Paclitaxel conjugated compounds, compositions, and methods of use thereof

Abstract

Provided herein are uses of paclitaxel conjugated compounds and pharmaceutical compositions thereof in the treatment or prevention of proliferative, dermatological or ophthalmic diseases or disorders, such as cancer.

Description

Cross-reference to related applications

[0001] This application claims priority to International Patent Application No. PCT / CN2023 / 077659, filed on February 22, 2023, which is hereby incorporated by reference in its entirety. Technical Field

[0002] This document provides peptide-paclitaxel conjugated compounds, compositions, and methods of treatment using said compounds and compositions. These compounds and compositions can be used for the treatment and prevention of proliferative, skin, or ophthalmic diseases or conditions, such as methods for treating cancer. 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] Additional therapies are needed for the treatment of proliferative, skin, or ophthalmic diseases and conditions. New therapies effective for intraperitoneal or intravenous administration are also needed for the treatment of proliferative, skin, or ophthalmic diseases and disorders. Summary of the Invention

[0012] This article provides a method for treating proliferative, skin, or ophthalmic diseases or conditions, the method comprising intravenously administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need: (I), where 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): (II), or a pharmaceutically acceptable salt.

[0013] In some embodiments, the effective amount is administered intravenously as a single dose or multiple doses. In some embodiments, the multiple doses are administered monthly, every two weeks, weekly, twice weekly, three times weekly, four times weekly, or daily. In some embodiments, the multiple doses are administered daily or at least once daily. In some embodiments, the multiple doses are administered weekly or at least once weekly. In some embodiments, the multiple doses are administered approximately once every three weeks or no more than once every three weeks. In some embodiments, the multiple doses are administered monthly or no more than once monthly.

[0014] In another aspect, a method for treating proliferative, skin, or ophthalmic diseases or conditions is provided, the method comprising administering to a subject in need multiple doses of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein each dose is independently greater than 0.1 mg / kg or between 0.1 mg / kg and 15 mg / kg. In some embodiments, the compound is administered systemically, such as intravenously, intraperitoneally, or subcutaneously. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered intraperitoneally or intravenously. In some embodiments, the multiple doses are administered monthly, every three weeks, every two weeks, weekly, twice weekly, three times weekly, four times weekly, or daily. In some embodiments, the multiple doses are administered daily or at least once daily. In some embodiments, the multiple doses are administered weekly or at least once weekly. In some embodiments, the multiple doses are administered about once every three weeks or no more than once every three weeks. In some embodiments, the multiple doses are administered monthly or no more than once monthly.

[0015] In some embodiments, the disease is cancer. In some embodiments, the cancer is brain cancer, liver cancer, lung cancer, ovarian cancer, stomach cancer, or colorectal cancer. In some embodiments, the cancer is head and neck cancer, oral cancer, or maxillofacial cancer. In some embodiments, the cancer is brain cancer. Attached Figure Description

[0016] Figure 1A is a graph showing the concentrations of the compound of formula (II) in various tissues when administered intraperitoneally or intravenously.

[0017] Figure 1B shows the concentrations of peptides in various tissues when administered intraperitoneally or intravenously.

[0018] Figure 1C shows the concentrations of paclitaxel in various tissues when administered intraperitoneally or intravenously.

[0019] Figure 2 is a graph showing the stability of the compound of formula (II) in a buffer solution over time.

[0020] Figure 3 is a graph showing the stability of the compound of formula (II) in the plasma of different species over time.

[0021] Figure 4 is a graph showing the fluorescent area of ​​tumors in mice administered the compound of formula (II) on day 17, compared with the medium, as described in Example 4. Detailed Implementation

[0022] This document describes peptide-paclitaxel conjugates that can be used to treat proliferative, skin, or ophthalmic diseases or conditions. This application is based on the surprising discovery that peptide-paclitaxel conjugates of formula (I), and particularly those of formula (II), exhibit favorable pharmacokinetic characteristics when administered systemically (e.g., intravenously or intraperitoneally). Unlike paclitaxel, these compounds do not exhibit a burst-release effect immediately after administration, but rather remain at desired levels in the blood for a sustained period. These favorable pharmacokinetic characteristics allow for more frequent administration of the compounds without significant toxicity issues. Alternatively, because the compounds remain at desired levels in the blood for a sustained period, the intervals between administrations can be longer than those typically used for other paclitaxel-based compounds. Therefore, this application provides specific dosing regimens suitable for the paclitaxel-peptide conjugates described herein. definition

[0023] 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.

[0024] As used herein, the singular forms “a”, “an”, and “the” include plural indicators unless the context clearly indicates otherwise.

[0025] 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.

[0026] 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.

[0027] 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).

[0028] 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.

[0029] "Pharmaceutically acceptable salt" means any such salt of the compounds provided herein that retains the biological properties of the compound and is non-toxic or otherwise not undesirable for pharmaceutical use. Such salts can be derived from a variety of organic and inorganic counter-charged ions well known in the art. For example, in some variations, a pharmaceutically acceptable salt as used herein refers to an acetate. In other variations, a pharmaceutically acceptable salt as used herein refers to a trifluoroacetate.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] "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.

[0036] "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.

[0037] "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.

[0038] "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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] "Neoadjuvant setting" refers to a clinical setting in which the methods described are performed prior to the initial / final treatment.

[0048] 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).

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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 pharmaceutical composition (e.g., the compounds or compositions provided herein) 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 therapies 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.

[0053] "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.

[0054] "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).

[0055] 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". Treatment

[0056] In one aspect, this document provides a method for treating the diseases or disorders described herein (e.g., proliferative, skin, or ophthalmic diseases or disorders), the method comprising administering multiple doses of a compound described herein (e.g., a compound of formula (I), (II), or (X)) or a pharmaceutically acceptable salt thereof to a subject of need at an appropriate frequency. 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 cancer.

[0057] In some embodiments, this document provides a method for treating cancer, the method comprising administering multiple doses of the compounds described herein (e.g., compounds of formula (I), (II), or (X)) or pharmaceutically acceptable salts thereof to a subject in need at appropriate frequencies.

