Stable plinabulin formulations and methods for preparing and using same

Abstract

Described herein are plinabulin unit dosage forms, kits, and methods of preparing and using plinabulin. Some embodiments relate to the use of light-tight containers, light-tight packaging, light-tight IV bags, and light-tight IV tubing.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims priority to U.S. Provisional Application No. 63 / 308,723, filed February 10, 2022, and U.S. Provisional Application No. 63 / 337,256, filed May 2, 2022. All of the foregoing applications are fully incorporated by reference herein in their entirety for all purposes.

[0002] The present disclosure relates to the fields of chemistry and medicine. More specifically, the present disclosure relates to stable Plinabulin formulations and methods of making and using same. [Background technology]

[0003] Many formulations containing therapeutic agents are sensitive to one or more elements or conditions, making them unstable over time. One such element or condition is sensitivity to one or more elements of air or light. Other such elements or conditions include the presence of gas or dissolved gas in the formulation, or exposure of one or more elements of the formulation to light, contaminants, or organisms such as bacteria. Another such condition or element is the amount of a particular molecule relative to the amount of one or more components in the formulation, including but not limited to the active agent of the formulation. Thus, there is a need for a formulation (including a pharmaceutical formulation) that retains the stability of the therapeutic agent or one or more other elements present in the formulation containing the therapeutic agent when the formulation is stored for a period of time, or for the time that the therapeutic agent is administered. Summary of the Invention

[0004] The present disclosure provides stable plinabulin formulations and methods for preparing and using the same. In some embodiments, the vessel is described. In some embodiments, the vessel contains a liquid formulation including plinabulin, propylene glycol, and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate) and is configured to block at least 85% of UV / visible light from 290 nm to 450 nm. In some embodiments, the vessel is a disposable amber glass vial. In some embodiments, the amber glass vial further comprises a rubber stopper and a flip-off cap. In some embodiments, the rubber stopper is a chlorobutyl rubber stopper with a B2-40 coating. In some embodiments, the rubber stopper further comprises a plug portion, and the plug portion comprises a FluroTec® coating. In some embodiments, the vessel is an IV bag. In some embodiments, the vessel is an IV bag covered with a light-tight sleeve. In some embodiments, the vessel is an IV tube in a light-tight sleeve. In some embodiments, the plinabulin is at a concentration of about 40 mg / 10 mL in the solution. In some embodiments, the solution comprises propylene glycol and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate) at a ratio of 60:40 (wt:wt). In some embodiments, the solution comprises less than 0.5% ether impurities. In some embodiments, the solution comprises less than 0.5% alcohol impurities. In some embodiments, the solution comprises less than 0.5% water. In some embodiments, the solution comprises less than 2.0% total impurities.

[0005] In some embodiments, the kit includes plinabulin in a light-protective container and light-protective packaging, the light-protective container blocking at least 85% of UV / visible light from 290 nm to 450 nm. In some embodiments, the plinabulin is at a concentration of about 40 mg / 10 mL in a liquid formulation. In some embodiments, the plinabulin is in a liquid formulation comprising propylene glycol and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate). In some embodiments, the liquid formulation comprises propylene glycol and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate) at a ratio of 60:40 (weight:weight). In some embodiments, the light-protective container is an amber vial. In some embodiments, the light-protective container further comprises a rubber stopper and a flip-off cap. In some embodiments, the rubber stopper is a chlorobutyl rubber stopper with a B2-40 coating. In some embodiments, the rubber stopper further comprises a plug portion, the plug portion comprising a FluroTec® coating. In some embodiments, the light-tight packaging has a solid black print on the interior thereof. In some embodiments, the kit further comprises an IV bag. In some embodiments, the IV bag is configured to block at least 85% of UV / visible light between 290 nm and 450 nm. In some embodiments, the IV bag comprises a light-tight sleeve. In some embodiments, the kit further comprises IV tubing. In some embodiments, the IV tubing is configured to block at least 85% of UV / visible light between 290 nm and 450 nm. In some embodiments, the IV tubing comprises a light-tight sleeve.

[0006] In an aspect of the present disclosure, a method of administering plinabulin to a subject is described. In some embodiments, the method of administering plinabulin to a subject in need thereof comprises providing plinabulin in a light-tight IV bag and administering plinabulin to a subject in need thereof via light-tight IV tubing. In some embodiments, the light-tight IV bag blocks at least 85% of ultraviolet / visible light from 290 nm to 450 nm. In some embodiments, the light-tight IV tubing blocks at least 85% of ultraviolet / visible light from 290 nm to 450 nm. In some embodiments, the method comprises providing plinabulin by injecting the plinabulin into the light-tight IV bag. In some embodiments, the method comprises providing plinabulin by injecting the plinabulin into a non-light-tight IV bag and then placing a light-tight sleeve over the non-light-tight IV bag. In some embodiments, the plinabulin is injected into D5W as a liquid formulation. In some embodiments, the solution comprises propylene glycol and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate). In some embodiments, the solution comprises propylene glycol and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate) at a ratio of 60:40 (weight:weight). In some embodiments, the solution comprises plinabulin at a concentration of about 40 mg / 10 mL. In some embodiments, the method comprises placing a non-light-tight IV tubing within a light-tight sleeve to form a light-tight IV tubing. [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 is a diagram of a box according to an embodiment of the present invention. [Diagram 2] FIG. 2 is a photograph of an amber IV bag cover according to an embodiment of the present invention. [Diagram 3] FIG. 3 is a photograph of an amber IV tube cover according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Described herein are plinabulin unit dosage forms, kits, and methods for preparing and using plinabulin compositions.Plinabulin, as (3Z,6Z)-3-benzylidene-6-{[5-(2-methyl-2-propanyl)-1H-imidazol-4-yl]methylene}-2,5-piperazinedione, is a synthetic analog of the natural compound phenylahistine.Plinabulin can be easily prepared according to the methods and procedures detailed in U.S. Patent Nos. 7,064,201 and 7,919,497, which are incorporated herein by reference in their entirety.

