Formulations of docetaxel

Abstract

To provide an infusible and stable pharmaceutical composition comprising docetaxel or a pharmaceutically acceptable salt thereof.SOLUTION: A pharmaceutical formulation of docetaxel or a pharmaceutically acceptable salt thereof comprising two compositions that are mixed prior to being infused or administered to a patient, the formulation comprising: (a) a first liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and ethanol; and (b) a second aqueous composition comprising human serum albumin and a parenterally acceptable vehicle, wherein the pharmaceutical formulation does not contain Polysorbate 80.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 62 / 970,055, filed February 4, 2020, U.S. Patent Application No. 62 / 984,465, filed March 3, 2020, and U.S. Patent Application Serial No. 63 / 142,811, filed January 28, 2021, the entire contents of each of which are incorporated herein by reference.

[0002] This document relates to formulations for treating proliferative diseases, more particularly to formulations comprising docetaxel or a pharmaceutically acceptable salt thereof, and human serum albumin, and more particularly to formulations comprising docetaxel or a pharmaceutically acceptable salt thereof, human serum albumin, and ethanol. [Background technology]

[0003] Many drugs for parenteral use are water-insoluble and therefore formulated with solubilizers, surfactants, solvents, and / or emulsifiers that are irritating, allergenic, or toxic when administered to patients. See, e.g., Briggs et al., Anesthesis 37, 1099 (1982), and Waugh et al., Am. J. Hosp. Pharmacists 48, 1520 (1991). Furthermore, many of these drugs, especially those administered intravenously, can cause undesirable side effects, such as venous irritation, phlebitis, burning and pain upon injection, venous thrombosis, extravasation, and other administration-related side effects. Alternatively, free drug present in the formulation often causes pain and irritation upon administration.

[0004] Taxanes play an important role in the treatment of various solid tumors. As a second-generation semisynthetic taxane derivative, docetaxel is approximately twice as potent as paclitaxel in inhibiting microtubule depolymerization and possesses a unique ability to alter a specific class of microtubules, unlike most spindle poisons currently used in the clinic. However, docetaxel has very low water solubility. Clinical intravenous administration of commercially available docetaxel (Taxotere®) is formulated as a highly concentrated solution containing 40 mg of docetaxel and 1040 mg of polysorbate 80 per mL. This concentrated solution must be carefully diluted with a solvent containing 13% ethanol in saline prior to administration, and due to its limited stability, it must be used within 4 hours. These attributes limit the administration of docetaxel. Furthermore, docetaxel administration has been reported to be associated with unpredictable (acute) hypersensitivity reactions and cumulative fluid retention. See, e.g., Trudeau ME et al., J Clin Oncol 1996;14:422-8, Piccart MJ et al., J Natl Cancer Inst 1995;87:676-81, Bruno R et al., J Clin Oncol 1998;16:187-96. These side effects are due, in part, to the presence of polysorbate 80.

[0005] US2005 / 0282734 describes a complex of paclitaxel and albumin. The formulations described herein require an acidic pH for successful implementation. WO2014 / 121033 describes a complex of camptothecin and albumin. US2012 / 0076862 describes nanoparticles of taxanes and albumin. US2010 / 0076008 describes paclitaxel non-covalently bound to human serum albumin. WO2016 / 187147 describes complexes and compositions of docetaxel and human serum albumin. WO2018 / 081520 describes neutral pH compositions of docetaxel and human serum albumin. WO2018 / 204386 describes formulations and compositions of docetaxel and human serum albumin. WO2019 / 200084 describes formulations and compositions of docetaxel, human serum albumin, and amino acids.

[0006] There is a further need in the art for docetaxel formulations that have a better safety profile and are more convenient for clinical use. The compositions and methods described in this application help to meet this need. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent Publication No. 2005 / 0282734 [Patent Document 2] International Publication No. 2014 / 121033 [Patent Document 3] U.S. Patent Publication No. 2012 / 0076862 [Patent Document 4] U.S. Patent Publication No. 2010 / 0076008 [Patent Document 5] International Publication No. 2016 / 187147 [Patent Document 6] International Publication No. 2018 / 081520 [Patent Document 7] International Publication No. 2018 / 204386 [Patent Document 8] International Publication No. 2019 / 200084 [Non-patent literature]

[0008] [Non-Patent Document 1] Briggs et al., Anesthesis 37, 1099 (1982) [Non-patent document 2] Waugh et al., Am. J. Hosp. Pharmacists, 48, 1520 (1991) [Non-patent document 3] Trudeau ME et al., J Clin Oncol1996;14:422-8, Piccart [Non-patent document 4] MJ et al., J Natl Cancer Inst1995;87:676-81 [Non-Patent Document 5] Bruno R et al., J Clin Oncol1998;16:187-96 Summary of the Invention [Problem to be solved by the invention]

[0009] The currently marketed formulations of Taxotere contain either a single-vial or a double-vial formulation (injectable and diluent). The single-vial formulation contains a solution of docetaxel in polysorbate 80 and ethanol. The double-vial formulation contains a solvent vial containing an aqueous solution of docetaxel in polysorbate 80 and ethanol.