[0058] In some embodiments, a method of treating the disease or disorder described herein (e.g., cancer) is provided, the method comprising administering, at an appropriate frequency, a single or multiple dose of a compound described herein (e.g., a compound of formula (I), (II), or (X)) or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, the interval between each administration is at least about one week (e.g., at least about two weeks, three weeks, four weeks, five weeks, or six weeks). In some embodiments, the compound is administered at a frequency not exceeding about once a week (e.g., once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks). In some embodiments, the dose at each administration is between about 0.1 mg / kg and about 1 mg / kg, such as about 0.1, 0.2, 0.25, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg / kg. In some embodiments, the compounds or compositions provided herein are administered at a dose between about 1 mg / kg and about 15 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 15 mg / kg. In some embodiments, the compounds are administered on a weekly basis, wherein the compound is administered at a dose between about 1 mg / kg and about 15 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 15 mg / kg.

[0059] In some embodiments, a method of treating the disease or disorder described herein (e.g., cancer) is provided, the method comprising administering to a subject in need a single or multiple dose of a compound described herein (e.g., a compound of formula (I), (II), or (X)) or a pharmaceutically acceptable salt thereof, wherein the compound is administered at a frequency of more than once a week (including, for example, twice a week, three times a week, four times a week, five times a week, six times a week, or daily). In some embodiments, the compound is administered periodically without any interruption. In some embodiments, the dose at each administration is between about 0.1 mg / kg and about 1 mg / kg, such as about 0.1, 0.2, 0.25, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg / kg. In some embodiments, the compound or composition provided herein is administered at a dose between about 1 mg / kg and about 15 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 15 mg / kg. In some embodiments, the compound is administered on a weekly basis, wherein the dose of the compound at each administration is between about 1 mg / kg and about 15 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 or 15 mg / kg.

[0060] In some embodiments, a method of treating the disease or disorder described herein (e.g., cancer) is provided, the method comprising intravenously administering an effective amount of a compound described herein (e.g., a compound of formula (I), (II), or (X)) or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, the effective amount is administered intravenously in a single or multiple doses. In some embodiments, the dose at each administration is between about 0.1 mg / kg and about 1 mg / kg, such as about 0.1, 0.2, 0.25, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg / kg. In some embodiments, the compound or composition provided herein is administered at a dose between about 1 mg / kg and about 15 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 15 mg / kg.

[0061] In some embodiments, a method of treating the disease or disorder described herein (e.g., cancer) is provided, the method comprising intravenously administering multiple doses of a compound described herein (e.g., a compound of formula (I), (II), or (X)) or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, the interval between each administration is at least about one week (e.g., at least about two weeks, three weeks, four weeks, five weeks, or six weeks). In some embodiments, the compound is administered at a frequency not exceeding about once a week (e.g., once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks). In some embodiments, the dose at each administration is between about 0.1 mg / kg and about 1 mg / kg, such as about 0.1, 0.2, 0.25, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg / kg. In some embodiments, the compounds or compositions provided herein are administered at a dose between about 1 mg / kg and about 15 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 15 mg / kg. In some embodiments, the compounds are administered on a weekly basis, wherein the compound is administered at a dose between about 1 mg / kg and about 15 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 15 mg / kg.

[0062] In some embodiments, a method of treating the disease or disorder described herein (e.g., cancer) is provided, the method comprising intravenously administering multiple doses of a compound described herein (e.g., a compound of formula (I), (II), or (X)) or a pharmaceutically acceptable salt thereof to a subject in need, wherein the compound is administered at a frequency of more than once a week (including, for example, twice a week, three times a week, four times a week, five times a week, six times a week, or daily). In some embodiments, the compound is administered regularly without any interruption. In some embodiments, the dose at each administration is between about 0.1 mg / kg and about 1 mg / kg, such as about 0.1, 0.2, 0.25, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg / kg. In some embodiments, the compound or composition provided herein is administered at a dose between about 1 mg / kg and about 15 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 15 mg / kg. In some embodiments, the compound is administered on a weekly basis, wherein the dose of the compound at each administration is between about 1 mg / kg and about 15 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 or 15 mg / kg.

[0063] Methods of treating cancer can be monotherapy or in the context of combination therapy. In some embodiments, this document provides a method of treating cancer comprising administering multiple doses of the compounds described herein (e.g., compounds of formula (I), (II), or (X)) or pharmaceutically acceptable salts thereof to a subject in need, wherein the subject is not receiving other therapies for cancer. In some embodiments, the method provided herein comprises administering to a subject in need a combination of: a) a first therapy comprising the compounds described herein (e.g., compounds of formula (I), (II), or (X)) and b) a second therapy available for treating cancer. In some embodiments, the second therapy includes surgery, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormone therapy, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, and / or chemotherapy (e.g., one or more compounds available for treating cancer). It should be understood that the following references and descriptions of methods of treating cancer are exemplary, and such descriptions are equally applicable to and include methods of treating cancer using combination therapies.

[0064] 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.

[0065] In some variants, 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. (e.g., gastrointestinal stromal tumors), colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small bowel cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal carcinoma, oropharyngeal carcinoma, hypopharyngeal carcinoma), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer ( Examples include 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, and 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).

[0066] In some embodiments, the cancer is brain cancer, liver cancer, lung cancer, ovarian cancer, stomach cancer, or colorectal cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is colorectal cancer.

[0067] In some implementations, the cancer is head and neck cancer, oral cancer, or maxillofacial cancer.

[0068] In some embodiments, this document provides a method of treating cancer, the method comprising administering multiple doses of the compounds described herein (e.g., compounds of formula (I), (II), or (X)) or pharmaceutically acceptable salts thereof to a subject of need at appropriate frequencies, wherein the cancer is a 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, optic pathway and hypothalamic glioma, or glioblastoma. In some embodiments, the brain cancer is a 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, glioblastoma may be infratentorial. In some embodiments, glioblastoma is supratentorial. In some embodiments, 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).

[0069] 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.

[0070] Any of the 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.

