The term "about" indicates and encompasses the indicated value and the range above and below that value. In some embodiments, the term "about" indicates a specified value ± 10%, ± 5%, or ± 1%. In some embodiments, the term "about" indicates a specified value ± one standard deviation of that value. In some embodiments, such as logarithmic scales (e.g., pH), the term "about" indicates a specified value ± 0.3, ± 0.2, or ± 0.1.

[0033] When referring to the compounds provided herein, the following terms have the following meanings unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Where multiple definitions exist for terms herein, those definitions in this section shall prevail unless otherwise stated.

[0034] As used herein, and unless otherwise stated, the term "protecting group" refers to a group added to an oxygen, nitrogen, or phosphorus atom to prevent further reaction or for other purposes. A variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. (See, for example, Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, 4th ed., 2006, which is incorporated herein by reference).

[0035] As used herein, "pharmaceuticalally acceptable" or "pharmacologically acceptable" means a material that is not biologically or otherwise undesirable, for example, a material that can be incorporated into a pharmaceutical composition administered to a patient without causing any significantly undesirable biological effects or interacting in a harmful manner with any other component of the composition containing it. Pharmaceutically acceptable carriers or excipients preferably meet toxicological and manufacturing testing requirements and / or are included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0036] The terms "substantially free of" or "substantially absent" in relation to a composition mean that the composition comprises at least 50%, 60%, 70%, 75%, 80%, 85%, or 90% by weight; in some embodiments, 95%, 98%, 99%, or 100% by weight; or in some embodiments, 95%, 98%, 99%, or 100% by weight of a specified enantiomer or diastereomer of the compound. In some embodiments, in the methods and compounds provided herein, the compound is substantially free of one of two enantiomers. In some embodiments, in the methods and compounds provided herein, the compound is substantially free of one of two diastereomers. In some embodiments, in the methods and compounds provided herein, the compound is substantially free of opposite D-cysteine ​​amino acid epimers.

[0037] The term "epomer" refers to one of a pair of diastereomers having opposite configurations at only one of at least two stereoisomeric source centers or chiral centers. For example, the compound of formula (I) and the corresponding compound containing the amino acid D-cysteine ​​are epimers.

[0038] Similarly, the term "isolated" in relation to a composition means that the composition comprises at least 50%, 60%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% to 100% of the compound by weight, with the remainder comprising other chemical species, enantiomers, or diastereomers.

[0039] As used herein, “enantiomer excess (ee)” refers to a dimensionless molar ratio describing the purity of a chiral substance containing, for example, a single stereoisomeric source center. For example, an enantiomer excess of zero would indicate racemization (e.g., a 50:50 mixture of enantiomers, or one enantiomer being in excess of another). Further exemplified, an enantiomer excess of ninety-nine would indicate an enantiomeric compound that is almost stereopure (i.e., one enantiomer being in significant excess of another). The percentage enantiomer excess %ee = ([(R)-compound] - [(S)-compound]) / ([(R)-compound] + [(S)-compound]) x 100, where (R)-compound > (S)-compound; or %ee = ([(S)-compound] - [(R)-compound]) / ([(S)-compound] + [(R)-compound]) x 100, where (S)-compound > (R)-compound.

[0040] As used herein, “diasteresome excess (de)” refers to a dimensionless molar ratio describing the purity of a chiral substance containing more than one stereoisomer source center. For example, a diasteresome excess of zero would indicate an equimolar mixture of diastereomers. Further, a diasteresome excess of ninety-nine would indicate a nearly stereopure diastereomer compound (i.e., one diastereomer in significant excess relative to another). Diasteresome excess can be calculated using a method similar to ee. As those skilled in the art will understand, de is typically reported as a percentage of de (% de). % de can be calculated in a manner similar to % ee.

[0041] "Solvate" means a compound or salt thereof provided herein that further comprises stoichiometric or non-stoichiometric amounts of a solvent bound by non-covalent intermolecular forces. In the case of water as the solvent, 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 of a given atom. Atoms containing their natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise specified, the atoms of compounds listed herein are intended to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is explicitly designated as hydrogen (H), that position should be understood to have hydrogen in its natural isotopic composition.

[0043] "Isotope enrichment" refers to the percentage of a given atom in a molecule that is replaced by a specific isotope at that atom, replacing the natural isotopic abundance of that atom. For example, a 1% enrichment of deuterium (D) at a given position means that 1% of the molecules in a given sample contain deuterium at that specified position. Since the natural distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is approximately 0.0156%. The isotopic enrichment of the compounds presented herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0044] "Isotope enriched" means that the isotopic composition of an atom is different from that of its natural isotopic composition. "Isotope enriched" can also refer to a compound containing at least one such atom whose isotopic composition is different from that of its natural isotopic composition.

[0045] As used in this article, the term "EC" 50 "" refers to the dose, concentration, or amount of a specific test compound that triggers, stimulates, or enhances a specific response by 50% of the maximum expression of the dose-dependent response.

[0046] As used herein, and unless otherwise stated, the term "IC" is used in conjunction with other terms. 50 "" refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of such a reaction in the determination of the measured reaction.

[0047] As used herein, the terms “subject” and “patient” are used interchangeably. The terms “subject” and “subjects” refer to animals, such as mammals, including non-primates (e.g., cattle, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys (such as cynomolgus monkeys), chimpanzees, and humans), and in some embodiments, to humans. In some embodiments, the subject is a farm animal (e.g., a horse, cattle, pig, etc.) or a pet (e.g., a dog or cat). In some embodiments, the subject is a human.

[0048] As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any one or more agents that can be used to treat or prevent a disorder or one or more symptoms thereof. In some embodiments, the term "therapeutic agent" includes compounds provided herein. In some embodiments, a therapeutic agent is an agent that is known to be, has been, or is currently being used to treat or prevent a disorder or one or more symptoms thereof.

[0049] As used herein, “treatment” or “treating” is a method for obtaining a beneficial or desired outcome, including clinical outcomes. For the purposes of this invention, a beneficial or desired clinical outcome includes, but is not limited to, one or more of the following: reducing one or more symptoms caused by a disease, reducing the severity of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease (e.g., metastasis), preventing or delaying the onset or recurrence of the disease, delaying or slowing the progression of the disease, improving the disease state, providing remission of the disease (whether partial or complete), reducing the dosage of one or more other medications required to treat the disease, delaying the progression of the disease, improving quality of life, and / or prolonging survival. In some embodiments, the composition reduces the severity of one or more cancer-related symptoms by at least one of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to corresponding symptoms in the same subject before treatment or compared to corresponding symptoms in other subjects who did not receive the composition. “Treatment” also encompasses reducing the pathological consequences of cancer. The methods of this invention are contemplated in relation to any one or more of these therapeutic aspects.

[0050] As used herein, "unit dosage form" refers to a physically discrete unit suitable as a unit dose, each unit containing a predetermined amount of active ingredient calculated to bind with the desired drug carrier to produce the desired therapeutic effect. Unit dosage forms may contain single or combination therapies.

[0051] As used in this article, an "at-risk" individual is an individual who is at risk of developing cancer. An "at-risk" individual may or may not have a detectable disease, and may or may not have exhibited a detectable disease prior to the treatments described herein. "At-risk" means that an individual has one or more so-called risk factors, which are measurable parameters related to the occurrence of cancer as described herein. Individuals with one or more of these risk factors are more likely to develop cancer than individuals without these risk factors.

[0052] A “favorable setting” refers to a clinical environment in which an individual has a history of cancer and typically (but not necessarily) responds to treatments, including but not limited to surgery (e.g., surgical resection), radiation therapy, and chemotherapy. However, due to their cancer history, these individuals are considered at risk for developing the disease. Treatment or administration in a “favorable setting” refers to the subsequent course of treatment. The level of risk (e.g., when an individual in a favorable setting is considered “high-risk” or “low-risk”) depends on several factors, most typically the severity of the disease at the time of the first treatment.