[0010] The two-vial formulation requires two dilutions before administration to the patient. In the two-vial formulation, the drug vial must be reconstituted with the solvent vial before use to ensure that the polysorbate 80 is properly reconstituted without significant foaming. The reconstituted solution is further diluted by injecting the appropriate amount of solution into an infusion bag. The one-vial formulation contains a drug solution in a single vial of known concentration. Before use, the drug solution is removed from the vial and injected into an infusion bag. The vial does not need to be reconstituted and homogenized before use. Therefore, with the one-vial formulation, there is no risk of molding, making it more convenient to use.

[0011] However, both the currently marketed two-vial and one-vial formulations of Taxotere contain polysorbate 80, which can cause severe hypersensitivity reactions in some patients. It would be highly desirable to develop an alternative docetaxel formulation that is polysorbate 80-free and convenient for use in the clinic. [Means for solving the problem]

[0012] Applicant has surprisingly discovered that the use of polysorbate 80 in the docetaxel formulations of the present disclosure is not required by adding a solution of human serum albumin to an infusion bag or bottle containing a parenterally acceptable vehicle (e.g., normal saline, dextrose solution, etc.) prior to infusion of the drug solution into the infusion bag, thereby allowing for convenient clinical use similar to that used in the currently commercially available single-vial formulation of Taxotere. [Brief explanation of the drawings]

[0013] [Figure 1A] 1 is a line graph showing DLS test results for docetaxel infusion solutions. [Figure 1B] 1 is a line graph showing the DLS test results of albumin saline solution. DETAILED DESCRIPTION OF THE INVENTION

[0014]

[0010] Provided herein is a pharmaceutical formulation of docetaxel or a pharmaceutically acceptable salt thereof, the pharmaceutical formulation comprising two compositions mixed prior to injection or administration to a patient, the two compositions comprising (a) a first liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and ethanol, and (b) a second aqueous composition comprising human serum albumin and a parenterally acceptable vehicle, wherein the pharmaceutical formulation does not contain polysorbate 80. In some embodiments, the two compositions are mixed less than 24 hours before injection or administration to a patient. In some embodiments, the mixing of the two compositions occurs within an infusion bag or bottle. In some embodiments, the two compositions are mixed less than 8 hours before injection or administration to a patient. In some embodiments, the two compositions are mixed less than 4 hours before injection or administration to a patient. In some embodiments, the two compositions are mixed less than 1 hour before injection or administration to a patient. In some embodiments, the mixing occurs within an infusion bag or bottle. In some embodiments, the second aqueous composition is contained within an infusion bag or bottle. In some embodiments, the first liquid composition is injected into an infusion bag or bottle containing the second aqueous composition.

[0015] In some embodiments, the pharmaceutical formulation does not include a lipid (e.g., soybean oil). In some embodiments, the first liquid composition does not include a lipid (e.g., soybean oil). In some embodiments, the lipid is soybean oil.

[0016] In some embodiments, the pharmaceutical formulation does not contain a surfactant. In some embodiments, the first liquid composition does not contain a surfactant. In some embodiments, the second aqueous composition does not contain a surfactant.

[0017] In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and another organic solvent (e.g., propylene glycol, polyethylene glycol 300, etc.). In some embodiments, the first liquid composition comprises docetaxel, ethanol, and propylene glycol. In some embodiments, the first liquid composition comprises docetaxel, ethanol, and polyethylene glycol 300. In some embodiments, the first liquid composition further comprises an acid. In some embodiments, the first liquid composition comprises docetaxel, ethanol, and an organic acid. The most preferred acid for use in accordance with the present invention is citric acid. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and citric acid. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, propylene glycol, and citric acid. In some embodiments, the first liquid composition is an ethanol solution containing docetaxel or a pharmaceutically acceptable salt thereof. In some embodiments, the first liquid composition is an ethanol solution containing docetaxel or a pharmaceutically acceptable salt thereof and citric acid. In some embodiments, the first liquid composition is an ethanol / propylene glycol solution containing docetaxel or a pharmaceutically acceptable salt thereof and citric acid. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is from about 5000:1 to about 5:1.In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5:1 to about 20:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5:1, about 10:1, about 15:1, or about 20:1. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.005 mg / ml to about 10 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.01 mg / ml to about 2 mg / ml.In some embodiments, the concentration of citric acid in the first liquid composition is about 0.01 mg / ml to about 1 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.02 mg / ml to about 0.5 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.02 mg / ml to about 0.2 mg / ml.