[0071] In some embodiments, this document provides a method for treating a disease or disorder, the method comprising administering multiple doses of a compound described herein (e.g., a compound of formula (I), (II), or (X)) or a pharmaceutically acceptable salt thereof to a subject in need at an appropriate frequency, wherein the disease is skin-related. In some embodiments, 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.

[0072] In some embodiments, this document provides a method for treating a disease or disorder, the method comprising administering multiple doses of a compound described herein (e.g., a compound of formula (I), formula (II), or formula (X)) or a pharmaceutically acceptable salt thereof to a subject in need at an appropriate frequency, wherein the disease is ophthalmic. In some implementations, the diseases are 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 insufficiency, 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. Dosage

[0073] In one aspect, this document provides a method of treating the disease or disorder described herein (e.g., cancer), the method comprising administering multiple doses of a compound described herein (e.g., a compound of formula (I), (II), or (X)) or a pharmaceutically acceptable salt thereof to a subject in need at an appropriate frequency. In some embodiments, the total dose, single dose, and frequency of administration may vary depending on the specific composition, method of administration, and specific stage of the cancer being treated. The dosage and frequency of administration should be sufficient to produce a desired response, such as a therapeutic or preventative response to cancer. In some embodiments, the dosage and frequency of administration of the compound described herein are therapeutically effective amounts. In some embodiments, the dosage and frequency of administration of the compound described herein are determined such that a therapeutically effective amount of the drug (e.g., paclitaxel) can be released from the compound described herein. In some embodiments, this amount of the compound described herein is a preventatively effective amount. In some embodiments, the dosage and frequency of administration of the compound described herein are determined such that a preventatively effective amount of the drug (e.g., paclitaxel) can be released from the compound described herein. In some embodiments, the dosage and frequency of administration of the compounds described herein or their pharmaceutically acceptable salts are below levels that induce toxicological effects (i.e., effects exceeding clinically acceptable toxicity levels) or are at levels where potential side effects can be controlled or tolerated. In some embodiments, the dosage and frequency of administration of the compounds described herein or their pharmaceutically acceptable salts are determined such that the release of the drug (e.g., paclitaxel) from the compounds described herein is below levels that induce toxicological effects (i.e., effects exceeding clinically acceptable toxicity levels) or is at levels where potential side effects can be controlled or tolerated.

[0074] Different therapeutically effective amounts may be applicable to different diseases and conditions, as will be readily apparent to those skilled in the art. In some embodiments, the dosage and frequency of administration of the compound described herein or a pharmaceutically acceptable salt thereof are sufficient to reduce tumor size, cancer cell number, or tumor growth rate by at least one of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In some embodiments, the dosage and frequency of administration of the compound described herein or a pharmaceutically acceptable salt thereof are sufficient to delay or prevent the onset of cancer.

[0075] In some embodiments, exemplary doses of the composition (e.g., unit dosage forms) include milligrams or micrograms of the compound described herein per kilogram of subject (e.g., human) 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, the dose of the compound provided herein administered for the prevention, treatment, administration, or improvement of a subject's disorder or one or more of its symptoms is about 0.1 mg / kg, based on the weight of the compound. In some embodiments, the dose is between 0.1 mg / kg and 15 mg / kg. In some embodiments, the dose is about 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 composition or the 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 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 20 ... 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.

[0076] In some embodiments, a dose of the compound or composition provided herein may be administered to achieve a steady-state concentration of the compound in the blood or serum of a subject. The steady-state concentration may be determined by measurement using techniques available to a technician, or it may be based on the subject's physical characteristics, such as height, weight, and age.

[0077] In some embodiments, exemplary dosing frequencies include, but are not limited to, daily, uninterrupted weekly; weekly, three out of four weeks; two out of three weeks; every two weeks; once every three weeks; and monthly. In some embodiments, multiple doses are administered weekly, every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks. In some embodiments, multiple doses are administered once, twice, three times, four times, five times, six times, or seven times weekly (i.e., daily). In some embodiments, multiple doses are administered daily or at least once daily. In some embodiments, multiple doses are administered weekly or at least once weekly. In some embodiments, multiple doses are administered approximately once every three weeks or no more than once every three weeks. In some embodiments, multiple doses are administered monthly or no more than once monthly.

[0078] In some embodiments, the interval between each dose is about or less than about 6 months, 3 months, 1 month, 20 days, 15 days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, the interval between each dose is about or greater than about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months. In some embodiments, there is no interruption in the dosing regimen. In some embodiments, the interval between each administration does not exceed about one week.

[0079] In some embodiments, multiple doses of the compounds or compositions provided herein are administered in the dosage and frequency regimens described herein. In some embodiments, the interval between each administration is about or no more than one week, wherein the dose at each administration is between about 0.1 mg / kg and about 1 mg / kg, such as about 0.1, 0.2, 0.25, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg / kg. In some embodiments, multiple doses are administered daily, wherein the dose at each administration is between about 0.1 mg / kg and about 1 mg / kg, such as about 0.1, 0.2, 0.25, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg / kg.

[0080] In some embodiments, the interval between each administration is about or not less than three weeks, wherein the dosage of the compound or composition provided herein at each administration is between about 1 mg / kg and about 15 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 15 mg / kg. In some embodiments, multiple doses are administered monthly, wherein the dosage at each administration is between about 1 mg / kg and about 15 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 15 mg / kg.

[0081] In some embodiments, the application of the compounds described herein (e.g., compounds of formula (II)) may be extended for an extended period, such as from about one month to about seven years. In some embodiments, the composition is applied for a period of time of at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 48, 60, 72 or 84 months. application

[0082] For the treatment methods provided herein, the compound is administered to a mammal (in some embodiments, a human) at a pharmaceutically acceptable dose suitable for its form of administration, such as those known in the art and those discussed herein, intravenously (e.g., bolus injection or by continuous infusion over a period of time), via intramuscular, intraperitoneal, intraspinal, subcutaneous, intra-articular, intrasynovial, intrathecal, inhalation, or intratumoral routes. The compound is also suitably administered via peritumoral, intralesional, or perilesional routes to exert both local and systemic therapeutic effects. In some embodiments, the compound is administered to a mammal (in some embodiments, a human) at a pharmaceutically acceptable dose suitable for its oral form of administration, such as those known in the art and those discussed herein, for example, sublingually. For example, the compounds of this disclosure may be administered orally 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. Pharmaceutical Composition Compounds of formulas (I)-(II)

[0083] In one aspect, the treatment methods provided herein include administration of the paclitaxel conjugates described herein. This document provides a method for treating proliferative, skin, or ophthalmic diseases or conditions, the method comprising administering multiple doses of the compounds and compositions described herein to a subject in need.