[0053] "Neoadjuvant setting" refers to a clinical setting in which the methods described are performed prior to the initial / final treatment.

[0054] As used herein, "pharmaceutically active compound" means a chemical compound that induces the desired effect (e.g., to treat, stabilize, prevent, and / or delay cancer).

[0055] As used herein, “combination therapy” means the combination of a first therapy comprising nanoparticles containing rapamycin or a derivative thereof and a carrier protein with a second therapy (e.g., a radiation, surgical, or chemotherapy agent) that can be used to treat, stabilize, prevent, and / or delay cancer. Administration in “combination” with another compound includes sequential, simultaneous, or sequential administration in one or more identical or different compositions. In some variations, the combination therapy optionally comprises one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutical active compounds, and / or inert substances.

[0056] As used herein, the terms "prophylactic agent" and "prophylactic agents" refer to any one or more agents that can be used to prevent a disorder or one or more symptoms thereof. In some embodiments, the term "prophylactic agent" includes compounds provided herein. In some other embodiments, the term "prophylactic agent" does not refer to compounds provided herein. For example, a prophylactic agent is an agent known to be, or has been, or is currently being used to prevent or inhibit the onset, development, progression, and / or severity of a disorder.

[0057] As used herein, the phrase “preventive effective amount” refers to an amount of a therapy (e.g., a preventive agent) sufficient to prevent or reduce the development, recurrence, or onset of one or more symptoms associated with the disorder, or sufficient to enhance or improve the preventive effect of another therapy (e.g., another preventive agent).

[0058] The term "effective amount" means an amount of a composition (e.g., a compound of formula (II)), a first therapy, a second therapy, or a combination therapy that, based on the knowledge of a practicing professional, should be effective in a given form of treatment in combination with its efficacy and toxicity parameters. In various embodiments, the effective amount of the composition or therapy may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, delay, mitigate to some extent, or preferably prevent the infiltration of cancer cells into peripheral organs; (iv) inhibit (e.g., mitigate to some extent, or preferably prevent) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay the occurrence and / or recurrence of tumors; and / or (vii) alleviate to some extent one or more cancer-related symptoms. In various embodiments, the amount is sufficient to improve, alleviate, reduce, and / or delay one or more symptoms of cancer.

[0059] In some embodiments, the amount of the composition, first therapy, second therapy, or combination therapy is sufficient to reduce tumor size, cancer cell number, or tumor growth rate by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to the corresponding tumor size, cancer cell number, or tumor growth rate in the same subject before treatment, or compared to the corresponding activity in other untreated subjects. Standard methods may be used to measure the magnitude of this effect, such as in vitro assays using purified enzymes, cell-based assays, animal models, or human tests.

[0060] As understood in the art, an "effective amount" can be one or more doses, i.e., a single or multiple doses may be required to achieve the desired therapeutic endpoint. An effective amount can be considered in the context of administering one or more therapeutic agents, and a nanoparticle composition (e.g., a composition comprising rapamycin and a carrier protein) can be considered to be administered in an effective amount if combining one or more other agents achieves or realizes the desired or beneficial result. Components in the combination therapy of the present invention (e.g., first and second therapies) can be administered sequentially, simultaneously, or consecutively using the same or different routes of administration for each component. Therefore, an effective amount of combination therapy includes the amount of the first therapy and the amount of the second therapy that produce the desired result when administered sequentially, simultaneously, or consecutively.

[0061] "Therapeutic effective amount" refers to an amount of a composition (e.g., a compound of formula (II)), a primary therapy, a secondary therapy, or a combination therapy sufficient to produce the desired therapeutic outcome (e.g., reducing the severity or duration of one or more symptoms of cancer, stabilizing the severity of one or more symptoms of cancer, or eliminating one or more symptoms of cancer). For therapeutic use, beneficial or desired outcomes include, for example, reducing one or more symptoms caused by the disease (biochemical, histological, and / or behavioral symptoms, including its complications and intermediate pathological phenotypes presented during disease development), improving the quality of life of those patients with the disease, reducing the dosage of other drugs needed to treat the disease, enhancing the effect of another drug, delaying disease progression, and / or prolonging patient survival.

[0062] "Prophylactic effective amount" refers to an amount of a composition (e.g., a compound of formula (II)), a primary therapy, a secondary therapy, or a combination therapy sufficient to prevent one or more future symptoms of cancer or reduce their severity when administered to an individual susceptible to and / or likely to develop cancer. For prophylactic use, beneficial or desired outcomes include, for example, outcomes such as: elimination or reduction of risk, reduction of the severity of future disease, or delay of the onset of disease (e.g., delay of biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that may appear during the future development of the disease).

[0063] It should be understood that the aspects and implementation schemes described herein as "comprising" include implementation schemes that are "composed of" and "substantially composed of". Pharmaceutical Composition

[0064] In one aspect, this document provides an aqueous pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (I) or (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 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 and 7 (e.g., between 3 and 4, 3 and 5, 3 and 5.5, 3 and 6, or 3 and 7). In some embodiments, the aqueous pharmaceutical composition has a pH less than 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH less than 5.0. In some embodiments, the aqueous pharmaceutical composition has a pH less than 4.5. In some embodiments, the aqueous pharmaceutical composition has a pH less than 4.0. In some embodiments, the aqueous pharmaceutical composition has a pH less than 3.5. In some embodiments, the aqueous pharmaceutical composition has a pH less than 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH not less than 2.5. In some embodiments, the aqueous pharmaceutical composition has a pH not less than 3.0. In some embodiments, the aqueous pharmaceutical composition has a pH not less than 3.5. In some embodiments, the aqueous pharmaceutical composition has a pH of not less than 4.0. In some embodiments, the aqueous pharmaceutical composition has a pH of not 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., a 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 compounds described herein (e.g., compounds of formula (I) or (II)) or their pharmaceutically acceptable salts are present in an aqueous pharmaceutical composition at a concentration 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 less than 5.5, and the concentration of the compound (e.g., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is about or greater 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 not exceeding 5.0, and the concentration of the compound (e.g., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is about or greater 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 not exceeding 4.5, and the concentration of the compound (e.g., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is about or greater 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 not exceeding 4.0, and the concentration of the compound (e.g., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is about or greater 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 not exceeding 3.5, and the concentration of the compound (e.g., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is about or greater 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 not exceeding 3.0, and the concentration of the compound (e.g., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is about or greater 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 25 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 50 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 75 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 100 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 150 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 200 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 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., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof is at least about 250 mg / mL, and the aqueous pharmaceutical composition has a pH not exceeding 7.0, 6.0, 5.5, 5.0, 4.0, 3.5, or 3.0. In some embodiments, a formulation of a compound of formula (I) (such as a compound of formula (II)) or a pharmaceutically acceptable salt thereof is provided, wherein the pH of the formulation does not exceed about 5.5 (such as any one 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 (e.g., any one of at least about 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, or 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 of the compound.

[0069] In some embodiments, a liquid formulation of a compound of formula (I) (such as a compound of formula (II)) or a pharmaceutically acceptable salt thereof is provided, wherein the concentration of the compound or a pharmaceutically acceptable salt thereof is at least about 25 mg / mL (e.g., any one of at least about 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, or 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 of the compound.

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

[0071] In some embodiments, in combination with any of the above or below embodiments, the pharmaceutical compositions provided herein are suitable for administration via any suitable route known in the art. For example, the pharmaceutical compositions described herein are suitable for administration via routes including, but not limited to, oral, inhalation, sublingual, sublingual, intra-arterial, intradermal, intramuscular, intraperitoneal (IP), intravenous (IV), nasal, parenteral, pulmonary, and subcutaneous routes. In some embodiments, the pharmaceutical compositions provided herein are suitable for parenteral administration. In some embodiments, the pharmaceutical compositions provided herein are suitable for intraperitoneal injection. In some embodiments, the pharmaceutical formulations provided herein are suitable for intravenous injection. In some embodiments, the pharmaceutical compositions provided herein are suitable for oral administration. Pharmaceutically acceptable excipients

[0072] The pharmaceutical compositions described herein may further comprise pharmaceutically acceptable carriers. The term "carrier" includes diluents, adjuvants (e.g., Freund's adjuvants (complete and incomplete)), excipients, or mediators administered with the therapeutic agent. Such drug carriers can be sterile liquids, such as water and oils, including petroleum, animal, plant, or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous solutions of dextran and glycerol can also be used as liquid carriers, particularly for injectable solutions. Examples of suitable drug carriers are described in Martin, EW, Remington's Pharmaceutical Sciences.