[0009] Before the present disclosure is further described, it is to be understood that the invention is not limited to particular embodiments described, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, as the scope of the present invention will be limited only by the appended claims.

[0010] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value between the upper and lower limit of that range, and any other stated or intervening value in that stated range, to the nearest tenth of the lower limit, is included in the invention. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are encompassed within the invention, subject to any specifically excluded limit in the stated range. Where one or both of the limits are included in the stated range, ranges excluding either or both of those included limits are also included in the invention.

[0011] Methods recited herein may be carried out in any order of the recited events that is logically possible, as well as the recited order of events.

[0012] 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 to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described herein.

[0013] All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials for which the publications are cited.

[0014] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should further be noted that the claims may be drafted to exclude any element. Accordingly, this statement is intended as a precondition for using exclusive terminology, such as "solely," "only," and the like, or for using "negative" limitations in connection with the recitation of claim elements.

[0015] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the publication dates provided may be different from the actual publication dates which may need to be independently confirmed.

[0016] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for a term in this specification, the definition in this section shall prevail unless otherwise specified.

[0017] The term "agent" is used herein to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials.

[0018] The terms "cancer," "neoplasm," and "carcinoma" are used interchangeably herein and refer to cancers characterized by relatively autonomous growth and resulting in a profound loss of control over cell proliferation. The term "cells" refers to cells that exhibit an aberrant proliferation phenotype associated with apoptosis. Typically, cells that are the subject of detection or treatment in this application include precancerous (e.g., benign), malignant, premetastatic, metastatic, and non-metastatic cells. Of particular interest is the detection of cancer cells.

[0019] As used herein, the term "subject" means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, as well as other vertebrates or invertebrates.

[0020] The term "mammal" is used in its ordinary biological sense, and thus specifically refers to primates, including simians (chimpanzees, apes, monkeys) and humans; These include, but are not limited to, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, and the like.

[0021] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent effective to relieve to some extent one or more symptoms of a disease or condition or reduce the likelihood of its occurrence, and can include curing the disease or condition.

[0022] The term "liquid dosage form" as used herein refers to a pharmaceutical formulation containing a mixture of active drug ingredients and non-drug ingredients (excipients) dissolved or suspended in a suitable solvent or solvent mixture. Liquid dosage forms may be supplied as ready-to-use liquids or powders for reconstitution. Liquid dosage forms may be monophasic and biphasic liquid dosage forms.

[0023] Generally, the compounds of the present disclosure are preferably administered in intravenous or subcutaneous unit dosage form, but other administration routes are also considered.Possible administration routes include, but are not limited to, oral, parenteral, intravenous, and subcutaneous.The compounds of the preferred embodiments can be formulated into liquids for oral administration, for example.Suitable forms include suspensions, syrups, elixirs, and the like.Oral liquids can usually be non-sterile, but liquids administered via parenteral routes can be utilized as sterile and non-sterile preparations.

[0024] The compounds of the present disclosure may be mixed with a suitable carrier, diluent, or excipient, such as sterile water, saline, glucose, and the like, and may contain auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing agents, preservatives, flavoring agents, coloring agents, and the like, depending on the route of administration and the preparation desired. See, e.g., “Remington: The Science and Practice of Pharmacy,” Lippincott Williams & Wilkins, 20th ed. (June 1, 2003) and “Remington's Pharmaceutical Sciences,” Mack Pub. Co., 18th and 19th eds. (December 1985 and June 1990, respectively);Ansel, H. (2010). Pharmaceutical Calculations (13th ed.), London: Wolters Kluwer Health and Lippincott Williams & Wilkins;Chaudhari, S. and Patil, P. (2012) Pharmaceutical Excipients: A review. International Journal of Advances in Pharmacy, Biology and Chemistry, 1(1): 21-34;Denton, P. and Rostron, C (2013) Pharmaceutics: The Science of Medicine Design, United Kingdom: Oxford University Press;Gautami, J. (2016). Liquid Dosage Forms. Nano Science & Nano Technology, 10(3):1-9.

[0025] Such formulations include complexing agents, metal ions, polymeric compounds (polylactic acid, polyglycolic acid, hydrogels, dextran, etc.), liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts or spheroblasts. Lipids suitable for liposomal formulations include, but are not limited to, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponins, bile acids, etc. The presence of such additional components may affect the physical state, solubility, stability, in vivo release rate, and in vivo clearance rate, and are therefore selected according to the intended use, with the properties of the carrier being tailored to the selected route of administration.