[0084] The embodiments described herein include the listed compounds and their pharmaceutically acceptable salts, hydrates, solvates, tautomers, and / or mixtures. In some embodiments, the compounds provided herein are in the form of acetates.

[0085] In some embodiments, this document provides a method for treating cancer, the method comprising administering to a subject in need multiple doses of 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.

[0086] In some embodiments, this document provides a method for treating cancer, the method comprising administering to a subject in need multiple doses of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, and / or mixture thereof: (II).

[0087] 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.

[0088] 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.

[0089] 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.

[0090] In some embodiments, this document provides a method for treating cancer, the method comprising administering to a subject in need multiple doses of 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.

[0091] 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.

[0092] 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.

[0093] In some embodiments, this document provides a method for treating cancer, the method comprising administering multiple doses of a pharmaceutical composition to a subject in need, the 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 method for treating cancer, the method comprising administering multiple doses of a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising 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 epimer. In some embodiments, in the methods and compounds of this disclosure, the compound is substantially free of other stereoisomers. In some embodiments, in the methods and compounds of this disclosure, the compound is substantially free of an opposite D-cysteine ​​amino acid epimer. In some embodiments, the composition comprises a compound, said compound being at least about 50%, 60%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% to 100% by weight of said compound, the remainder comprising other chemical species or stereoisomers. In some embodiments, this document provides a method of treating cancer comprising administering multiple doses of a pharmaceutical composition to a subject in need, wherein the composition comprises a compound of formula (I) or (II), said compound being at least about 50%, 60%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% to 100% by weight of the opposite D-cysteine ​​amino acid epimer of the compound of formula (I) or (II). In some embodiments, this document provides a method of treating cancer comprising administering multiple doses of a pharmaceutical composition to a subject in need, said pharmaceutical composition comprising a compound of any one of formulas (I)-(II), said compound being substantially free of a specified stereoisomer of said compound. In some embodiments, the compounds in the methods and compounds of this disclosure are substantially free of other stereoisomers. In some embodiments, the composition comprises a compound in which at least about 50%, 60%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% to 100% of the compound by weight, the remainder comprising other chemical species or stereoisomers. Isotope-enriched compounds

[0094] In one aspect, this article provides a method for treating cancer, the method comprising administering multiple doses of a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising an isotopically enriched compound, including but not limited to an isotopically enriched compound of any one of formulas (I)-(II).

[0095] 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).

[0096] 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.

[0097] 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 ( 2H 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.

[0098] 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.

[0099] In one aspect, this document provides a method for treating cancer, the method comprising administering multiple doses of the compounds described herein to a subject in need, wherein the compounds provided herein are formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any compounds provided herein may be provided in a suitable pharmaceutical composition and administered via a suitable route of administration. In one embodiment, a pharmaceutical composition comprising a compound of formula (X) and one or more pharmaceutically acceptable carriers, excipients, or diluents is provided, wherein the composition 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).

[0100] In one embodiment, a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers, excipients, or diluents is provided, 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% of the opposite D-cysteine ​​amino acid epimers by weight. In one embodiment, the pharmaceutical composition comprising the compound of formula (I) is free from about 85% to 95% of the opposite D-cysteine ​​amino acid epimers by weight. In one embodiment, the pharmaceutical composition comprising the compound of formula (I) is free from about 90% to 95% of the opposite D-cysteine ​​amino acid epimers by weight. In one embodiment, the pharmaceutical composition comprising the compound of formula (I) is free from about 85% of the opposite D-cysteine ​​amino acid epimers by weight. 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.

[0101] In one embodiment, a pharmaceutical composition comprising a compound of formula (II) and one or more pharmaceutically acceptable carriers, excipients, or diluents is provided, 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% of the opposite D-cysteine ​​amino acid epimers by weight. In one embodiment, the pharmaceutical composition comprising the compound of formula (II) is free from about 85% to 95% of the opposite D-cysteine ​​amino acid epimers by weight. In one embodiment, the pharmaceutical composition comprising the compound of formula (II) is free from about 90% to 95% of the opposite D-cysteine ​​amino acid epimers by weight. In one embodiment, the pharmaceutical composition comprising the compound of formula (II) is free from about 85% of the opposite D-cysteine ​​amino acid epimers by weight. 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 free of the opposite D-cysteine ​​amino acid epimer.

[0102] The methods provided herein cover the administration of pharmaceutical compositions comprising at least one compound provided herein and one or more compatible and pharmaceutically acceptable carriers. In this context, the term "pharmaceuticalally acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals and, in some embodiments, for use in humans. The term "carrier" includes diluents, adjuvants (e.g., Freund's adjuvants (complete and incomplete)), excipients, or mediators administered with the therapeutic agent. Such pharmaceutical 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 pharmaceutical carriers are described in Martin, EW, Remington's Pharmaceutical Sciences.

[0103] In clinical practice, the pharmaceutical compositions or compounds provided herein may be administered via any route known in the art. Exemplary routes of administration include, but are not limited to, oral, inhalation, sublingual, sublingual, intra-arterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes. In some embodiments, the pharmaceutical compositions or compounds provided herein are administered parenterally. In some embodiments, the pharmaceutical compositions or compounds provided herein are administered orally.

[0104] Compositions for parenteral administration can be emulsions or sterile solutions. Parenteral compositions may include, for example, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters (e.g., ethyl oleate). These 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. Parenteral compositions can 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.

[0105] In some embodiments, the compositions provided herein are pharmaceutical compositions or single-unit dosage forms. The pharmaceutical compositions and single-unit dosage forms provided herein comprise one or more preventative or therapeutically effective amounts of a compound.