[0018] In some embodiments, the first liquid composition comprises a solvent containing docetaxel or a pharmaceutically acceptable salt thereof and ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof is dissolved in the solvent. In some embodiments, the first liquid composition comprises a solvent containing docetaxel or a pharmaceutically acceptable salt thereof, an acid, and ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof and the acid are dissolved in the solvent. In some embodiments, the first liquid composition comprises a solvent containing docetaxel or a pharmaceutically acceptable salt thereof, an organic acid, and ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof and the organic acid are dissolved in the solvent. In some embodiments, the first liquid composition comprises a solvent containing docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof and citric acid are dissolved in the solvent. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, and ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof is dissolved in ethanol. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof, and citric acid are dissolved in ethanol. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, and absolute ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof is dissolved in absolute ethanol. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and absolute ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof, and citric acid are dissolved in absolute ethanol.

[0019] In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof in alcohol (e.g., ethanol). In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof and citric acid in alcohol (e.g., ethanol). In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof in ethanol and propylene glycol. In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof and citric acid in ethanol and propylene glycol. In some embodiments, the concentration of docetaxel in the alcohol (e.g., ethanol and / or propylene glycol) is about 10 mg / ml to about 30 mg / ml. In some embodiments, the concentration of docetaxel in the alcohol (e.g., ethanol and / or propylene glycol) is about 10 mg / ml, about 20 mg / ml, or about 30 mg / ml.

[0020] In some embodiments, the second aqueous composition is prepared by adding a human serum albumin solution to a parenterally acceptable vehicle. In some embodiments, the second aqueous composition is prepared by adding the human serum albumin solution to an infusion bag or bottle containing a parenterally acceptable vehicle. In some embodiments, the second aqueous composition is prepared by adding the human serum albumin solution to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding the human serum albumin solution to an infusion bag or bottle containing normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a solution of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a solution of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 20% solution (w / v) of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 25% solution (w / v) of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 5% solution (w / v) of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a solution of human serum albumin for injection to an infusion bag or bottle containing normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a solution of human serum albumin for injection to an infusion bag or bottle containing normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 20% solution (w / v) of human serum albumin for injection to an infusion bag or bottle containing normal saline or dextrose solution.In some embodiments, the second aqueous composition is prepared by adding a 25% solution (w / v) of human serum albumin for injection to an infusion bag or bottle containing normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 5% solution (w / v) of human serum albumin for injection to an infusion bag or bottle containing normal saline or dextrose solution. In some embodiments, the concentration of human serum albumin in the second aqueous composition is about 0.1% to about 20% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is about 0.5% to about 10% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is 0.5% to 5% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is 1% to 3% (w / v). In some embodiments, the second aqueous composition comprises about 1 g to about 50 g of human serum albumin, hi some embodiments, the second aqueous composition comprises about 2 g to about 20 g of human serum albumin.

[0021] Also provided herein is a clear parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof, comprising human serum albumin and said docetaxel or a pharmaceutically acceptable salt thereof, but free of precipitate, wherein the concentration of docetaxel in a parenterally acceptable vehicle is from about 0.05 mg / ml to about 1 mg / ml, wherein said parenteral infusion solution is obtained by injecting a first liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and ethanol into an infusion bag or bottle containing a second aqueous composition comprising human serum albumin in a parenterally acceptable vehicle, wherein no mixing or stirring is required during the injection process, and said docetaxel infusion solution does not contain polysorbate 80. In some embodiments, the parenterally acceptable vehicle is normal saline or dextrose solution.

[0022] In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof does not contain a lipid (e.g., soybean oil). In some embodiments, the first liquid composition does not contain a lipid (e.g., soybean oil). In some embodiments, the lipid is soybean oil.

[0023] In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof does not contain a surfactant. In some embodiments, the first liquid composition does not contain a surfactant. In some embodiments, the second aqueous composition does not contain a surfactant.