[0026] When administered orally in liquid form, the active ingredient may be added to a liquid carrier such as water, petroleum, oils of animal or vegetable origin, such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oil. Saline, dextrose, or other sugar solutions, or glycols, such as ethylene glycol, propylene glycol, or polyethylene glycol, are also suitable liquid carriers. The pharmaceutical composition may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents include natural gums, such as gum acacia and gum tragacanth, natural phospholipids, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0027] When the compound of the preferred embodiment is administered intravenously, parenterally, or by other injection, the compound is preferably in the form of a pyrogen-free, parenterally acceptable aqueous or oleaginous suspension. The suspension can be formulated according to methods well known in the art using suitable dispersing or wetting agents and suspending agents. The preparation of an acceptable aqueous solution with appropriate pH, isotonicity, stability, and the like is within the skill of the art. A preferred injectable pharmaceutical composition preferably contains an isotonic medium such as 1,3-butanediol, water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, dextrose and sodium chloride solution, lactated Ringer's solution, or other medium known in the art. In addition, sterile fixed oils can be conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used to form injectables as well. The pharmaceutical composition can also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those skilled in the art.

[0028] The duration of the injection can be adjusted depending on a variety of factors, and can include a single injection within a few seconds to continuous intravenous administration for 0.5, 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours or more.

[0029] As used herein, the terms "treat", "treatment" or "treating" refer to the administration of a compound or pharmaceutical composition to a subject for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of the disease or condition, but who is susceptible to or at risk of developing a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject who is already suffering from a disease or condition.

[0030] overview In an embodiment of the present disclosure, plinabulin, propylene glycol, and polyoxyl 15 A container may be included that contains a liquid formulation that includes hydroxystearate (PEG 15-hydroxystearate). In some embodiments, the container may be configured to block at least 85% of UV / visible light from 290 nm to 450 nm. In some embodiments, the container may be a disposable amber glass vial.

[0031] In some embodiments, the amber glass vial may include a rubber stopper and a flip-off cap. In some embodiments, the rubber stopper may be a chlorobutyl rubber stopper with a B2-40 coating. In some embodiments, the rubber stopper may include a plug portion. In some embodiments, the plug portion may include a FluroTec® coating. In any of these previous embodiments, the container may include a liquid formulation including plinabulin, propylene glycol, and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate). In any of these previous embodiments, the container may include a liquid formulation including plinabulin and any other suitable liquid formulation.

[0032] In some embodiments, the container may be an IV bag covered with a light-tight sleeve. In some embodiments, the container may be an IV bag. In some embodiments, the container may be IV tubing in a light-tight sleeve. In some embodiments, the plinabulin may be at a concentration of about 40 mg / 10 mL in the solution. In any of these previous embodiments, the container may contain a solution including plinabulin, propylene glycol, and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate). In any of these previous embodiments, the container may contain a solution including plinabulin and any other suitable solution.

[0033] In some embodiments, the container of any of the preceding embodiments may contain propylene glycol and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate) in a ratio of 60:40 (w:w). In some embodiments, the container of any of the preceding embodiments may contain a liquid formulation, which may contain less than 0.5% ether impurities. In any of these preceding embodiments, the container may contain a liquid formulation comprising plinabulin, propylene glycol, and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate). In any of these preceding embodiments, the container may contain a liquid formulation comprising plinabulin and any other suitable liquid formulation.

[0034] In some embodiments, the liquid formulation may contain less than 0.5% alcohol impurities. In some embodiments, the liquid formulation may contain less than 0.5% water. In some embodiments, the liquid formulation may contain less than 2.0% total impurities. In any of these previous embodiments, the container may contain a liquid formulation comprising plinabulin, propylene glycol, and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate). In any of these previous embodiments, the container may contain a liquid formulation comprising plinabulin and any other suitable liquid formulation.

[0035] The embodiments of the present disclosure may also include a kit comprising plinabulin in a light-resistant container. The embodiments may also include light-resistant packaging. In some embodiments, the light-resistant container blocks at least 85% of UV / visible light from 290 nm to 450 nm. In some embodiments, the plinabulin may be at a concentration of about 40 mg / 10 mL in a solution. In any of these aforementioned kit embodiments, the container may contain a solution comprising plinabulin, propylene glycol, and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate). In any of these aforementioned embodiments, the container may contain a solution comprising plinabulin and any other suitable solution.

[0036] In some embodiments, the plinabulin may be present in a solution comprising propylene glycol and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate). In some embodiments, the solution may comprise propylene glycol and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate) at a ratio of 60:40 (weight:weight). In some embodiments, the light-proof container may be an amber vial.

[0037] In some embodiments, the light-tight container may comprise a rubber stopper and a flip-off cap. In some embodiments, the rubber stopper may be a chlorobutyl rubber stopper with a B2-40 coating. In some embodiments, the rubber stopper may include a plug portion. In some embodiments, the plug portion may include a FluroTec® coating.

[0038] In some embodiments, the light-resistant packaging may have solid black printing on the inside. In some embodiments, the kit may further include an IV bag. In some embodiments, the IV bag may be configured to block at least 85% of UV / visible light from 290 nm to 450 nm.

[0039] In some embodiments, the IV bag may include a light-tight sleeve. In some embodiments, the kit may further include IV tubing. In some embodiments, the IV tubing may be configured to block at least 85% of UV / visible light from 290 nm to 450 nm. In some embodiments, the IV tubing may include a light-tight sleeve.

[0040] Embodiments of the present disclosure may also include a method of administering plinabulin to a subject in need thereof, the method comprising providing plinabulin in a light-tight IV bag. An embodiment comprises administering plinabulin to a subject in need thereof via light-tight IV tubing. In some embodiments, the light-tight IV bag blocks at least 85% of UV / visible light between 290 nm and 450 nm. Any of the foregoing embodiments of kits and formulations may be advantageously used to carry out the disclosed methods.