[0073] Any suitable pharmaceutical excipient can be used, wherein a person skilled in the art can select a suitable pharmaceutical excipient. Non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, ethanol, etc. 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 manner in which the dosage form is administered to a subject and the specific compounds in the dosage form. If desired, the composition or single unit dosage form may also contain small amounts of wetting agents or emulsifiers or pH buffers. Therefore, the pharmaceutical excipients described below are intended to be illustrative and not limiting. Other pharmaceutical excipients include, for example, those described in Handbook of Pharmaceutical Excipients, Rowe et al. (eds.), 6th edition (2009) (incorporated herein by reference in its entirety).

[0074] In some embodiments, the pharmaceutical composition comprises an antifoaming agent. Any suitable antifoaming agent can be used. In some aspects, the antifoaming agent is selected from alcohols, ethers, oils, waxes, silicones, surfactants, and combinations thereof. In some aspects, the antifoaming agent is selected from mineral oils, vegetable oils, ethylene bis-stearamide, paraffin wax, ester waxes, fatty alcohol waxes, long-chain fatty alcohols, fatty acid soaps, fatty acid esters, silicone glycols, fluorinated organosilicones, polyethylene glycol-polypropylene glycol copolymers, polydimethylsiloxane-silica, ethers, octyl alcohol, capryl alcohol, sorbitan trioleate, ethanol, 2-ethylhexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof. In some embodiments, the pharmaceutical compositions provided herein do not contain any antifoaming agent.

[0075] In some embodiments, the pharmaceutical composition includes a solubilizer. Illustrative examples of solubilizers include, for example, ethanol, polyethylene glycol, butanediol, dimethylacetamide, glycerol, and propylene glycol. In some embodiments, the pharmaceutical compositions provided herein are aqueous solutions that do not contain any solubilizer.

[0076] In some embodiments, the pharmaceutical composition comprises a buffer. Illustrative examples of buffers include, for example, acetates, borates, carbonates, lactates, malates, phosphates, citrates, hydroxides, diethanolamine, monoethanolamine, glycine, methionine, glucuronide, and monosodium glutamate. In some embodiments, the pharmaceutical compositions provided herein do not contain any buffer.

[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 guru gum.

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

[0079] In some embodiments, this document provides an aqueous pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (I) or (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 does not contain a buffer. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 5.0 and does not contain a buffer. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 4.5 and does not contain a buffer. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 4.0 and does not contain a buffer. In some embodiments, the aqueous pharmaceutical composition has a pH of less than 3.0 and does not contain a buffer. In some embodiments, the pharmaceutical composition comprises water for injection.

[0080] In some embodiments, the aqueous pharmaceutical composition has a concentration of a compound (e.g., a compound of formula (I) or (II)) or a pharmaceutically acceptable salt thereof greater than 0.1 mg / mL, and the pharmaceutically acceptable carrier comprises mannitol. In some embodiments, the pharmaceutical composition has a concentration greater than 1 mg / mL, and the pharmaceutically acceptable carrier comprises mannitol. In some embodiments, the pharmaceutical composition has a concentration greater than 25 mg / mL, and the pharmaceutically acceptable carrier comprises mannitol. In some embodiments, the pharmaceutical composition has a concentration greater than 50 mg / mL, and the pharmaceutically acceptable carrier comprises mannitol. In some embodiments, the pharmaceutical composition has a concentration greater than 100 mg / mL, and the pharmaceutically acceptable carrier comprises mannitol. In some embodiments, the pharmaceutical composition has a concentration greater than 200 mg / mL, and the pharmaceutically acceptable carrier comprises mannitol. In some embodiments, the pharmaceutical composition does not contain a surfactant.

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

[0082] In some embodiments, a formulation of a compound of formula (I) (such as a compound of formula (II)) or a pharmaceutically acceptable salt thereof is provided, wherein the pH of the formulation does not exceed about 5.5 (such as any one 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 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, or 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 of the compound.

[0083] In some embodiments, a formulation of a compound of formula (I) (such as a compound of formula (II)) or a pharmaceutically acceptable salt thereof is provided, 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 of the compound.

[0084] In some embodiments, a formulation of a compound of formula (I) (such as a compound of formula (II)) or a pharmaceutically acceptable salt thereof is provided, wherein the pH of the formulation is about 3.0, and 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 of the compound.

[0085] In some embodiments, a formulation of a compound of formula (I) (such as a compound of formula (II)) or a pharmaceutically acceptable salt thereof is provided, 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 of the compound.

[0086] In some embodiments, a formulation of a compound of formula (I) (such as a compound of formula (II)) or a pharmaceutically acceptable salt thereof is provided, 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 of the compound.

[0087] In some embodiments, a formulation of a compound of formula (I) (such as a compound of formula (II)) or a pharmaceutically acceptable salt thereof is provided, 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 of the compound.

[0088] In some embodiments, the pharmaceutical composition comprises a surfactant. Illustrative examples of surfactants include, for example, d-α-tocopherol, benzalkonium chloride, benzyl chloride, trimethylammonium bromide, cetylpyridinium chloride, sodium docusate, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15-hydroxystearate, myristic acid, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, polyoxyglycerol esters, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene glycol succinate. In some embodiments, the pharmaceutical compositions provided herein do not contain 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 (ternary), hydroxymethyl cellulose, hydroxypropyl cellulose, and magnesium oxide. In some embodiments, the pharmaceutical compositions provided herein do not contain any anti-caking agent.

[0090] Other excipients that may be used with pharmaceutical compositions include, for example, albumins, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled-release agents, diluents, dispersants, solubilizers, emulsifiers, gelling agents, ointment bases, transdermal absorption enhancers, preservatives, solubilizers, solvents, stabilizers, and sugars. Specific examples of each of these agents are described, for example, in Handbook of Pharmaceutical Excipients, Rowe et al. (eds.), 6th edition (2009), The Pharmaceutical Press (incorporated herein by reference in its entirety). In some embodiments, the pharmaceutical compositions provided herein do not contain any antioxidants. In some embodiments, the pharmaceutical compositions provided herein do not contain any chelating agents. In some embodiments, the pharmaceutical compositions provided herein do not contain any emulsifiers. In some embodiments, the pharmaceutical compositions provided herein do not contain any solubilizers. In some embodiments, the pharmaceutical compositions provided herein do not contain any stabilizers.

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

[0092] The anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low-aqueous components and under low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient containing a primary or secondary amine may be anhydrous if substantial contact with moisture and / or humidity is anticipated during manufacturing, packaging, and / or storage.

[0093] Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous properties. Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water, allowing them to be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, gas-sealed foil, plastics, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0094] The lactose-free compositions described herein may contain excipients well known in the art and listed, for example, in the United States Pharmacopeia (USP) SP(III) / NF(XVI). Typically, lactose-free compositions contain an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms contain an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate. Parenteral dosage form

[0095] In some embodiments, the pharmaceutical compositions provided herein are parenteral dosage forms. Parenteral dosage forms can be administered to subjects via a variety of routes, including but not limited to subcutaneous, intravenous (including bolus), inhalation, intramuscular, and intra-arterial administration. Because their administration typically bypasses the subject's natural defenses against contaminants, parenteral dosage forms are generally sterile or can be sterilized prior to administration to the 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 injectable medium, suspensions ready for injection, emulsions, lyophilized powders ready to be reconstituted from pharmaceutically acceptable solutions for injection, and nebulized droplets ready for inhalation.