[0024] In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is prepared less than 24 hours before injection or administration to a patient. In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is prepared less than 8 hours before injection or administration to a patient. In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is prepared less than 6 hours before injection or administration to a patient. In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is prepared less than 4 hours before injection or administration to a patient. In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is prepared less than 1 hour before injection or administration to a patient.

[0025] In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the parenteral injection composition is about 0.1 mg / ml to about 0.8 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the parenteral injection composition is about 0.1 mg / ml to about 0.5 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the parenteral injection composition is about 0.2 mg / ml to about 0.4 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the parenteral injection composition is about 0.25 mg / ml to about 0.35 mg / ml. In some embodiments, the weight ratio of human serum albumin to docetaxel or a pharmaceutically acceptable salt thereof is about 20:1 to about 200:1. In some embodiments, the weight ratio of human serum albumin to docetaxel or a pharmaceutically acceptable salt thereof is about 20:1, about 30:1, about 40:1, about 50:1, about 80:1, about 90:1, about 95:1, about 100:1, or about 150:1.

[0026] In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and another organic solvent (e.g., an alcohol such as propylene glycol or polyethylene glycol 300). In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and propylene glycol. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and polyethylene glycol 300. In some embodiments, the first liquid composition further comprises an acid. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and an organic acid. The most preferred acid for use in accordance with the present invention is citric acid. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and citric acid. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, propylene glycol, and citric acid. In some embodiments, the first liquid composition is an ethanol solution containing docetaxel or a pharmaceutically acceptable salt thereof. In some embodiments, the first liquid composition is an ethanol solution containing docetaxel or a pharmaceutically acceptable salt thereof and citric acid. In some embodiments, the first liquid composition is an ethanol / propylene glycol solution containing docetaxel and citric acid. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is from about 500:1 to about 1:1.In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5:1 to about 20:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5:1, about 10:1, about 15:1, or about 20:1.In some embodiments, the concentration of citric acid in the first liquid composition is from about 0.005 mg / ml to about 10 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is from about 0.01 mg / ml to about 2 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is from about 0.01 mg / ml to about 1 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is from about 0.02 mg / ml to about 0.5 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is from about 0.02 mg / ml to about 0.2 mg / ml.

[0027] In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof in alcohol (e.g., ethanol). In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof and citric acid in ethanol. In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof in ethanol and propylene glycol. In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof and citric acid in ethanol and propylene glycol.

[0028] In some embodiments, the second aqueous composition is prepared by adding a human serum albumin solution to a parenterally acceptable vehicle. In some embodiments, the second aqueous composition is prepared by adding a human serum albumin solution to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a solution of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 20% solution (w / v) of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 25% solution (w / v) of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 5% solution (w / v) of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the concentration of human serum albumin in the second aqueous composition is about 0.1% to about 20% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is about 0.5% to about 10% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is 0.5% to 5% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is 1% to 3% (w / v). In some embodiments, the second aqueous composition comprises about 1 g to about 50 g of human serum albumin. In some embodiments, the second aqueous composition comprises about 2 g to about 20 g of human serum albumin.

[0029] The injection of the first liquid composition into the infusion bag or bottle containing the second aqueous composition is rapid. In some embodiments, the injection time is 60 seconds or less. In some embodiments, the injection time is 30 seconds or less. In some embodiments, the injection time is 15 seconds or less. In some embodiments, the injection time is 10 seconds or less. In some embodiments, the injection time is 5 seconds or less.

[0030] No mixing or stirring is required during the process of injecting the first liquid composition into the infusion bag or bottle containing the second aqueous composition. After the injection of the first liquid composition into the infusion bag or bottle is complete, the first liquid composition and the second aqueous composition are thoroughly mixed (e.g., by gently inverting the bag containing the compositions by hand) to obtain a clear infusion solution free of precipitates. In some embodiments, the infusion bag or bottle containing the second aqueous composition is kept stationary during the injection process. In some embodiments, the first liquid composition is injected below the liquid surface of the second aqueous composition during the injection process. In some embodiments, after the injection is complete, the infusion bag or bottle is gently inverted repeatedly to thoroughly mix the first liquid composition and the second aqueous composition. In some embodiments, after the injection is complete, the infusion bag or bottle is gently inverted until a clear solution free of precipitates is obtained. In some embodiments, after the injection is complete, the infusion bag or bottle is gently inverted for about 5 seconds to about 10 minutes. In some embodiments, after the infusion is complete, the infusion bag or bottle is gently inverted for about 10 seconds to about 5 minutes. In some embodiments, after the infusion is complete, the infusion bag or bottle is gently inverted for about 0.5 minutes to about 3 minutes. In some embodiments, after the infusion is complete, the first liquid composition and the second aqueous composition are thoroughly mixed until a clear infusion solution without sediment is obtained.