[0041] In some embodiments, the light-tight IV tubing blocks at least 85% of UV / visible light between 290 nm and 450 nm. In some embodiments, the method of any one of claims 1 to 32. (In some embodiments, the method of any one to 32.) In some embodiments, providing the plinabulin may include injecting the plinabulin into the light-tight IV bag. In some embodiments, the plinabulin may be injected into D5W as a liquid formulation.

[0042] In some embodiments, the solution may include propylene glycol and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate). In some embodiments, the solution may include propylene glycol and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate) at a ratio of 60:40 (weight:weight). In some embodiments, the solution may include plinabulin at a concentration that may be about 40 mg / 10 mL.

[0043] In some embodiments, providing the plinabulin may include injecting the plinabulin into a non-light-tight IV bag and then placing a light-tight sleeve over the non-light-tight IV bag. In some embodiments, the method may include placing non-light-tight IV tubing into a light-tight sleeve to form light-tight IV tubing.

[0044] Light-protective Vessel In some embodiments, plinabulin is provided to a care-giver as a liquid formulation. In some embodiments, the plinabulin solution comprises a solvent, polyoxyl 15 hydroxystearate and propylene glycol. In some embodiments, the solvent comprises 40% by weight polyoxyl 15 hydroxystearate and 60% by weight propylene glycol. In some embodiments, the concentration of plinabulin in the solution is 40 mg / 10 mL. It has been discovered that such solutions of plinabulin are highly sensitive to light. Thus, in some embodiments, the plinabulin solution is provided in a light-proof container.

[0045] In some embodiments, the light-tight container is configured to block or reduce transmission of UV / Visible light. In some embodiments, the light-tight container is configured to preferentially block or reduce transmission of UV / Visible light below a certain wavelength (e.g., below 520 nm). In some embodiments, the light-tight container is configured to block at least 99%, at least 98%, at least 97%, at least 96%, at least 95%, at least 94%, at least 93%, at least 92%, at least 91%, at least 90%, at least 85%, at least 80% of UV / Visible light (in some embodiments, UV / Visible light below 520 nm), or within a range including and / or spanning the aforementioned values. In some embodiments, containers used to package parenteral and oral solutions shall be made from materials that are sufficiently transparent at some wavelengths to allow visual inspection of the contents.

[0046] In some embodiments, the light-tight container is configured to block or reduce the transmission of ultraviolet / visible light less than 580 nm. In some embodiments, the light-tight container is configured to block or reduce the transmission of ultraviolet / visible light less than 520 nm. In some embodiments, the light-tight container is configured to block or reduce the transmission of ultraviolet / visible light less than 450 nm. In some embodiments, the light-tight container is configured to block or reduce the transmission of ultraviolet / visible light less than 400 nm. In some embodiments, the light-tight container is configured to block or reduce the transmission of ultraviolet light less than 315 nm. In some embodiments, the light-tight container is configured to block or reduce the transmission of ultraviolet light less than 280 nm. In some embodiments, the light-tight container is configured to block or reduce the transmission of light having a wavelength of about 100 nm to about 580 nm. In some embodiments, the light-tight container is configured to block or reduce the transmission of light having a wavelength of about 100 nm to about 400 nm. In some embodiments, the light-tight container is configured to block or reduce the transmission of light having a wavelength of about 290 nm to about 450 nm. In some embodiments, the light-tight container is configured to block or reduce the transmission of light having a wavelength of about 100 nm to about 315 nm. In some embodiments, the light-tight container is configured to block or reduce the transmission of light having a wavelength of about 100 nm to about 280 nm. In various embodiments, the aforementioned reduction in light transmission at the specified wavelength is at least a 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, or 60% reduction. In some embodiments, the light-tight container is configured such that the maximum percentage of spectral transmission at any wavelength between 290 nm and 450 nm is less than 25%, 20%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

[0047] In some embodiments, the light-tight container is an amber bottle. In some embodiments, the light-tight container is an amber polypropylene bottle. In some embodiments, the light-tight container is an amber glass vial. In some embodiments, the light-tight container is a borosilicate glass vial. In some embodiments, the light-tight container is a low actinic glass vial. In some embodiments, the light-tight container is a soda-lime glass vial. In some embodiments, the light-tight container is a disposable vial.

[0048] In some embodiments, the light-tight container includes a coating. In some embodiments, the coating is an ethylene acrylate coating. In some embodiments, the coating is a PTFE liner.

[0049] In some embodiments, the light-tight container includes a flip-off cap. In some embodiments, the light-tight container includes a polypropylene plug seal cap. In some embodiments, the light-tight container includes a rubber stopper. In some embodiments, the rubber stopper is a chlorobutyl rubber stopper with a B2-40 coating. In some embodiments, the rubber stopper includes a plug portion. In some embodiments, the plug portion includes a coating. In some embodiments, the coating is a FluroTec® coating. In some embodiments, the light-tight container includes a rubber-lined cap. In some embodiments, the rubber-lined cap is a black phenolic rubber-lined cap.

[0050] Light blocking packaging In some embodiments, the light-resistant container is further provided to the care provider in light-resistant packaging. In some embodiments, the light-resistant packaging is UV / Vis light blocking packaging. In some embodiments, the light-resistant packaging is configured to block at least 99%, 98%, at least 97%, at least 96%, at least 95%, at least 94%, at least 93%, at least 92%, at least 91%, at least 90% UV / Vis light, at least 85% UV / Vis light, at least 80% UV / Vis light, or within a range including and / or spanning the aforementioned values.