[0096] In some embodiments, in combination with any of the above or below embodiments, 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 may also contain wetting agents, isotonic agents, emulsifiers, dispersants, and stabilizers. Sterilization can be performed in several ways, such as using a bacterial filter, via radiation, or via heat. These pharmaceutical compositions may also be prepared as sterile solid compositions that can be dissolved in sterile water or any other injectable sterile medium at the time of use.

[0097] Suitable media for delivering parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to, water for injection (USP); aqueous media, such as, but not limited to, sodium chloride injection, Ringer's solution injection, dextran injection, dextran and sodium chloride injection, and lactated Ringer's solution injection; water-miscible media, such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous media, such as, but not limited to, corn 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 powders prepared for injection by reconstitution from a pharmaceutically acceptable solution (e.g., water for injection). In some embodiments, the lyophilized powder is prepared from an aqueous pharmaceutical composition comprising a compound of formula (II), water for injection, mannitol, and HCl. In some embodiments, the lyophilized powder is prepared from an aqueous pharmaceutical composition wherein the starting solution has a pH below 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH below 5.0. In some embodiments, the aqueous pharmaceutical composition has a pH below 4.5. In some embodiments, the aqueous pharmaceutical composition has a pH below 4.0. In some embodiments, the aqueous pharmaceutical composition has a pH below 3.5. In some embodiments, the aqueous pharmaceutical composition has a pH below 3.0. In some embodiments, the lyophilized powder is prepared from an aqueous pharmaceutical composition wherein the concentration of the compound of formula (II) is from about 10 mg / mL to about 200 mg / mL. In some embodiments, the lyophilized powder is prepared from an aqueous pharmaceutical composition wherein the concentration of the compound of formula (II) is about 50 mg / mL. In some embodiments, the lyophilized powder is prepared from an aqueous pharmaceutical composition comprising about 1.0 wt.% to about 10 wt.% mannitol. In some embodiments, the lyophilized powder is prepared from an aqueous pharmaceutical composition comprising about 1.0 wt.% to about 5 wt.% mannitol. In some embodiments, the lyophilized powder is prepared from an aqueous pharmaceutical composition comprising about 2.5 wt.% mannitol. In some embodiments, the lyophilized powder is prepared from an aqueous pharmaceutical composition comprising a compound of formula (II) at a concentration of 50 mg / mL, water for injection, and about 2.5 wt.% mannitol. In some embodiments, the lyophilized powder is surfactant-free.

[0099] In some embodiments, the pharmaceutical compositions provided herein are lyophilized powders prepared for injection by reconstitution with pharmaceutically acceptable solutions, wherein the pharmaceutically acceptable solutions include water for injection (WFI) and 5% dextran in water (D5W). In some embodiments, the pharmaceutically acceptable solution is water for injection (WFI). In some embodiments, the pharmaceutically acceptable solution is D5W. In some embodiments, the lyophilized powder may be diluted by a pharmaceutically acceptable solution by a factor of not less than 5, not less than 10, not less than 50, or not less than 100.

[0100] In some embodiments, the pharmaceutical compositions provided herein are lyophilized powders prepared for reconstitution from pharmaceutically acceptable solutions for injection, wherein the reconstituted composition has a pH value less than 5.5. In some embodiments, the reconstituted composition has a pH value less than 5.0. The reconstituted composition has a pH value less than 4.5. The reconstituted composition has a pH value less than 4.0.

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

[0102] The pharmaceutical compositions provided herein comprise paclitaxel conjugates that can be used to treat or prevent proliferative, skin, or ophthalmic diseases or disorders. The compounds can be prepared, formulated, and administered as described herein, and are used for therapeutic or diagnostic purposes. In some embodiments, the therapy is the treatment of a proliferative, skin, or ophthalmic disease or disorder.

[0103] The embodiments described herein include the listed compounds and their pharmaceutically acceptable salts, hydrates, solvates, tautomers and / or mixtures.

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

[0105] In some embodiments, a pharmaceutical composition is provided comprising a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof: (II).

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

[0107] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from 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 97%, at least about 99%, or 100% by weight of opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from about 85% to 95% of opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from about 90% to 95% of opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from at least about 85% opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from at least about 90% opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from at least about 95% opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from at least about 97% opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salt, hydrate, solvate, tautomer and / or mixture is 100% free of opposite D-cysteine ​​amino acid epimers.

[0108] In some embodiments, the compound of formula (II) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from 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 97%, at least about 99%, or 100% by weight of opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (II) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from about 85% to 95% of opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (II) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from about 90% to 95% of opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (II) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from at least about 85% opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (II) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from at least about 90% opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (II) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from at least about 95% opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (II) or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures thereof are free from at least about 97% opposite D-cysteine ​​amino acid epimers. In one embodiment, the compound of formula (II) or its pharmaceutically acceptable salt, hydrate, solvate, tautomer and / or mixture is 100% free of opposite D-cysteine ​​amino acid epimers.

[0109] In some embodiments, a pharmaceutical composition is provided comprising a compound of formula (X) or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof: (X) The compound of formula (X) comprises, by weight, 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% of the compound of formula (I) compared to the total weight of all stereoisomers of formula (X): (I); Where n is an integer selected from 1 to 20.

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

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

[0112] In some embodiments, this document provides a pharmaceutical composition comprising a compound of any one of formulas (I)-(II) substantially free of a specified stereoisomer of the compound. In some embodiments, this document provides a composition of a compound of any one of formulas (I)-(II) substantially free of a specified stereoisomer of the compound, wherein the specified stereoisomer is an opposite D-cysteine ​​amino acid epiisomer. In some embodiments, in the methods and compounds of this disclosure, the compound is substantially free of other stereoisomers. In some embodiments, in the pharmaceutical compositions of this disclosure, the compound is substantially free of an opposite D-cysteine ​​amino acid epiisomer. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or (II) that is free of at least about 50%, 60%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% to 100% by weight of an opposite D-cysteine ​​amino acid epiisomer of the compound of formula (I) or (II). In some embodiments, this document provides a pharmaceutical composition comprising a compound of any one of formulas (I)-(II) substantially free of a specified stereoisomer of the compound. In some embodiments, the pharmaceutical composition of this disclosure is substantially free of other stereoisomers. Isotope-enriched compounds

[0113] In one aspect, this document provides a pharmaceutical composition comprising isotopically enriched compounds, including but not limited to isotopically enriched compounds of any one of formulas (I)-(II).

[0114] Isotopic enrichment (e.g., deuteration) of drugs has previously been demonstrated to improve pharmacokinetic (“PK”), pharmacodynamic (“PD”), and / or toxicological characteristics in several 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).

[0115] Isotopic enrichment of drugs can be used, for example, to (1) reduce or eliminate unwanted metabolites; (2) increase the half-life of the parent drug; (3) reduce the number of doses required to achieve the desired effect; (4) reduce the amount of dose required to achieve the desired effect; (5) increase the formation of active metabolites (if any); and / or (6) reduce the production of harmful metabolites in specific tissues. Isotopic enrichment of drugs can also be used to produce more effective and / or safer drugs for combination therapy, whether or not the combination therapy is intentional.

[0116] The compounds described herein may contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. In some embodiments, the compounds are isotopically labeled, such as isotopically labeled compounds of formula (I) as described herein, or variations thereof, wherein one or more atoms are replaced by isotopes of the same element. Exemplary isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 O、 17 O、 32 P,35 S, 18 F, 36 Cl. Doping with heavier isotopes such as deuterium ( 2 H or D) can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life) and may therefore be preferred in some cases. As used herein, each instance of hydrogen being replaced by deuterium is also a disclosure of replacing that hydrogen with tritium. As used herein, each instance of enriching, substituting, or replacing an atom with its corresponding isotope encompasses an isotope enrichment level of about one of the following: 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 aforementioned percentages.