[0031] Following injection of the first liquid composition into an infusion bag or bottle containing the second aqueous composition, after the first liquid composition and the second aqueous composition are thoroughly mixed, a precipitate-free, clear infusion solution is obtained comprising human serum albumin, docetaxel or a pharmaceutically acceptable salt thereof, and ethanol in a parenterally acceptable vehicle. In some embodiments, the clear infusion solution further comprises citric acid. In some embodiments, the parenterally acceptable vehicle is normal saline or dextrose solution. In some embodiments, the clear infusion solution remains precipitate-free for at least 1 hour. In some embodiments, the clear infusion solution remains precipitate-free for at least 2 hours. In some embodiments, the clear infusion solution remains precipitate-free for at least 3 hours. In some embodiments, the clear infusion solution remains precipitate-free for at least 4 hours. In some embodiments, the clear infusion solution remains precipitate-free for at least 6 hours. In some embodiments, the clear infusion solution remains precipitate-free for at least 8 hours. In some embodiments, the clear injection solution remains clear and precipitate-free for at least 1 hour, 2 hours, 3 hours, 4 hours, or 6 hours when the clear solution is kept at about 20-25° C. In some embodiments, the clear solution remains clear and precipitate-free for at least 2 hours, 4 hours, 6 hours, 8 hours, or 12 hours when the clear solution is kept at about 2-8° C.

[0032] Also provided herein is a kit for preparing a parenteral infusion solution, comprising a first container containing a composition comprising docetaxel or a pharmaceutically acceptable salt thereof and a second container containing a composition comprising human serum albumin. In some embodiments, the kit comprises a first container containing a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and a second container containing a liquid composition comprising human serum albumin.

[0033] In some embodiments, the first container does not contain a lipid (e.g., soybean oil). In some embodiments, the lipid is soybean oil. In some embodiments, the first container does not contain a surfactant. In some embodiments, the second container does not contain a surfactant.

[0034] In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, an acid or a pharmaceutically acceptable salt thereof, and ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, an organic acid, and ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and another organic solvent (e.g., an alcohol such as propylene glycol, polyethylene glycol 300, etc.). In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and propylene glycol. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and polyethylene glycol 300. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and citric acid. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, citric acid, ethanol, and propylene glycol. In some embodiments, the first container contains an ethanol solution comprising docetaxel or a pharmaceutically acceptable salt thereof. In some embodiments, the first container contains an ethanol solution comprising docetaxel or a pharmaceutically acceptable salt thereof and citric acid. In some embodiments, the first container contains an ethanol / propylene glycol solution comprising docetaxel or a pharmaceutically acceptable salt thereof and citric acid. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is from about 5000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is from about 2000:1 to about 1:1.In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 1000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 500:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 5000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 2000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 1000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 500:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 5000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 2000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 1000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 500:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 2000:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 1000:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 500:1 to about 100:1. In some embodiments, the concentration of citric acid in the first container is about 0.005 mg / ml to about 10 mg / ml.In some embodiments, the concentration of citric acid in the first container is about 0.01 mg / ml to about 2 mg / ml. In some embodiments, the concentration of citric acid in the first container is about 0.01 mg / ml to about 1 mg / ml. In some embodiments, the concentration of citric acid in the first container is about 0.02 mg / ml to about 0.5 mg / ml. In some embodiments, the concentration of citric acid in the first container is about 0.02 mg / ml to about 0.2 mg / ml.

[0035] In some embodiments, the amount of docetaxel contained in the first container is about 10 mg to about 300 mg of docetaxel. In some embodiments, the amount of docetaxel contained in the first container is about 20 mg to about 200 mg of docetaxel. In some embodiments, the amount of docetaxel contained in the first container is about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, or about 160 mg of docetaxel. In some embodiments, the amount of docetaxel contained in the first container is about 80 mg of docetaxel. In some embodiments, the amount of docetaxel contained in the first container is about 100 mg of docetaxel. In some embodiments, the amount of ethanol contained in the first container is about 0.5 ml to about 50 ml of ethanol. In some embodiments, the amount of ethanol contained in the first container is about 1 ml to about 20 ml of ethanol. In some embodiments, the amount of ethanol contained in the first container is about 1 ml to about 10 ml of ethanol. In some embodiments, the amount of ethanol contained in the first container is about 3 ml to about 6 ml of ethanol. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first container is about 1 mg / ml to about 200 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first container is about 5 mg / ml to about 100 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first container is about 10 mg / ml to about 50 mg / ml. In some embodiments, the concentration of docetaxel in the first container is about 20 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the alcohol in the first container is about 10 mg / ml to about 30 mg / ml. In some embodiments, the concentration of docetaxel in the alcohol in the first container is about 10 mg / ml, about 20 mg / ml, or about 30 mg / ml.