[0106] Pharmaceutical compositions may contain one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may 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 a 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. Additional 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).

[0107] 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.

[0108] In some embodiments, the pharmaceutical composition includes a cosolvent. Illustrative examples of cosolvents include, for example, ethanol, polyethylene glycol, butanediol, dimethylacetamide, glycerol, and propylene glycol.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] Other excipients that can 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).

[0114] In some embodiments, the pharmaceutical composition comprises a solvent. In some aspects, the solvent is an aqueous saline solution (such as a sterile isotonic saline solution) or a dextran solution. In some aspects, the solvent is water for injection.

[0115] This article further provides anhydrous pharmaceutical compositions and dosage forms containing compounds, since in some embodiments, water can promote the degradation of some compounds.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] Pharmaceutical compositions and dosage forms comprising one or more excipients that reduce the decomposition rate of the compound are also provided. Such excipients, referred to herein as “stabilizers,” include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers. Parenteral dosage form

[0120] In some implementations, a parenteral dosage form is provided. The parenteral dosage form can be administered to the subject via a variety of routes, including but not limited to subcutaneous, intravenous (including bolus), inhalation, intramuscular, and intra-arterial administration. Because its administration typically bypasses the subject's natural defenses against contaminants, the parenteral dosage form is usually 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, and nebulized droplets ready for inhalation.

[0121] Suitable media for providing 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, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's solution; 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.

[0122] Dosage forms used for drug delivery via inhalation include propellants, non-aqueous inhalers, dry powder inhalers, and jet or ultrasonic nebulizers.

[0123] Excipients that increase the solubility of one or more of the compounds disclosed herein may also be incorporated into parenteral dosage forms. oral dosage form

[0124] In some embodiments, an oral dosage form is provided. The oral dosage form can be administered to a subject via a variety of routes, including but not limited to sublingual, sublipal, and sublingual administration. Typical dosage forms for oral administration include pills, tablets, capsules, gel caps, solutions, suspensions, or emulsions. Dosage forms may also be characterized by compartmentalization. For example, when the dosage form is a pill, tablet, or capsule, it can have different layers of material with different excipients or different concentrations of excipients. For example, enteric-coated oral tablets can be used to enhance the bioavailability of compounds intended for oral administration. The enteric coating will be a layer of excipients that allows the tablet to withstand gastric acid. In one embodiment, the oral dosage form is an orally disintegrating tablet. In one embodiment, the oral dosage form is a chewable tablet. Reagent test kit

[0125] In some embodiments, the compounds provided herein are provided as a kit (i.e., a pre-packaged combination of reagents with instructions for performing the procedure). In some embodiments, the procedure is a diagnostic assay. In some embodiments, the procedure is a therapeutic procedure.

[0126] In some embodiments, the kit further includes a solvent for compound reconstitution. In some embodiments, the compound is provided in the form of a pharmaceutical composition.

[0127] In some embodiments, the kit may contain the compounds or compositions provided herein, optional second agents or compositions, and instructions for use to provide healthcare professionals with information on 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 compounds or compositions provided herein, or the second agents or compositions, may include a dose such that, when administered to a subject, it maintains a therapeutic or preventatively effective plasma level of the compound or composition in the subject for at least one day. In some embodiments, the compounds or compositions may be contained as sterile aqueous pharmaceutical compositions or dry powder (e.g., lyophilized) compositions.

[0128] 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

[0129] Unless otherwise specified, reagents and solvents should be used exactly as received from the commercial supplier. Example 1. Distribution of the drug in tissues

[0130] The distribution of the compound of formula (II) in different organs and tissues after administration was studied in mice. One week after inoculation, mice were randomly divided into two groups of three female mice each, based on body weight and tumor size (fluorescence intensity). The day of administration was defined as day 0. Grouping and administration regimens are shown in Table 1-1 below. Results are summarized in Table 1-2 and Figures 1A-1C. Table 1-1. Animal grouping and dosing regimens Table 1-2. Distribution of compounds, peptides and paclitaxel of formula (II) in different tissues. *BLQ: Below the limit of quantitation.

[0131] As shown in Tables 1-2 and Figures 1A-1C, following a third intraperitoneal or intravenous administration of the compound of formula (II), the compound of formula (II), its metabolite peptide, and paclitaxel were distributed to the collected tissues at 2 h. For the distribution of the compound of formula (II), the highest tissue exposure was observed in the liver, and exposure in the liver was significantly higher with intravenous administration at lower doses than with intraperitoneal administration. The distribution characteristics of the metabolite peptide and paclitaxel were similar. These results suggest that hepatic metabolism may be the primary pathway for drug elimination, allowing for a readily and sustained release of the payload. This mechanism not only demonstrates faster drug distribution and higher tissue exposure via intravenous administration compared to intraperitoneal administration, but also allows for a more sustained and slower release of paclitaxel following administration of the compound of formula (II).

[0132] Furthermore, a brain-to-plasma ratio (B / P ratio) of approximately 8 was observed. This is significant because it is a measure of whether an administered drug can cross the blood-brain barrier. This B / P ratio clearly demonstrates the ability of compounds of formula (II) to be delivered across the BBB. This gives compounds of formula (II) a particular advantage in the treatment of brain-related cancers. Example 2. In vivo pharmacokinetics (PK) of the compound of formula (II) In mice, intraperitoneal administration of compound (II) and paclitaxel