[0051] In some embodiments, the light-tight packaging includes a box (e.g., a cardboard box). In some embodiments, the box includes a coating that provides light-tight properties. The coating can be applied to the inside or outside of the box. In some embodiments, the coating is printed onto the cardboard. In some embodiments, the printing includes solid black printing on the inside of the box. FIG. 1 illustrates one embodiment of a box that can be used as described herein. FIG. 1 illustrates a piece of cardboard cut into a shape that can be bent into a box shape. One side of the cardboard is printed with solid black. The cardboard can be folded into the shape of a box, and the inside of the box is printed with solid black. A light-tight container (e.g., an amber vial) containing a plinabulin liquid formulation is then placed into the box. The light-tightness provided by the box reinforces the light-tightness provided by the light-tight container.

[0052] In some embodiments, the light-proof container and packaging allows the plinabulin solution to be stored long term while the solution maintains total impurities at less than 5.0 w / w%, less than 4.5 w / w%, less than 4.0 w / w%, less than 3.5 w / w%, less than 3.0 w / w%, less than 2.5 w / w%, less than 2.0 w / w%, less than 1.5 w / w%, less than 1.0 w / w%, less than 0.5 w / w%, or within a range including and / or spanning the aforementioned values. In some embodiments, the stored plinabulin solution contains less than 0.5% ether impurities. In some embodiments, the plinabulin solution contains less than 0.5% alcohol impurities. In some embodiments, the solution contains less than 0.5% water.

[0053] Light-blocking administration protocol It has also been found that plinabulin solutions are highly sensitive to light and therefore require protection of said solutions throughout the administration protocol, and thus in some embodiments, plinabulin is maintained in a light-tight container throughout administration.

[0054] In some embodiments, the light-tight container is an IV bag configured to block UV / visible light as described above. In some embodiments, the IV bag is a translucent amber IV bag. In some embodiments, the IV bag is a dark amber bag. In some embodiments, the IV bag is a light amber bag. In some embodiments, the light-tight container is an IV bag covered with a light-tight sleeve. Figure 2 shows an example of a light-tight sleeve for an IV bag.

[0055] In some embodiments, the light-tight container is an IV tubing configured to block UV / visible light as described above. In some embodiments, the IV tubing is a translucent amber IV tubing. In some embodiments, the IV tubing is a dark amber tubing. In some embodiments, the IV tubing is a light amber tubing. In some embodiments, the light-tight container is an IV tubing covered with a light-tight sleeve. FIG. 3 shows an example of a light-tight sleeve for an IV tubing.

[0056] Some embodiments include adding the plinabulin solution contained in the light-tight vial to a light-tight IV bag. Some embodiments include administering plinabulin from the light-tight IV bag to a subject in need thereof via light-tight IV tubing. In some embodiments, the method includes gently mixing the light-tight IV bag several times to ensure adequate mixing.

[0057] In some embodiments, the light-tight IV bag contains D5W (water with 5% dextrose) solution prior to the addition of plinabulin. In various embodiments, the IV bag contains 150 mL, 200 mL, 250 mL, 300 mL, 350 mL, 400 mL, 450 mL, 500 mL of D5W, or a range including and / or spanning the aforementioned values. In some embodiments, after the addition of plinabulin solution from the light-tight vial, the light-tight IV bag contains plinabulin solution at a concentration of about 0.08 mg / mL to about 0.2 mg / mL.

[0058] In some embodiments, the method of administering plinabulin to a subject in need thereof comprises providing plinabulin in a light-tight IV bag and administering plinabulin to a subject in need thereof via light-tight IV tubing. In some embodiments, the light-tight IV bag blocks at least 85% of UV / visible light from 290 nm to 450 nm. In some embodiments, the light-tight IV tubing blocks at least 85% of UV / visible light from 290 nm to 450 nm. In some embodiments, providing the plinabulin comprises injecting the plinabulin into the light-tight IV bag. In some embodiments, providing the plinabulin comprises injecting the plinabulin into a non-light-tight IV bag and then placing a light-tight sleeve over the non-light-tight IV bag. In some embodiments, the plinabulin is infused as a solution in D5W in the light-tight IV bag. In some embodiments, the solution comprises propylene glycol and polyoxyl 15-hydroxystearate (PEG 15-hydroxystearate). In some embodiments, the solution comprises propylene glycol and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate) at a ratio of 60:40 (weight:weight). In some embodiments, the solution comprises plinabulin at a concentration of about 40 mg / 10 mL. In some embodiments, the method may further comprise placing a non-light-tight IV tubing within a light-tight sleeve to form a light-tight IV tubing.

[0059] In some embodiments, the plinabulin solution in the IV bag can be administered within 6 hours after preparation, hi some embodiments, the plinabulin is maintained at room temperature while being administered to a subject in need thereof.

[0060] Stable plinabulin composition In some embodiments, the plinabulin solution in the light-proof container is a stable formulation of plinabulin. In some embodiments, the stable formulation is stable over a storage period of at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 36 months, or at least about 48 months. In some embodiments, the stable formulation retains at least about 99%, 95%, 90%, 80%, 70%, or 60% plinabulin strength after the storage period.

[0061] In some embodiments, the stable formulations and stable pharmaceutical formulations described herein are stable when stored for a period of time at any one or more of -20°C, -10°C, 0°C, 5°C, 10°C, 25°C, 20°C, 30°C, 40°C, or within a range including and / or spanning the aforementioned values.