[0036] In some embodiments, the first container contains a solid composition comprising docetaxel or a pharmaceutically acceptable salt thereof. In some embodiments, the first container contains a solid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and an organic acid. In some embodiments, the first container contains a solid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and citric acid.

[0037] In some embodiments, the second container contains a liquid composition comprising human serum albumin. In some embodiments, the second container contains a human serum albumin solution. In some embodiments, the second container contains a human serum albumin solution having a concentration of human serum albumin in the solution of about 1% to about 25% (w / v). In some embodiments, the second container contains a human serum albumin solution having a concentration of human serum albumin in the solution of about 5% to about 25% (w / v). In some embodiments, the second container contains a solution of human serum albumin for injection. In some embodiments, the second container contains a 20% solution (w / v) of human serum albumin for injection. In some embodiments, the second container contains a 25% solution (w / v) of human serum albumin for injection. In some embodiments, the second container contains a 5% solution (w / v) of human serum albumin for injection. In some embodiments, the second container contains a liquid composition comprising about 1 g to about 50 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 1 g to about 30 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 1 g to about 20 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 2 g, about 4 g, about 6 g, about 8 g, about 10 g, about 12 g, or about 16 g of human serum albumin.

[0038] In some embodiments, the kit further comprises instructions for adding the composition comprising docetaxel or a pharmaceutically acceptable salt thereof to the composition comprising human serum albumin.

[0039] Also provided herein is a parenteral pharmaceutical formulation comprising two compositions that are mixed prior to injection or administration to a patient, the two compositions comprising: (a) a first liquid composition comprising a substantially water-insoluble pharmaceutically active agent, or a pharmaceutically acceptable salt thereof; and (b) a second aqueous composition comprising human serum albumin and a parenterally acceptable vehicle, wherein the substantially water-insoluble pharmaceutically active agent, or a pharmaceutically acceptable salt thereof, is the API (active pharmaceutical ingredient) of said parenteral pharmaceutical formulation.

[0040] In some embodiments, the formulation does not include a lipid (e.g., soybean oil). In some embodiments, the first liquid composition does not include a lipid (e.g., soybean oil). In some embodiments, the lipid is soybean oil.

[0041] In some embodiments, the pharmaceutical formulation does not contain a surfactant. In some embodiments, the first liquid composition does not contain a surfactant. In some embodiments, the second aqueous composition does not contain a surfactant.

[0042] Detailed Description Provided herein are pharmaceutical formulations of docetaxel or a pharmaceutically acceptable salt thereof, comprising compositions mixed prior to injection or administration to a patient, the compositions comprising: (a) a first liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and an alcohol (e.g., ethanol); and (b) a second aqueous composition comprising human serum albumin and a parenterally acceptable vehicle, wherein the pharmaceutical formulation does not comprise polysorbate 80. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and an alcohol (e.g., ethanol). In some embodiments, the two compositions are mixed less than 24 hours before injection or administration to a patient. In some embodiments, the mixing of the two compositions occurs within an infusion bag or bottle. In some embodiments, the two compositions are mixed less than 12 hours before injection or administration to a patient. In some embodiments, the two compositions are mixed less than 8 hours before injection or administration to a patient. In some embodiments, the two compositions are mixed less than 4 hours before injection or administration to a patient. In some embodiments, the two compositions are mixed less than one hour before being injected or administered to a patient. In some embodiments, the mixing occurs within an infusion bag or bottle. In some embodiments, the second aqueous composition is contained in an infusion bag or bottle. In some embodiments, the first liquid composition is injected into an infusion bag or bottle containing the second aqueous composition. In some embodiments, both the first liquid composition and the second aqueous composition are sterile solutions. In some embodiments, the first liquid composition is a sterile solution. In some embodiments, the second aqueous solution is a sterile solution. In some embodiments, the mixing of the first liquid composition and the second aqueous composition occurs in a hospital or clinic before being injected or administered to a patient.

[0043] In some embodiments, the pharmaceutical formulation does not include a lipid (e.g., soybean oil). In some embodiments, the first liquid composition does not include a lipid (e.g., soybean oil). In some embodiments, the lipid is soybean oil.