[0133] A three-group, single-dose pharmacokinetic (PK) study was conducted in CD-1 mice. Twelve animals in each group were administered intraperitoneal (IP) doses of either paclitaxel or a compound of formula (II) at different doses. Serial or terminal plasma samples were collected from the study animals at predetermined times after administration (n = 3 at each time point). Each mouse underwent two consecutive exsanguinations (orbital exsanguination) and one terminal exsanguination. For all procedures, samples were collected in pre-chilled tubes. Samples were analyzed using LC-MS / MS after the in vivo phase was completed. Detailed grouping and administration protocols are shown in Table 2-1. Detailed PK parameters are shown in Tables 2-2-1 and 2-2-2. Table 2-1. Animal groups and drug administration in PK studies Dissolve paclitaxel in partially dehydrated ethanol. When fully dissolved, add one part cremophor EL and mix well to prepare a 6 mg / mL paclitaxel solution in cremophor EL / ethanol (same concentration as clinical injection). Then dilute the solution with 1X PBS to prepare a 1 mg / mL paclitaxel solution, vortexing for 20–30 seconds to ensure the solution is clear (precipitation may occur after several hours, so it should be freshly prepared before administration). Filter the solution using a 0.22 μm filter. Dissolve N1-109 in 1X PBS and mix well. Filter the solution through a 0.22 μM filter and then aliquot it into three 2 mL vials. ***The N1-109 doses of 9.6 and 38.4 mg / kg represent doses of the active ingredient of 5.9 and 23.8 mg / kg, respectively. Table 2-2-1 PK Results of In Vivo Studies Table 2-2-2 PK Results of In Vivo Studies

[0134] As indicated in Tables 2-2-1 and 2-2-2, following intraperitoneal administration of a single dose of compound (II) ranging from 5.9 to 23.8 mg / kg, systemic exposure to compound (II) increased more than dose-proportionately with increasing dose level, while systemic exposure to paclitaxel (a metabolite of compound (II)) increased less than dose-proportionately with increasing dose level. At both doses, T... 1 / 2 It takes 19.1-21.7 hours.

[0135] Following a single intraperitoneal administration of 10 mg / kg of pure paclitaxel, the C60 of paclitaxel... max The concentration was 713 nmol / L, which is significantly higher than that of the compound of formula (II) administered at a dose of 23.8 mg / kg (equivalent to 10 mg / kg of paclitaxel). Surprisingly, the AUC of paclitaxel was 1883 h* nmol / L, which is also significantly lower than that of the compound of formula (II) administered at a dose of 23.8 mg / kg.

[0136] These results collectively suggest that, at equivalent dose levels of paclitaxel, compounds of formula (II) can offer greater safety and longer efficacy compared to paclitaxel. This may allow for lower doses and reduced toxicity. In rats, the compound of formula (II) was administered intraperitoneally and intravenously.

[0137] Two-group, single-dose studies were conducted in male SD rats. Rats weighing approximately 300 g in each group were administered the compound of formula (II) in saline. The dosing regimens are summarized in Table 2-3. Plasma samples were collected at the time points also described in Table 2-3. Table 2-3. Animal groups, dosing regimens, and sampling time points * Dissolve the compound of formula (II) in 1× PBS and mix well. Filter the solution through a 0.22 μM filter, and then aliquot the solution sample into 3 vials, 2 mL / vial. The 9.6 mg / kg dose of compound (II) represents a dose of 5.9 mg / kg of active ingredient.

[0138] After collecting the samples, they were gently mixed by inversion and immediately placed in an ice bath until centrifuged (refrigerated). The plasma was then collected and frozen at -80ºC. Following in vivo studies, the samples were further processed and analyzed using LC-MS / MS, and concentrations were calculated. The results are summarized in Tables 2-4. Table 2-4. Characteristics of PK in male SD rats administered intraperitoneally and intravenously.

[0139] As shown in Table 2-4, following a single intravenous or intraperitoneal administration of a compound of formula (II) at a dose of 5.9 mg / kg, the C-value of the compound of formula (II) administered intravenously... max The AUC is much higher than that of intraperitoneal administration, as is that of its metabolite paclitaxel. The T value of compounds of formula (II) administered intravenously is significantly higher. 1 / 2 Its duration of action is much longer than that of intraperitoneal administration, as is that of its metabolite paclitaxel. The Vss of paclitaxel administered intravenously is 432 L / kg, indicating its wide biodistribution. In dogs, compounds of formula (II) are administered intraperitoneally and intravenously.

[0140] Two-group, single-dose studies were conducted in beagle dogs. Two groups of dogs, each weighing approximately 10 kg, were administered the compound of formula (II) in 0.9% saline. The dosing regimens are summarized in Table 2-5. Plasma samples were collected at the time points also described in Table 2-5. Table 2-5. Animal groups, dosing regimens, and sampling time points * Dissolve the compound of formula (II) in 0.9% saline solution and mix well. Filter the solution using a 0.22 μM filter. All administered samples were clear solutions. Samples for IV administration had a pH of 5.75; samples for IP administration had a pH of 5.96.

[0141] After collecting the samples, they were gently mixed by inversion and immediately placed in an ice bath until centrifuged (refrigerated). The plasma was then collected and frozen at -80ºC. Following in vivo studies, the samples were processed and analyzed using LC-MS / MS to determine plasma concentrations. The results are shown in Tables 2-6. Table 2-6. Characteristics of PK in Beagle dogs administered intraperitoneally and intravenously.

[0142] As shown in Table 2-6, following a single dose of compound (II) administered intravenously or intraperitoneally, the elimination of compound (II) is rapid, T 1 / 2 The time to elimination was 0.46 or 0.79 hours. In contrast, the time to elimination of the released peptide and paclitaxel (a metabolite of the compound of formula (II)) was [not specified]. 1 / 2 The duration of action ranged from 14.1 to 29.8 hours, which is significantly longer than the reported duration of action for directly administered paclitaxel. 1 / 2 The bioavailability of intraperitoneal administration was 30.5%.

[0143] After dose-normalization for intravenous and intraperitoneal administration, similar to rat PK data, systemic exposure of the compound of formula (II) was significantly higher via intravenous administration than via intraperitoneal administration. Compared to intravenous administration, intraperitoneal administration resulted in higher systemic exposure and lower C60 levels for the dose-normalized peptide. max (Approximately 32%) and a higher AUC (approximately 136%). This is likely due to slower peptide elimination after intraperitoneal administration. In contrast, intraperitoneal administration of paclitaxel, after dose normalization, resulted in lower systemic exposure and lower C-value compared to intravenous administration. max (approximately 70%) and lower AUC (approximately 78%).