[0062] Use and Method Some embodiments relate to methods of halting or reversing progressive cancer in a subject. In some embodiments, the methods include administering plinabulin to the subject. Some embodiments relate to methods of inhibiting the progression of cancer. Additional uses of plinabulin are described in U.S. Patent Nos. 7,919,497, 10,238,650, 10,155,748, 10,076,518, and 10,596,169, and PCT Publication Nos. WO 2016 / 130839, WO 2017 / 214052, WO 2018 / 144764, WO 2018 / 15216, WO 2018 / 16 ... / 169887, WO 2019 / 147615, WO 2019 / 147615, WO 2019 / 152530, WO 2020 / 037285, WO 2021 / 076485, and WO 2021 / 225908, all of which are incorporated by reference in their entirety.

[0063] In some embodiments, the treatment schedule includes plinabulin administration once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, the treatment schedule includes plinabulin administration twice every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, the treatment schedule includes plinabulin administration once per week for a 1, 2, 3, 4, 5, 6, 7, or 8 week treatment cycle. In some embodiments, the treatment schedule includes plinabulin administration twice per week for a 1, 2, 3, 4, 5, 6, 7, or 8 week treatment cycle. In some embodiments, the treatment schedule includes plinabulin administration on days 1, 8, and 15 of a 21 day treatment cycle.

[0064] The treatment cycle can be repeated as long as the treatment regimen is clinically tolerated. In some embodiments, the treatment cycle of plinabulin is repeated n times, where n is an integer in the range of 2 to 30. In some embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the new treatment cycle can occur immediately after the completion of the previous treatment cycle. In some embodiments, the new treatment cycle can occur a certain period of time after the completion of the previous treatment cycle. In some embodiments, the new treatment cycle can occur 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks after the completion of the previous treatment cycle.

[0065] In some embodiments, the method comprises administering a dose of about 5 mg / m 2 ~150mg / m 2 In some embodiments, the plinabulin is administered at a dose of 30 mg / m 2 In some embodiments, plinabulin is administered at a dose of greater than about 40 mg / m 2 is administered at a dose of

[0066] In some embodiments, plinabulin is administered on day 1 of a 14 day administration cycle. In some embodiments, plinabulin is administered on day 1 of a 21 day administration cycle.

[0067] In some embodiments, the plinabulin solution is administered in combination with one or more G-CSF agents, hi some embodiments, the one or more G-CSF agents is Paclitaxel.

[0068] kit Some embodiments include a kit comprising one or more containers.

[0069] In some embodiments, the container comprises plastic or glass or a combination thereof, including but not limited to any one or more of plastic or glass that one of skill in the art would use based on the teachings herein. In some embodiments, the portion of the container where the liquid formulation is exposed is made of amber glass. In some embodiments, the container is colored amber. In some embodiments, the container is opaque or translucent to protect the formulation from light or other forms of radiation, and some are transparent or translucent. In some embodiments, the administration kit and packaging are selected from the group consisting of amber vials to protect from light and stoppers with special coatings to improve shelf-life stability.

[0070] In some embodiments, the container is a vial. In some embodiments, the vial contains about 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, or an amount of plinabulin in a range including and / or spanning the aforementioned values.

[0071] In some embodiments, the container is an IV bag. In some embodiments, the IV bag includes a dark amber IV cover. In some embodiments, the IV bag is UV / visible light blocking. In some embodiments, the IV bag blocks 95% of UV / visible light. In some embodiments, the IV bag is opaque. In some embodiments, the IV bag is clear but hides color differences in IV fluid.

[0072] In some embodiments, the kit further comprises an IV tube cover. In some embodiments, the IV tube cover is an amber IV tube cover. In some embodiments, the amber IV tube cover further protects the plinabulin composition or pharmaceutical composition.

[0073] In some embodiments, the containers described herein are secondary packaged. In some embodiments, the secondary package is configured to maintain the stability of the therapeutic agent compared to the stability of the therapeutic agent prior to packaging. In some variations, the secondary package is designed to eliminate or reduce exposure of the formulation to light. In some embodiments, the secondary package is designed to eliminate or reduce exposure of the formulation to one or more components of air, such as oxygen. In some variations, the container is an ampoule, vial, or pre-filled syringe.

[0074] In some embodiments, the kit may contain plinabulin for injection in a disposable amber glass vial with a chlorobutyl rubber stopper and FluroTec® coating on the stopper plug and flip-off cap.

[0075] In some embodiments, the formulations described herein are provided in one or more unit dosage forms, the unit dosage forms containing an amount of a liquid plinabulin formulation described herein effective to treat or prevent the disease or condition for which it is administered.

[0076] In some embodiments, the unit dosage form is prepared at the concentration at which it is to be administered, hi some variations, the unit dosage form is diluted prior to administration to a subject.

[0077] In a further aspect, provided herein is a kit comprising one or more unit dosage forms described herein. In some embodiments, the kit comprises one or more packaging and instructions for use to treat one or more diseases or conditions. In some embodiments, the kit comprises a diluent that is not in physical contact with the formulation or pharmaceutical formulation. In some embodiments, the kit comprises any one or more unit dosage forms described herein in one or more sealed containers. In some embodiments, the kit comprises any one or more sterile unit dosage forms.