[0044] In some embodiments, the pharmaceutical formulation does not contain a surfactant. In some embodiments, the first liquid composition does not contain a surfactant. In some embodiments, the second aqueous composition does not contain a surfactant.

[0045] In some embodiments, mixing the first liquid composition with the second aqueous composition involves two steps. In the first step, the first liquid composition is injected into an infusion bag or bottle containing the second aqueous composition. During the injection process, the infusion bag or bottle is kept stationary, and no mixing or stirring is required. In the second step, immediately after injection, the infusion bag or bottle is inverted until a clear infusion solution without sediment is obtained.

[0046] During the process of injecting the first liquid composition into an infusion bag or bottle containing the second aqueous composition, the infusion bag or bottle is kept stationary, eliminating the need for mixing or agitation during the injection process. Surprisingly, it has been found that simply inverting the infusion bag or bottle repeatedly (e.g., 5 to 30 times) after injection results in a clear infusion solution free of sediment.

[0047] In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the formulation after mixing the first liquid composition with the second aqueous composition is about 0.05 mg / ml to about 1 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the formulation after mixing the first liquid composition with the second aqueous composition is about 0.1 mg / ml to about 0.5 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the formulation after mixing the first liquid composition with the second aqueous composition is about 0.15 mg / ml to about 0.4 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the formulation after mixing the first liquid composition with the second aqueous composition is about 0.2 mg / ml to about 0.3 mg / ml.

[0048] In the present disclosure, the formulation obtained after mixing the first liquid composition and the second aqueous composition is not a nanoparticle suspension but a clear infusion solution. In some embodiments, at least 30% of the docetaxel in the formulation (clear infusion solution) is free (unbound) docetaxel. In some embodiments, at least 40% of the docetaxel in the formulation (clear infusion solution) is free (unbound) docetaxel. In some embodiments, at least 50% of the docetaxel in the formulation (clear infusion solution) is free (unbound) docetaxel. In some embodiments, at least 60% of the docetaxel in the formulation (clear infusion solution) is free (unbound) docetaxel. In some embodiments, at least 70% of the docetaxel in the formulation (clear infusion solution) is free (unbound) docetaxel. Free (unbound) docetaxel refers to the fraction of docetaxel in the infusion composition (solution) that is not bound to human serum albumin. The concentration of free (unbound) docetaxel in the parenteral infusion composition (solution) is measured by ultrafiltration through a 30 kDa membrane. The experimental details of the free (unbound) docetaxel measurement are described in the Examples section.

[0049] In some embodiments, a pharmaceutical formulation of docetaxel or a pharmaceutically acceptable salt thereof, having two compositions to be mixed before injection or administration to a patient, comprises: (a) a first liquid composition comprising about 20 mg to about 200 mg of docetaxel or a pharmaceutically acceptable salt thereof dissolved in alcohol (e.g., ethanol), and (b) a second aqueous composition comprising about 0.5 g to about 20 g of human serum albumin in a parenterally acceptable vehicle. In some embodiments, a pharmaceutical formulation of docetaxel or a pharmaceutically acceptable salt thereof, having two compositions to be mixed before injection or administration to a patient, comprises: (a) a first liquid composition comprising about 20 mg to about 200 mg of docetaxel or a pharmaceutically acceptable salt thereof dissolved in alcohol (e.g., ethanol), and citric acid, and (b) a second aqueous composition comprising about 0.5 g to about 20 g of human serum albumin in a parenterally acceptable vehicle. In some embodiments, a pharmaceutical formulation of docetaxel or a pharmaceutically acceptable salt thereof, having two compositions to be mixed before injection or administration to a patient, comprises: (a) a first liquid composition comprising about 20 mg to about 200 mg of docetaxel or a pharmaceutically acceptable salt thereof dissolved in alcohol (e.g., ethanol), and (b) a second aqueous composition comprising about 1 g to about 10 g of human serum albumin in a parenterally acceptable vehicle. In some embodiments, a pharmaceutical formulation of docetaxel or a pharmaceutically acceptable salt thereof, having two compositions to be mixed before injection or administration to a patient, comprises: (a) a first liquid composition comprising about 20 mg to about 200 mg of docetaxel or a pharmaceutically acceptable salt thereof dissolved in alcohol (e.g., ethanol) and citric acid, and (b) a second aqueous composition comprising about 1 g to about 10 g of human serum albumin in a parenterally acceptable vehicle. In some embodiments, the pharmaceutical formulation does not contain lipids (e.g., soybean oil). In some embodiments, the pharmaceutical formulation does not include a surfactant.