[0117] The isotope-labeled compounds of the present invention can generally be prepared by means of standard methods and techniques known to those skilled in the art or by means of procedures similar to those described in the appended examples, using appropriate isotope-labeled reagents instead of corresponding unlabeled reagents.

[0118] In one embodiment, the pharmaceutical composition provided herein comprises a compound of formula (X), wherein the preparation 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 of a compound of formula (I) relative to the total weight of all stereoisomers of formula (X).

[0119] In one embodiment, the pharmaceutical composition provided herein comprises a compound of formula (I) and one or more pharmaceutically acceptable excipients as described herein, wherein the composition is free from 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 of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising a compound of formula (I) is free from about 85% to 95% by weight of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising a compound of formula (I) is free from about 90% to 95% by weight of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising a compound of formula (I) is free from about 85% by weight of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising the compound of formula (I) is free of about 90% by weight of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising the compound of formula (I) is free of about 95% by weight of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising the compound of formula (I) is free of about 97% by weight of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising the compound of formula (I) is 100% by weight free of the opposite D-cysteine ​​amino acid epimer.

[0120] In one embodiment, the pharmaceutical composition provided herein comprises a compound of formula (II) and one or more pharmaceutically acceptable excipients as described herein, wherein the formulation contains, by weight, 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% of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising a compound of formula (II) contains, by weight, about 85%-95% of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising a compound of formula (II) contains, by weight, about 90%-95% of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising a compound of formula (II) contains, by weight, about 85% of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising the compound of formula (II) is free of about 90% by weight of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising the compound of formula (II) is free of about 95% by weight of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising the compound of formula (II) is free of about 97% by weight of the opposite D-cysteine ​​amino acid epimer. In one embodiment, the pharmaceutical composition comprising the compound of formula (II) is 100% 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 glucuronide. How to use

[0121] This document also provides methods of using pharmaceutical compositions comprising the compounds described herein. In some embodiments, the pharmaceutical compositions described herein are administered to a subject in need. In some embodiments, the subject is a mammal (in some embodiments, a human) at a pharmaceutically acceptable dose suitable for a form of administration such as those known in the art and those discussed herein, intravenously such as a bolus or by continuous infusion over a period of time, via intramuscular, intraperitoneal, intraspinal, subcutaneous, intra-articular, intrasynovial, intrathecal, inhalation, or intratumoral routes. The pharmaceutical compositions are also suitably administered via peritumoral, intralesional, or perilesional routes to exert local and systemic therapeutic effects. In some embodiments, the compounds are administered to a mammal (in some embodiments, a human) at a pharmaceutically acceptable dose suitable for an oral form of administration such as those known in the art and those discussed herein, for example, sublingually. For example, the pharmaceutical compositions of this disclosure can be orally administered to humans in liquid or solid form. Solid dosage forms include, for example, capsules, tablets, pills, powders, and granules. In such solid dosage forms, a 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 starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin wax; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) adsorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer. Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol. In one embodiment, the oral dosage form is an orally disintegrating tablet.

[0122] In clinical practice, the pharmaceutical compositions or compounds provided herein may be administered via any suitable route known in the art. Exemplary routes of administration for the formulations described herein include, but are not limited to, oral, inhalation, sublingual, sublingual, intra-arterial, intradermal, intramuscular, intraperitoneal (IP), intravenous (IV), nasal, parenteral, pulmonary, and subcutaneous routes. In some embodiments, the pharmaceutical compositions provided herein are administered parenterally. In some embodiments, the pharmaceutical compositions provided herein are administered via intraperitoneal injection. In some embodiments, the pharmaceutical compositions provided herein are administered via intravenous injection. In some embodiments, the pharmaceutical compositions provided herein are administered orally. Dosage and unit dose

[0123] In human therapeutics, doctors determine what they consider the most appropriate dosage based on whether the treatment is preventative or curative, as well as on the age, weight, condition, and other factors specific to the subject being treated.

[0124] In some embodiments, the pharmaceutical compositions provided herein are in a single-unit dosage form. The pharmaceutical compositions provided herein comprise a preventative or therapeutically effective amount of one or more of the preventative or therapeutic compounds described herein.

[0125] The amount of a compound and / or the amount of the pharmaceutical composition in a drug composition that will be effective in the prevention or treatment of a disorder or one or more of its symptoms will vary depending on the nature and severity of the disease or disorder and the route of administration of the compound. Frequency and dosage will also vary based on individual subject-specific factors, depending on the specific therapy administered (e.g., a therapeutic or preventative agent), the severity of the disorder, the disease or disorder and the route of administration, as well as the subject's age, weight, response, and medical history. The effective dose can be extrapolated from dose-response curves derived from in vitro or animal model testing systems.

[0126] In some embodiments, exemplary doses of pharmaceutical compositions comprising a compound of formula (I) or a compound of formula (II) include milligrams or micrograms of the compound of formula (I) or a compound of formula (II) per kilogram of subject or sample weight (e.g., about 10 micrograms / kg to about 50 milligrams / kg, about 100 micrograms / kg to about 25 milligrams / kg, or about 100 micrograms / kg to about 10 milligrams / kg). In some embodiments, based on the weight of the compound, the dose of the compound provided herein (e.g., a compound of formula (I) or a compound of formula (II)) administered for the prevention, treatment, administration, or improvement of a subject's disorder or one or more of their symptoms 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 of subject weight or more. In another embodiment, the dosage of the pharmaceutical composition provided herein, administered for the prevention, treatment, management, or improvement of a subject's disorder or one or more of its symptoms, 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 to 5 mg, 0.1 mg to 2.5 mg, 0.25 mg to 20 mg, 0.25 mg to 15 mg, 0.25 mg to 12 mg, 0.25 mg 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 mg to 15 mg, 0.5 mg to 12 mg, 0.5 mg to 10 mg, 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 20 ...20 mg, 0.5 mg to 20 mg, 0.5 mg to 20 mg, 0.5 mg to 20 mg, 0.5 mg to 20 mg, 0.5 mg to 20 mg, 0.5 mg to 20 mg, 0.5 mg to 20 mg, 0.5 mg to 20 mg, 0.5 mg to 20 mg 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] Dosage may be administered according to a suitable regimen (e.g., daily, once weekly, twice weekly, three times weekly, or four times weekly, or monthly, twice monthly, or three times monthly). In some cases, it may be necessary to use dosages of pharmaceutical compositions containing compounds described herein (e.g., compounds of formula (I) or (II)) that are outside the scope disclosed herein, as will be apparent to those skilled in the art. Furthermore, it should be noted that clinicians or treating physicians will consider the patient's response to understand how and when to interrupt, adjust, or discontinue therapy.

[0128] Different therapeutically effective amounts may be applicable to different diseases and conditions, as will be readily apparent to those skilled in the art. Similarly, amounts sufficient to prevent, manage, treat, or improve such disorders but insufficient to cause or reduce adverse effects associated with the compounds or pharmaceutical compositions provided herein are also covered by the dosage and frequency regimens described herein. Furthermore, when multiple doses of the pharmaceutical compositions provided herein are administered to a subject, not all doses need to be identical. For example, the dose administered to the subject may be increased to improve the preventive or therapeutic effect of the composition, or the dose may be decreased to reduce one or more side effects being experienced by a particular subject.

[0129] In some embodiments, treatment or prevention may begin with one or more loading doses of the compounds or pharmaceutical compositions provided herein, followed by one or more maintenance doses.

[0130] In some embodiments, a dose of the compound or composition provided herein may be administered to achieve a steady-state concentration of the compound (e.g., a compound of formula (I) or a compound of formula (II)) in the blood or serum of a subject. The steady-state concentration may be determined by means of measurements available to a person skilled in the art, or may be based on the subject’s physical characteristics (e.g., height, weight, and age).