[0078] In some embodiments, the kit may include a G-CSF agent. Granulocyte colony-stimulating factor (G-CSF) refers to a compound or factor that stimulates the proliferation, differentiation, commitment, and activation of end-cell functions of granulocytes in animals, including human subjects. G-CSF compounds include, but are not limited to, Filgrastim and Pegfilgrastim. Examples of commercially available G-CSF include, but are not limited to, NEUPOGEN® (Amgen), TEVAGRASTIM® (Teva), BIOGRASTIM® (CT Arzneimittel), RATIOGRASTIM® (Ratiopharm GmbH), ZARXIO® (Sandoz GmbH), FILGRASTIM HEXAL® (Hexal AG), NEULASTA® (Amgen), GRANOCYTE® and NEUTROGIN® (Chugai Pharmaceutical Co., Ltd.), and NEU-UP® (Kyowa Hakko Co., Ltd.). G-CSF is often administered to manage chemotherapy-induced severe neutropenia. G-CSF, such as pegfilgrastim, is a colony-stimulating factor that acts on hematopoietic cells by binding to specific cell surface receptors to stimulate proliferation, differentiation, commitment, and activation of end-cell functions. EXAMPLES

[0079] The following examples are provided to further illustrate the present invention. Needless to say, these examples should not be construed as specifically limiting the present invention. Variations of these examples within the scope of the claims are within the knowledge of those skilled in the art and are considered to be included within the scope of the invention described and claimed herein. The reader will recognize that a person skilled in the art with the present disclosure and the skills of the art can prepare and use the present invention without the need for exhaustive examples.

[0080] Example 1 In this comparative example, we report plinabulin stress testing of solid plinabulin showing its relative stability to 30 days of light storage. Table 1 shows the results of impurity analysis after exposing plinabulin to light for 30 days. Table 2 reports the results of impurity analysis of a control sample stored in the dark. The results show that total impurities only increased to 0.3%-0.6% even after 30 days of light exposure. [Table 1] [Table 2]

[0081] Example 2 This example presents the results of a study conducted to evaluate the photostability of a 4 mg / mL (40 mg / 10 mL) plinabulin solution in 40% by weight polyoxyl 15 hydroxystearate and 60% by weight propylene glycol in different packaging configurations. The packaging used is described and the results of the study are presented in Table 4. [Table 3]

[0082] The following configurations were tested:

[0083] 1) Unexposed finished product in primary packaging (control).

[0084] 2) The finished primary packaged product was wrapped in aluminum foil and exposed to UV / visible light (dark control).

[0085] 3) Expose the finished product in its primary packaging (amber vial) to UV-Vis (ultraviolet-visible) light.

[0086] 4) Expose the finished vials in secondary packaging (IFC cartons) to UV-Vis (ultraviolet-visible) light.

[0087] Exposure to light intensity was determined on the day of testing and actual testing times were recorded. Photostability testing was performed according to VP5740 and ICH-Q1B: "Photostability Testing of New Drug Substances and Products" (November 1996).

[0088] Samples of Plinabulin liquid in primary packaging (amber vials) and secondary packaging (IFC cartons) were exposed to a total illumination of 1.21 million lux hours and an integrated near-UV energy of 326.6 watt-hours / m 2 UV / Vis light exposure of 1.2 million lux hours or more in total illumination and 200 watt-hours / m2 of accumulated near-ultraviolet energy, in accordance with ICH-Q1B Option 1. 2 The above criteria were met. Unexposed control samples were evaluated for informational purposes only. Aluminum foil wrapped finished product samples (dark controls) were exposed to light to evaluate the contribution of thermally induced changes to the total changes observed. Light stability was determined based on appearance, retention time identification, UV spectrum match / PDA identification, moisture content, assay, impurities, container contents, and particulate matter.

[0089] At the end of the photostability study, the samples were evaluated for changes in the physical properties (i.e., appearance) of the solutions and were also tested for retention time identification, UV spectrum match / PDA identification, moisture content, assay values, impurities, container contents, and particulate matter. [Table 4-1] [Table 4-2]

[0090] Analytical results and individual and total impurities did not meet the acceptance criteria for the primary packaging (amber vials), suggesting that the primary packaging was not adequately protected from light. All other results for the control, dark control, and secondary packaging (IFC cartons) met the defined acceptance criteria.

[0091] Based on the results generated, it can be concluded that the amber vials in the IFC carton provide sufficient light protection for the 4 mg / mL (40 mg / 10 mL) plinabulin solution.

[0092] Example 3 This example reports the results of a study conducted to determine the effect of light exposure on the appearance, ID, assays, and impurities of plinabulin solutions in infusion lines after dilution of 4 mg / mL solutions (40% polyoxyl 15 hydroxystearate and 60% propylene glycol by weight) 1:20 and 1:50 in infusion bags of 5% dextrose in water (D5W). The target illuminance was 1000 lux on the infusion line in accordance with ANSI / IES RP-29-20 (Recommended Practice: Lighting in Hospitals and Healthcare Facilities, American National Standard).

[0093] In this study, 200-500 mL non-PVC bags were used with dilutions of 1:20 and 1:50 at various time intervals. The dilutions were performed using clear vials of 4 mg / mL plinabulin liquid. Samples were taken from the infusion line after light exposure at intervals of 3, 5, 7, 11, 14, and 22 minutes. A control sample (T=0) was taken from the outlet port of the D5W bag containing the diluted plinabulin drug product at 0 minutes.

[0094] Materials and Methods

[0095] Plinabulin 4mg / mL solution: 10mL amber vial. D5W solution: 200-500mL bag of sterile D5W in non-PVC bag, B.Braun, lot number J9N016. Dark amber D5W bag cover: Health Care Logistics, part number 7589D. Amber IV tubing sleeves: Amber tubing cover roll cut to 72" and 103", Health Care Logistics, part number 19645. DUO-VENT spiked solution set, 103" polyethylene lined tubing, Baxter, part number 2C8875. Photometer: ID number 2359506.