[0144] Comparisons of PK parameters among different species are summarized in Tables 2-7 and 2-8. As shown in Tables 2-7 and 2-8, for intraperitoneal administration, the PK characteristics observed in mice were significantly different from those in rats and dogs. Systemic exposure and release of paclitaxel were higher in mice than in rats or dogs. For intravenous administration, higher systemic exposure of compounds of formula (II) and paclitaxel was observed in rats compared to mice or dogs, while similar levels of paclitaxel release were observed in mice, rats, and dogs. Table 2-7. PK parameters in different species (intraperitoneal administration) Table 2-8. PK parameters in different species (intravenous administration) Example 3. Stability of the compound of formula (II)

[0145] To further optimize the dosing parameters of the compound of formula (II), the stability of the compound of formula (II) in buffer solutions and plasma of different species was tested.

[0146] Prepare a working solution (1 mM) of the compound of formula (II). Prepare a buffer solution (199 µL) and aliquot it into seven incubation tubes. Preheat the tubes at 37ºC for 15 min. Add 1 mM of the working solution of the compound of formula (II) to each of the seven incubation tubes (1 µL), resulting in a final concentration of 5 µM. Incubate each sample at 37ºC for 0, 4, 8, 24, 48, 72, or 120 h. Perform assays in duplicate. After incubation for 0, 4, 8, 24, 48, 72, or 120 h, quench the reaction by adding 1000 µL of methanol (pre-cooled at 4ºC) containing 2% FA and an internal standard. Vortex all samples for 10 min. Transfer 150 μL of supernatant from each sample to a new plate. Add 150 μL of pure water to each sample for analysis by LC-MS / MS (cooler temperature: 15ºC). Use Microsoft Excel for all calculations. Determine the peak area ratio from the extracted ion chromatogram. Calculate the percentage of remaining compound at each time point using the following formula: Remaining percentage t min (%) = (peak area ratio) t min / peak area ratio 0 min ) × 100 in Peak area ratio t min It is the peak area ratio of the test compound at t min; and Peak area ratio 0 min It is the peak area ratio of the test compound at time zero.

[0147] The slope value k was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug with the incubation time curve.

[0148] Determining the in vitro half-life (in vitro t) from the slope value 1 / 2 ): In vitro t 1 / 2 = (0.693 / k)

[0149] Paclitaxel concentration (nM) = Peak area ratio tmin / peak area ratio (paclitaxel: 5 µM) × 5000

[0150] %Paclitaxel % = Peak area ratio t min / peak area ratio (paclitaxel: 5 µM) × 100

[0151] The data processing rules are shown in Table 3-1. Table 3-1. Data processing rules

[0152] The results of the stability of the compound of formula (II) in buffer solution are shown in Table 3-2 and Figure 2. Table 3-2 *The working solution is DMSO

[0153] For plasma stability, a working solution of the compound of formula (II) was prepared in PBS (pH 7.4). Propamidol was used as a positive control in human, monkey, dog, and mouse plasma for the assay. Mevinolin was used as a positive control in rat plasma for the assay. A 1 mM propamidol working solution was prepared in acetonitrile. A 1 mM mevinolin working solution was prepared in DMSO. For each well, 475 µL of plasma incubation buffer was added to the incubation plate and preheated at 37ºC for 15 min. After pre-incubation, 25 µL of the working solution (test compound or control compound) was added to the plasma. For the compound of formula (II), the final concentration of the organic solvent was 0%. For paclitaxel, the final concentration of the organic solvent was 0.25%. The assay was performed in duplicate. The reaction samples were incubated at 37ºC. At 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, 50 µL aliquots were taken from the reaction sample. The reaction was stopped by adding 450 µL of ice-cold quenching solution (methanol with 2% FA and containing the internal standard). All samples were vortexed for 10 min, followed by centrifugation at 3,220 g for 30 min to precipitate proteins. 100 μL of supernatant from each well was transferred to a new plate. The supernatant was diluted with ultrapure water. The samples were analyzed by LC-MS / MS. All calculations were performed using Microsoft Excel. Peak area ratios were determined from the extracted ion chromatograms. The percentage of remaining compounds at each time point was calculated using the following formula:

[0154] Remaining percentage t min (%) = Peak area ratio t min / peak area ratio 0 min × 100 in Peak area ratio t min It is the peak area ratio of the control and test compounds at t min; and Peak area ratio 0 minIt is the ratio of the peak areas of the control and test compounds at time zero.

[0155] The slope value k was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug with the incubation time curve.

[0156] Determining the in vitro half-life (in vitro t) from the slope value 1 / 2 ): In vitro t 1 / 2 = (0.693 / k)

[0157] The data processing rules are shown in Table 3-3. Table 3-3. Data processing rules

[0158] The results are shown in Tables 3-4 and Figure 3. The longer half-life of the compound of formula (II) in the plasma of different species indicates that the compound of formula (II) can be more stable in vivo than compound 5. Example 4. Efficacy of the compound of formula (II) against brain cancer.

[0159] Cell culture: Luciferase-labeled NCI-H460-luc2 human intracranial cells were maintained as a monolayer in vitro at 37ºC in a 5% CO2 atmosphere in ATCC-prepared RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 100 U / mL penicillin, and 100 µg / mL streptomycin. Tumor cells were routinely passaged twice weekly via trypsin-EDTA treatment. Cells in the exponential growth phase were harvested and counted for tumor inoculation.

[0160] Tumor inoculation and animal grouping: Female BALB / c nude mice were anesthetized with afodin (20 µL / g). Thirty minutes postoperatively, 10 mg / kg carbofen was administered intraperitoneally to relieve pain.