[0131] In some embodiments, the same pharmaceutical composition may be administered repeatedly, and the administrations may be spaced at intervals of 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, the same preventative or therapeutic agent may be administered repeatedly, and the administrations may be spaced at intervals of 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 applications

[0132] In one aspect, the pharmaceutical compositions provided herein can be used to treat any of the diseases or disorders described herein (e.g., proliferative, skin, or ophthalmic diseases or disorders). In some embodiments, the diseases or disorders described herein are proliferative diseases or disorders (e.g., cancer). In some embodiments, the diseases or disorders described herein are skin diseases or disorders. In some embodiments, the diseases or disorders described herein are ophthalmic diseases or disorders.

[0133] In some embodiments, this document provides a method for treating cancer in a subject (e.g., a person) of need, the method comprising administering to the individual an effective amount of the pharmaceutical composition provided herein. The treatment may be a monotherapy or in the context of a combination therapy. In yet another aspect, this document provides a method for treating cancer in a subject (e.g., a person) of need, the method comprising administering to the individual an effective amount of the following combination: a) a first therapy comprising the pharmaceutical composition described herein, and b) a second therapy that can be used to treat 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 that can be used to treat cancer). It should be understood that the following references and descriptions of methods for treating cancer are exemplary, and that description is equally applicable to and includes methods for treating cancer using combination therapies.

[0134] Examples of cancers treatable by the methods of this invention include, but are not limited to, adrenocortical carcinoma, myeloid metaplasia of unknown cause, HIV-related cancers (e.g., HIV-related lymphoma), anal cancer, appendiceal cancer, astrocytomas (e.g., cerebellar astrocytoma and cerebral astrocytoma), basal cell carcinoma, bile duct cancer (e.g., extrahepatic bile duct cancer), bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain tumors (e.g., glioma, brainstem glioma, cerebellar or cerebral astrocytoma (e.g., pilocytic astrocytoma, diffuse astrocytoma, anaplastic (malignant) astrocytoma), malignant glioma, ependymoma, oligodendroglioma, meningioma, craniopharyngioma, hemangioblastoma, medulloblastoma, supratentorial primitive neuroectodermal tumor. Breast cancer, bronchial adenoma / carcinoid, carcinoid tumors (e.g., gastrointestinal carcinoid tumors), cancers of unknown primary origin, central nervous system lymphoma, cervical cancer, colon cancer, colorectal cancer, chronic myelodysplastic disorder, endometrial cancer (e.g., uterine cancer), ependymoma, esophageal cancer, Ewing tumor family, eye cancer (e.g., intraocular melanoma and retinoblastoma), gallbladder cancer, gastric (gastric / stomach) cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors (e.g., extracranial germ cell tumors, gonadal germ cell tumors, ovarian germ cell tumors), gestational trophoblastic tumors, head and neck cancer, hepatocellular carcinoma (e.g., liver cancer). Hepatocellular carcinoma (HCC and hepatocellular carcinoma), hypopharyngeal carcinoma, islet cell carcinoma (endocrine pancreatic tumor), 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, lung adenocarcinoma, and lung squamous cell carcinoma), lymphocytic tumors (e.g., lymphoma), medulloblastoma, melanoma, mesothelioma, metastatic squamous neck cancer, oral cancer, multiple endocrine tumor syndrome, myelodysplastic syndrome, myelodysplastic / myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, neuroendocrine carcinoma, oropharyngeal cancer, ovarian cancer (e.g., ovarian epithelial carcinoma, ovarian germ cell tumor, low-potency ovarian tumor), pancreatic cancer, parathyroid carcinoma, penile cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, Pineal blastoma and supratentorial primitive neuroectodermal tumors, pituitary adenomas, pleural pulmonary blastomas, lymphomas, primary central nervous system lymphomas (microgliomas), pulmonary lymphangioleiomyomatosis, rectal cancer, renal cancer, renal pelvis and ureter cancer (transitional cell carcinoma), rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., non-melanoma skin cancers (e.g., squamous cell carcinoma), melanoma and Merkel cell carcinoma), small bowel cancer, squamous cell carcinoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, tuberous sclerosis, urethral cancer, vaginal cancer, vulvar cancer, nephroblastoma, and post-transplant lymphoproliferative disorder (PTLD), abnormal angiogenesis associated with nevus hamartomatosis, edema (e.g., edema associated with brain tumors), and Megs syndrome.

[0135] In some implementations, suitable examples of cancer include breast cancer (e.g., invasive ductal breast cancer, non-invasive ductal breast cancer, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), and rectal cancer. Cancers such as gastrointestinal stromal tumors (GISTs), colorectal cancers (familial colorectal cancer, hereditary nonpolyposis colorectal cancer, GISTs), small bowel cancers (non-Hodgkin's lymphoma, GISTs), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancers (nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannomas, and liver cancers. (e.g., primary liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumors, ovarian germ cell tumors, low-potency ovarian tumors), 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 carcinoma) Cancers include: parathyroid carcinoma, nasal cavity carcinoma, sinus carcinoma, bone tumors (e.g., osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumors, pediatric solid tumors (e.g., nephroblastoma, pediatric kidney tumors), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemias (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0136] In some embodiments, the disease or obstacle is brain cancer, liver cancer, lung cancer, ovarian cancer, stomach cancer, or colorectal cancer. In some embodiments, the disease or obstacle is liver cancer. In some embodiments, the disease or obstacle is lung cancer. In some embodiments, the disease or obstacle is ovarian cancer. In some embodiments, the disease or obstacle is stomach cancer. In some embodiments, the disease or obstacle is colorectal cancer.

[0137] In some implementations, 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 a glioma, brainstem glioma, cerebellar or cerebral astrocytoma (e.g., pilocytic astrocytoma, diffuse astrocytoma, or anaplastic (malignant) astrocytoma), malignant glioma, ependymoma, oligodendroglioma, meningioma, craniopharyngioma, hemangioblastoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic glioma, or glioblastoma. In some embodiments, the brain cancer is glioblastoma (also known as glioblastoma multiforme or grade 4 astrocytoma). In some embodiments, the glioblastoma is radioresistant. In some embodiments, the glioblastoma is radiosensitive. In some embodiments, the glioblastoma may be infratentorial. In some embodiments, the glioblastoma is supratentorial. In some implementations, an individual may be a person who has genes, gene mutations or polymorphisms (e.g., NRP / B, MAGE-E1, MMACI-E1, PTEN, LOH, p53, MDM2, DCC, TP-73, Rb1, EGFR, PDGFR-α, PMS2, MLH1 and / or DMBT1) associated with brain cancer (e.g., glioblastoma), or has one or more additional copies of genes (e.g., MDM2, EGFR and PDGR-α) associated with brain cancer (e.g., glioblastoma).

[0139] Any treatment methods provided herein can be used to treat individuals (e.g., people) who have been diagnosed with or are suspected of having cancer. In some embodiments, the individual may be a person exhibiting one or more symptoms associated with cancer. In some embodiments, the individual may have advanced disease or a lower degree of disease, such as low tumor burden. In some embodiments, the individual is in an early stage of cancer. In some embodiments, the individual is in a late stage of cancer. In some embodiments of any treatment methods provided herein, the individual may be a person who has been diagnosed with or has not yet been diagnosed with cancer and who is genetically or otherwise predisposed to developing cancer (e.g., risk factors). In some embodiments, these risk factors include, but are not limited to, age, sex, race, diet, medical history, presence of pre-existing conditions, genetic (e.g., heredity) considerations, and environmental exposure. In some embodiments, individuals at risk of cancer include, for example, those with relatives who have experienced the disease and those whose risk has been determined by analysis of genetic or biochemical markers.

[0140] Any treatment methods described herein can be used to treat, stabilize, prevent, and / or delay cancer of any type or stage. In some implementations, the individual is at least about 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 years old. In some implementations, one or more symptoms of cancer are improved or eliminated. In some implementations, the size of the tumor, the number of cancer cells, or the growth rate of the tumor is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In some implementations, cancer is delayed or prevented.