[0096] Sample Procedure

[0097] All operations were performed in a dark room, and drug solutions were not heated or refrigerated after dilution. All D5W non-PVC IV bags used in this study were from the same manufacturer / supplier and were from the same manufacturer lot. Infusion bags were prepared for this study. 4 mg / mL plinabulin solution was diluted 1:20 or 1:50 with D5W in non-PVC IV bags to produce the diluted IV infusion product (infusion bag).

[0098] Preparation of infusion solutions

[0099] The volume of the IV line was measured and recorded; 7 mL for the 72" line and 10 mL for the 103" line. One D5W IV bag was removed and a light-tight sleeve was placed over the D5W IV bag and tubing set. The required volume was drawn from the vial using a Luer Lock syringe. The required volume of medication was immediately diluted to the required dilution ratio of 1:20 or 1:50 into a light-tight D5W bag containing 200-500 mL of D5W labeled formulation. The IV bag was gently inverted several times to ensure adequate mixing. The resulting dilution was visually confirmed to be a clear solution. A sample at TA0 was drawn from each prepared bag and transferred to a labeled sample container and protected from light. Separate infusion lines were filled at each time point from the prepared infusion bags and these samples were used to test the effect of light exposure on bare IV infusion lines and IV infusion lines with amber sleeve protection. The filled infusion lines were protected from light and appropriately labeled prior to exposure to white light.

[0100] Exposure Procedure

[0101] All operations were performed in a dark room. White light was installed in the dark room. The light intensity was measured and recorded at the beginning of the exposure of the samples. The target illuminance was 1000 lux at the exposure site (infusion line) according to ANSI / IES RP-29-20. Table 5 shows the light intensity measurement results. [Table 5]

[0102] Samples of plinabulin injection diluted 1:20 and 1:50 in D5W in non-PVC bags were loaded into bare and amber-sleeved infusion lines at ambient conditions and then exposed to light at timed intervals by turning on a white light for a set period of time.

[0103] Test Plan

[0104] Samples other than the T=0 sample were exposed to light under the conditions described above. Light-tight conditions for filled infusion lines: bare line (unprotected): 72 inches, bare line (unprotected): 103 inches, infusion line with amber sleeve: 72 inches, and infusion line with amber sleeve: 103 inches. The entire contents of each IV line were transferred to pre-labeled amber sample containers and stored at room temperature protected from light until analytical testing was performed. Samples were tested within 6 hours of product dilution. Samples were tested as described herein.

[0105] Test methods and acceptance criteria

[0106] Impurities / degradants were analyzed by HPLC. During infusion line light exposure testing, samples were taken from individual infusion lines or outlet ports as appropriate and tested directly without further dilution and / or filtration. The acceptance criteria and results of infusion line light exposure testing are shown in Table 6 (1:20 dilution) and Table 7 (1:50 dilution). [Table 6-1] [Table 6-2] [Table 6-3] [Table 7-1] [Table 7-2] [Table 7-3]

[0107] The NPI-2489 impurity results did not meet the acceptance criteria of NMT 0.5% for bare IV infusion lines at 72 inches and 103 inches, except at 1 minute at 72 inches. All other results met the defined acceptance criteria. Based on the data from this study, it can be concluded that the results generated using bare IV infusion lines did not meet the specification acceptance criteria for NPI-2489 impurities and that placement of an amber IV tubing sleeve on the infusion line provides sufficient protection from light for up to 22 minutes.

[0108] Example 4 In this comparative example, solid plinabulin was found to have no photosensitivity.Table 8 shows the stability of solid plinabulin in the photosensitivity test. [Table 8]

Claims

1. A vessel containing a liquid formulation comprising plinabulin, propylene glycol, and polyoxyl 15 hydroxystearate (PEG 15-hydroxystearate), A container configured to block at least 85% of UV / visible light between 290 nm and 450 nm.

2. 10. The container of claim 1, which is a disposable amber glass vial, said amber glass vial further comprising a rubber stopper and a flip-off cap.

3. 3. The container of claim 2, wherein the rubber stopper further comprises a plug portion, the plug portion comprising a FluroTec® coating.

4. 10. The container of claim 1, which is an IV bag.

5. 10. The container of claim 1, which is a transparent container covered with a light-tight sleeve.

6. 2. The container of claim 1, wherein the liquid formulation comprises plinabulin at a concentration of about 40 mg / 10 mL.

7. The container of claim 1, wherein the liquid contains a solvent that is 60:40 (weight:weight) propylene glycol and polyoxyl 15 hydroxystearate (PEG 15 hydroxystearate).

8. 10. The container of claim 1, wherein the solution contains less than 0.5% ether impurities.

9. 10. The container of claim 1, wherein the liquid formulation contains less than 0.5% alcohol impurities.

10. 10. The container of claim 1, wherein the liquid formulation contains less than 0.5% water.

11. 10. The container of claim 1, wherein the liquid formulation contains less than 2.0% total impurities.

12. A container as described in claim 1 for use in administering plinabulin to a subject in need thereof, comprising: A container, wherein said use comprises providing plinabulin in said container and administering plinabulin to a subject in need thereof via light-tight IV tubing.

13. The container of claim 12, wherein providing the plinabulin comprises injecting the plinabulin into a non-light-shielding IV bag and then placing a light-shielding sleeve over the non-light-shielding IV bag.

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