[0161] Position the anesthetized mouse correctly. Prepare the surgical area with a 70% ethanol solution. Using a sterile scalpel, make a sagittal incision approximately 1 cm long on the parietal-occipital bone. Then clean the exposed skull surface with a cotton swab soaked in 0.9% saline. Before injecting the tumor cells, use a sterile 25-gauge needle to puncture the skull 2 ​​mm to the right of the anterior fontanelle and 1 mm anterior to the coronal suture to create an opening for injecting the tumor cells. Before drawing the cells into the syringe, mix the contents of the cell suspension by tapping with your fingers. Load the required amount of cell suspension into the syringe, taking extra care to avoid air bubbles. Then clean the outside of the syringe with an alcohol swab to wipe away any adhering cells, which helps prevent the establishment and growth of extracranial tumors. To ensure proper injection depth, cut a 3 mm section from the tip of a P20 pipette tip using a scalpel. Attach this section of the tip to the syringe to limit the injection depth and ensure that the tip of the syringe needle is 3 mm from the underside of the skull. Place the syringe perpendicular to the skull into the previously created opening. Slowly inject the cell suspension (3 μL of a suspension containing 1 x 10⁵ NCI-H460-luc2 cells in 20% matrix gel should be injected over 1 minute). Use the appropriate angle of syringe insertion to prevent intraventricular injection of cells and subsequent spinal dissemination. After injection, leave the needle in place for one minute, then slowly withdraw it. Seal the opening with medical adhesive (OB). Use forceps to pull the scalp together on the skull and close the incision with surgical sutures. Keep the mouse warm until fully recovered from anesthesia.

[0162] Animals were selected and randomly assigned to groups (based on their bioluminescence density) on day 4 post-tumor implantation. Treatment was initiated according to the predetermined protocol, as shown in Table 4-1.

[0163] Observation: During routine monitoring, examine animals daily for any effects of tumor growth and treatment on normal behavior, such as activity level, food and water consumption (by observation only), weight gain / loss (measured twice weekly or daily), dull eyes / coat, and any other abnormal effects described in the protocol. Record deaths and observed clinical signs based on the number of animals within each subset.

[0164] Bioluminescence measurement and endpoint: Surgically inoculated mice were weighed and luciferin was administered intraperitoneally at a dose of 150 mg / kg. Ten to fifteen minutes after luciferin injection, the animals were pre-anesthetized with a mixture of oxygen and isoflurane. When the animals were fully anesthetized, they were moved into the imaging chamber for bioluminescence measurement using an IVIS (Lumina II) imaging system.

[0165] The primary endpoint was to determine whether tumor bioluminescent growth could be delayed, reduced, or eliminated. Mice were weighed twice weekly or daily when showing obvious signs of disease. Bioluminescence of the entire animal body (including primary and metastatic tumors) was measured and recorded weekly according to the protocol (bioluminescence data not shown). Animals exhibiting signs of dying, such as significant weight loss exceeding 20% ​​or inability to eat normally or paralysis, were defined as near-death.

[0166] The median survival time (in days) of each group was calculated based on the survival time of animals in the treatment group and the vector group, and the life extension (ILS) was analyzed based on the median survival time of the treatment group and the vector group.

[0167] Statistical analysis: All animals were still alive on day 7 after grouping, so the differences in bioluminescence between groups were statistically analyzed using a t-test. SPSS 17.0 was used to analyze all data. p < 0.05 was considered statistically significant.

[0168] Survival time was analyzed using the Kaplan-Mayer method. The event of interest was animal death. Survival time was defined as the time from drug administration to death. For each group, the median survival time and corresponding 95% confidence interval were calculated. Kaplan-Mayer curves were also constructed for each group, and the log-rank test was used to compare survival curves between groups.

[0169] Survival time: The effects of compound (II) and paclitaxel (Taxol) treatment on survival in a female BALB / c nude mouse model of NCI-H460-luc2 are shown in Table 4-1. At the endpoint, one mouse in the compound (II) 38.4 mg / kg group was still alive.

[0170] The survival time of animals in each group is shown in Figure 4 and Table 4-1. The median survival time (MST) for the vector group was 14 days. The MST values ​​for the paclitaxel (10 mg / kg) and compound (II) (38.4 mg / kg) groups were 10 days (95% confidence interval: 7.60–12.40 days) and 14 days (95% confidence interval: 11.61–16.39 days), respectively. Table 4-1. Effects of compounds of formula (II) and paclitaxel on survival time (MST) a. Median survival time (MST) ± SEM. b. The p-value was obtained by comparing the treatment group with the mediator group. c. The p-value was obtained by comparing the treatment group with the paclitaxel 10 mg / kg group. d. p-values ​​were obtained by comparing the treatment group with the group receiving 9.6 mg / kg of the compound of formula (II). e. p-values ​​were obtained by comparing the treatment group with the group containing compound (II) at 19.2 mg / kg. Equivalent scheme

[0171] 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.

[0172] 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.

[0173] 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 method for treating proliferative, skin, or ophthalmic diseases or disorders, said method comprising intravenously administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need: (I)， Where n is an integer from 1 to 20.

2. The method of claim 1, wherein the effective amount is administered in a single dose or multiple doses.

3. A method for treating proliferative, skin, or ophthalmic diseases or disorders, said method comprising administering multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need: (I)， Where n is an integer from 1 to 20, and each dose is independently greater than 0.1 mg / kg.

4. The method according to any one of claims 1-3, wherein each dose is independently between 0.1 mg / kg and 15 mg / kg.

5. The method according to claim 2 or 3, wherein the multiple doses are administered monthly, bi-weekly, weekly, twice weekly, three times weekly, four times weekly, or daily.

6. The method of claim 5, wherein the multiple doses are administered daily.

7. The method of claim 5, wherein the multiple doses are administered every three weeks.

8. The method of claim 3, wherein the compound or a pharmaceutically acceptable saline thereof is administered intraperitoneally or intravenously.

9. The method of claim 8, wherein the compound or a pharmaceutically acceptable saline thereof is administered intravenously.

10. The method according to any one of claims 1-3, wherein the proliferative, skin or ophthalmic disease or disorder is cancer.

11. The method according to claim 10, wherein the cancer is brain cancer, liver cancer, lung cancer, ovarian cancer, stomach cancer, colorectal cancer, head and neck cancer, oral cancer, or maxillofacial cancer.

12. The method of claim 10, wherein the cancer is brain cancer.

13. The method according to any one of claims 1-3, wherein n is 8.

14. The method according to any one of claims 1-3, wherein the compound is (II), Or its pharmaceutically acceptable salt.

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