[0141] In some implementations, the disease is skin-related. In some implementations, the disease is selected from acne scars, actinic keratosis, age spots (melasma), atopic dermatitis (eczema), autoimmune diseases, basal cell carcinoma, bullous pemphigoid, burning mouth syndrome, calcium allergy, cancer, oral ulcers, chronic urticaria, connective tissue disorders, contact dermatitis, cutaneous lupus, cutaneous T-cell lymphoma, dermatitis, dermatomyositis, Ehlers-Danlow syndrome, epidermolysis bullosa, erythromelalgia, hereditary skin disorders, graft-versus-host disease, granuloma annulare, Graves' disease, hair disorders, alopecia, hemangioma, hidradenitis suppurativa, hypereosinophilic syndrome, hyperhidrosis, pruritus ( Pruritus, keloids, venous malformation, osteomalacia syndrome, lichen planus, lip cancer, lymphoma, melanoma, Merkel cell carcinoma, nevus, morphine, mucosal diseases, nail diseases, renal systemic fibrosis, neurofibromatosis, non-melanoma skin cancer, oral lichen planus, panniculitis, pemphigus, pigmentary disorders, polymorphic light eruption, primary biliary cholangitis, psoriasis, pyoderma gangrenosa, rosacea, scleroderma, skin cancer, skin infections, spider angiopathy, squamous cell carcinoma of the skin, Schleck-Johnson syndrome, subcutaneous fat diseases, sun allergy, varicose veins, vascular malformations, vasculitis, vitiligo, vulvar skin disorders and wrinkles.

[0142] In some implementations, the disease is ophthalmic. In some implementations, the disease is selected from age-related macular degeneration, amblyopia, anophthalmia and microphthalmia, astigmatism, Behçet's disease, Bietti's crystalline dystrophy, blepharitis, blepharospasm, cataracts, cerebral visual impairment (CVI), ocular defects, color blindness, convergence dysfunction, corneal diseases, diabetic retinopathy, leukoderma, hyperopia, floaters, glaucoma, idiopathic intracranial hypertension, low vision, macular edema, macular hole, macular fold, myopia, ocular histoplasmosis syndrome (OHS), conjunctivitis, presbyopia, rare diseases, refractive errors, retinal detachment, retinitis pigmentosa, retinoblastoma, retinopathy of prematurity, Staggart's disease, Usher syndrome, uveitis, and vitreous detachment.

[0143] In some embodiments, this document provides a treatment method comprising administering a pharmaceutical composition provided herein, comprising an effective amount of the pharmaceutical composition provided herein. In some embodiments, the method encompasses the step of administering to a subject in need an effective amount of a combination of the compound described herein in a pharmaceutical formulation for treating a disease or disorder and a second agent for treating or preventing the disease or disorder.

[0144] In some implementations, the subject is an untreated subject. In other implementations, the subject has previously received therapy. For example, in some implementations, the subject did not respond to a single-drug treatment regimen.

[0145] In some embodiments, the subject is a subject who has discontinued other therapies due to one or more adverse events associated with those other therapies. In some embodiments, the subject has already received other therapies and discontinued them prior to administration of the methods provided herein. In other embodiments, the subject has already received a therapy and continues to receive that therapy in conjunction with administration of the compounds provided herein. The compounds described herein can be co-administered with other therapies for treating diseases or disorders, in the judgment of someone skilled in the art. In some embodiments, the methods or formulations provided herein can be co-administered with other therapies for treating diseases or disorders at reduced doses. Reagent test kit

[0146] In some embodiments, the pharmaceutical compositions provided herein are provided in the form of a kit (i.e., a pre-packaged combination of reagents with instructions for performing the procedure). In some embodiments, the procedure is a therapeutic procedure.

[0147] In some embodiments, the provided pharmaceutical composition is a lyophilized powder, and the kit further includes a solvent for reconstituted the pharmaceutical composition. In some embodiments, the pharmaceutical composition is provided as an aqueous solution ready for application.

[0148] In some embodiments, the kit may contain the pharmaceutical composition provided herein, an optional second agent or composition, and instructions for use to provide healthcare professionals with information about its use in treating the disorder. The instructions may be provided in printed form, on electronic media (such as floppy disks, CDs, or DVDs), or as a URL in which such instructions are available. The unit dose of the pharmaceutical composition or second agent or composition provided herein may include a dose such that, when administered to a subject, it maintains a therapeutic or preventative effective plasma level of the compound in the subject for at least one day.

[0149] In some implementations, suitable packaging is provided. As used herein, “packaging” includes a solid matrix or material commonly used in systems and is capable of holding the compounds and / or second agents provided herein within fixed limits suitable for administration to a subject. Such materials include glass or plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, plastic-foil laminated envelopes, etc. If electron beam sterilization technology is used, the packaging should have a sufficiently low density to allow for the sterilization of the contents. Example Example 1. Solubility of the compound of formula (II)

[0150] To optimize the buffer system and pH conditions for the formulation of the compound of formula (II), the solubility of the compound of formula (II) was measured under different pH conditions and in multiple buffer systems. The compound of formula (II) was first dissolved at an initial concentration of 100 mg / mL in target buffer systems with multiple pH values. The mixtures were shaken at 700 rpm and 25ºC for 24 hours, and their pH was measured. If the pH changed, the mixture with the changed pH was readjusted back to the specific target pH and then equilibrated for one hour. This process was repeated until no pH change was observed. The solid and liquid were then separated by centrifugation and diluted for HPLC analysis. The results are summarized in Table 1-1. Table 1-1. Solubility of compounds of formula (II) in different buffer solutions

[0151] As shown in Table 1-1, at an initial concentration of 100 mg / mL, the compound of formula (II) exhibits good solubility in buffer systems with a pH below 7, but precipitation is observed under alkaline conditions. Therefore, the compound of formula (II) may be unstable under alkaline conditions.

[0152] Following a similar procedure, the solubility of the compound of formula (II) in water for injection (WFI) under different pH conditions was then measured and evaluated. Solutions of the compound of formula (II) were prepared by dissolving the compound of formula (II) in a prepared WFI with the target pH, or by dissolving the compound of formula (II) in a WFI and then adjusting the pH. HCl and / or NaOH were used to achieve the target pH. The results are shown in Tables 1-2. As shown in Tables 1-2, the compound of formula (II) also showed good solubility in WFI (above 100 mg / mL) up to pH 7. Table 1-2. Solubility of compounds of formula (II) in WFI at different pH values

[0153] To further optimize the solutions for formulations of the compound of formula (II), the effect of different initial concentrations of the compound of formula (II) on its solubility in the buffer systems and WFI shown in Table 1-1 was investigated. As shown in Figures 1A-1D, at initial concentrations of 100 mg / mL or 200 mg / mL, clear solutions of the compound of formula (II) were obtained in the buffer systems up to pH 6-7. However, at initial concentrations of 1 mg / mL or 10 mg / mL, clear solutions of the compound of formula (II) could not be obtained in several pH buffers. In contrast, as shown in Figures 1E and 1F, at an initial concentration of 5 mg / mL, clear solutions were obtained in the WFI even after 24 hours up to pH 5-6. Therefore, the WFI provided better dissolution efficiency compared to the buffer systems.

[0154] The solubility of the compound of formula (II) was then evaluated in several common solubilization systems, and the results are shown in Tables 1-3. As shown in Table 3-1, the cosolvent and cyclodextrin SEBEBCD significantly impaired the solubility of the compound of formula (II), and the surfactant did not improve the solubility. Therefore, cosolvents, surfactants, and cyclodextrins are not necessary to achieve the desired solubility of the compound of formula (II). Pure WFI provided the best solubility results and was used for stability testing and further optimization. Table 1-3. Solubility of compounds of formula (II) in solubilization systems Example 2. Stability of the compound of formula (II)

[0155] The stability of the compound of formula (II) and its WFI solution was measured and evaluated under different pH conditions. The results are shown in Tables 2-1-1, 2-1-2, and Figure 2. As shown in Tables 2-1-1, 2-1-2, and Figure 2, the compound of formula (II) and its WFI solution remained stable up to pH 6. Significant degradation was detected under alkaline conditions at pH 6–9. Therefore, pH 3–5 is the more optimized pH range for formulations of the compound of formula (II). Table 2-1-1. Stability of compounds of formula (II) in WFI (time points: initial and 1 d) Table 2-1-2. Stability of compounds of formula (II) in WFI (time points: 4 d and 7 d)

[0156] Subsequently, the stability of the compound of formula (II) and its WFI solution was further investigated in the pH range of 3–5. The results are shown in Tables 2-2-1, 2-2-2, and Figure 3. As shown in Tables 2-2-1, 2-2-2, and Figure 3, pH 3–4 allows for greater stability of the compound of formula (II) and its WFI solution, and is therefore a more suitable pH range for further formulation development. Table 2-2-1. Stability between pH 3 and 5 (time points: initial and 1 day) Table 2-2-2. Stability between pH 3 and 5 (time points: 3 days and 7 days)

[0157] The stability of the compound of formula (II) and its WFI solution was further evaluated at different temperatures. The results are shown in Tables 2-3-1, 2-3-2, and 2-3-3. As the results indicate, the compound of formula (II) and its WFI solution are stable for at least 8 days at -20ºC or 5ºC and pH 3-9. At 25ºC and pH 3-5, the compound of formula (II) and its WFI solution remain stable for at least 8 days. This room temperature stability allows for lower transportation and storage costs for formulations of the compound of formula (II). Table 2-3-1. Stability of compound (II) in WFI solution (100 mg / mL) (initial and -20ºC, 8 days) Table 2-3-2. Stability of compounds of formula (II) in WFI solutions (100 mg / mL) (5ºC, 8 days and 25ºC, 8 days) Table 2-3-2. Stability of compound (II) in WFI solution (100 mg / mL) (40ºC, 8 days)

[0158] The stability of the compound of formula (II) was also evaluated in a variety of buffer systems with different pH values, and the results are shown in Tables 2-4. For solution stability, the pH buffer system did not show a significant advantage over pure WFI, and therefore, formulations of the compound of formula (II) are not necessary. Table 2-4. pH stability of compounds of formula (II) in buffer systems

[0159] The stability of the compound of formula (II) and its WFI solution was then evaluated at different concentrations of the compound of formula (II) without any pH adjustment. The results are shown in Tables 2-5 and Figure 4. As shown in Tables 2-5 and Figure 4, the pH stability of the compound of formula (II) is concentration-dependent, and unexpectedly, faster degradation was detected at lower concentrations compared to higher concentrations. Therefore, the compound of formula (II) and its WFI solution are more stable at higher concentrations of the compound of formula (II) compared to lower concentrations. Table 2-5. Stability of compounds of formula (II) at different concentrations

[0160] The stability of a WFI solution of compound (II) at a concentration of 200 mg / mL is shown in Tables 1-2 of Example 1. The WFI solution of compound (II) (200 mg / mL) remained stable up to pH 7, but precipitation was observed under alkaline conditions. Example 3. Excipient compatibility study

[0161] The compatibility of compounds of formula (II) with commonly used excipients was evaluated over a period of at least 14 days, and the results are shown in Tables 3-1, 3-2, and 3-3. For each sample, the pH was adjusted to the target value via 6N HCl solution. As the results show, monothioglycerol, sodium bisulfite, and tromethamine exhibited compatibility issues with compounds of formula (II) and should be avoided in formulations containing compounds of formula (II). Table 3-1. Excipient compatibility - initial solution Table 3-2. Excipient compatibility -25ºC, 7 days Table 3-3. Excipient compatibility -25ºC, 14 days Example 4. Formulation Screening

[0162] Based on the solubility and stability test results, four candidate formulations were designed and successfully prepared, and stability studies were conducted at 5ºC and 25ºC. The designed and prepared formulations are shown in Table 4-1. The results of the stability tests on the four candidate formulations are shown in Tables 4-2 and 4-3. Table 4-1. Preparations Table 4-2. Stability of formulations *Applies the Test 1.A standard. USP <788> (# / container, at least 10 µm) not exceeding 6000 pieces / container and (# / container, not less than 25 µm) not exceeding 600 pieces / container (qualified) Table 4-3. Stability of Formulations - Accelerated Stability

[0163] As shown in Table 4-3, all four candidate formulations exhibited low levels of degradation at 25ºC over 4 weeks; however, this hypersensitivity reaction can be reduced during clinical use or through appropriate packaging. The addition of additional excipients (such as benzyl alcohol) did not provide a significant advantage over the pure (II) compound WFI solution. Example 5. Preparation of lyophilized formulations of compounds of formula (II)

[0164] Formulations containing compounds of formula (II) and mannitol were prepared by lyophilization. Detailed information on the formulations is shown in Table 5-1, and detailed information on the lyophilization process is shown in Table 5-2. Amber vials were used for the lyophilization process, and a clear solution (pH 3.50, KF: approximately 1.5%) was obtained after reconstruction. Table 5-1. Detailed Information on Preparations Table 5-2. Detailed information on freeze-drying

[0165] The dilution properties and reconstitution potential of the obtained lyophilized powders were tested. The reconstitution results are shown in Table 5-3. As shown in Table 5-3, after dilution with D5W and WFI by 5, 50, and 100 times, no significant increase in impurity levels was detected at 25ºC for up to 2 hours. However, at 25ºC for up to 24 hours, D5W showed a slightly lower degradation level and therefore outperformed WFI. Table 5-3. Dissolution tests in WFI and D5W Equivalent scheme

[0166] The above-described disclosure may cover multiple different embodiments with independent utility. While each of these embodiments has been disclosed, the specific embodiments disclosed and shown herein should not be considered limiting, as many variations are possible. The subject matter of the embodiments includes all novel and non-obvious combinations and sub-combinations of the various elements, features, functions, and / or characteristics disclosed herein. The following claims specifically point to certain combinations and sub-combinations considered novel and non-obvious. Alternative embodiments, such as those in other combinations and sub-combinations of features, functions, elements, and / or characteristics, may be claimed in this application, in applications claiming priority to this application, or in related applications. Such claims, whether relating to different or the same embodiments, and whether broader, narrower, equivalent, or different in scope from the original claims, are also considered to be included within the subject matter of this disclosure.

[0167] Without departing from the scope of this disclosure, one or more features of any embodiment described herein or in the accompanying drawings may be combined with one or more features of any other embodiment described herein or in the accompanying drawings.

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

Claims

1. A formulation comprising... (1) Acetates of compounds of formula (I): (I)， Where n is an integer selected from 1 to 20, and (2) Mannitol.

2. The formulation according to claim 1, wherein the amount of mannitol accounts for about 2.5 wt% of the formulation.

3. The formulation according to claim 1 or 2, wherein the formulation is substantially free of surfactants.

4. The formulation according to any one of claims 1-3, wherein the formulation is aqueous in water for injection.

5. The formulation according to any one of claims 1-3, wherein the aqueous formulation is lyophilized.

6. An aqueous pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: (I)， Where n is an integer selected from 1 to 20, and The aqueous pharmaceutical composition has a pH not exceeding 5.

5.

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

5.

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

9. The aqueous pharmaceutical composition according to any one of claims 1-4 and 6-8, wherein the concentration of said 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: (I)， Where n is an integer selected from 1 to 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 according to any one of claims 1-4 and 6-10, wherein the concentration is about 50 mg / mL.

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

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

15. The aqueous pharmaceutical composition according to any one of claims 1-13, wherein the compound is (II), Or its pharmaceutically acceptable salt.

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

17. The aqueous pharmaceutical composition according to any one of claims 6-16, wherein the aqueous pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

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

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