[0050] In some embodiments, the ethanol in the first liquid composition is absolute ethanol. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and another organic solvent (e.g., an alcohol such as propylene glycol or polyethylene glycol 300). In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and propylene glycol. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and polyethylene glycol 300. In some embodiments, the first liquid composition further comprises an acid. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and an organic acid. Preferably, the organic acid is selected from the group consisting of citric acid, acetic acid, formic acid, ascorbic acid, benzoic acid, tartaric acid, lactic acid, maleic acid, and succinic acid, or pharmaceutically acceptable salts thereof. The organic acid excludes aspartic acid and glutamic acid. The most preferred acid for use in accordance with the present invention is citric acid. In some embodiments, the citric acid is anhydrous citric acid. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and citric acid. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, propylene glycol, and citric acid. In some embodiments, the first liquid composition is an ethanol solution comprising docetaxel or a pharmaceutically acceptable salt thereof. In some embodiments, the first liquid composition is an ethanol solution comprising docetaxel or a pharmaceutically acceptable salt thereof, and citric acid.

[0051] In some embodiments, the first liquid composition is an ethanol / propylene glycol solution containing docetaxel or a pharmaceutically acceptable salt thereof and citric acid. In some embodiments, the first liquid composition is an absolute ethanol solution containing docetaxel or a pharmaceutically acceptable salt thereof and citric acid. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 10:1.In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 100:1. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.005 mg / ml to about 10 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.01 mg / ml to about 2 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.01 mg / ml to about 1 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.02 mg / ml to about 0.5 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.02 mg / ml to about 0.2 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first liquid composition is about 1 mg / ml to about 200 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first liquid composition is about 5 mg / ml to about 100 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first liquid composition is about 10 mg / ml to about 50 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first liquid composition is about 20 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first liquid composition is about 10 mg / ml to about 30 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first liquid composition is about 10 mg / ml, about 20 mg / ml, or about 30 mg / ml.

[0052] In some embodiments, the first liquid composition comprises a solvent containing docetaxel or a pharmaceutically acceptable salt thereof and ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof is dissolved in the solvent. In some embodiments, the first liquid composition comprises a solvent containing docetaxel or a pharmaceutically acceptable salt thereof, an acid, and ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof and the acid are dissolved in the solvent. In some embodiments, the first liquid composition comprises a solvent containing docetaxel or a pharmaceutically acceptable salt thereof, an organic acid, and ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof and the organic acid are dissolved in the solvent. In some embodiments, the first liquid composition comprises a solvent containing docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof and citric acid are dissolved in the solvent. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, and ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof is dissolved in ethanol. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof, and citric acid are dissolved in ethanol. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, and absolute ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof is dissolved in absolute ethanol. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and absolute ethanol, wherein the docetaxel or a pharmaceutically acceptable salt thereof, and citric acid are dissolved in absolute ethanol. In some embodiments, the first liquid composition does not contain a lipid (e.g., soybean oil) or a surfactant.

[0053] In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof in ethanol. In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof and citric acid in ethanol. In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof in ethanol and propylene glycol. In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof and citric acid in ethanol and propylene glycol.

[0054] In some embodiments, the second aqueous composition is prepared by adding a human serum albumin solution to a parenterally acceptable vehicle. In some embodiments, the second aqueous composition is prepared by adding the human serum albumin solution to an infusion bag or bottle containing a parenterally acceptable vehicle. In some embodiments, the second aqueous composition is prepared by adding the human serum albumin solution to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding the human serum albumin solution to an infusion bag or bottle containing normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a solution of human serum albumin for injection to a parenterally acceptable vehicle. In some embodiments, the second aqueous composition is prepared by adding a solution of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 20% solution (w / v) of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 25% solution (w / v) of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 5% solution (w / v) of human serum albumin for injection to normal saline or dextrose solution.

[0055] In some embodiments, the second aqueous composition is prepared by adding a solution of human serum albumin for injection to an infusion bag or bottle containing normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a solution of human serum albumin for injection to an infusion bag or bottle containing normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 20% solution (w / v) of human serum albumin for injection to an infusion bag or bottle containing normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 25% solution (w / v) of human serum albumin for injection to an infusion bag or bottle containing normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 5% solution (w / v) of human serum albumin for injection to an infusion bag or bottle containing normal saline or dextrose solution. In some embodiments, the concentration of human serum albumin in the second aqueous composition is about 0.1% to about 20% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is about 0.5% to about 15% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is about 0.5% to about 10% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is 0.5% to 5% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is about 1% to about 10% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is 1% to 3% (w / v). In some embodiments, the second aqueous composition comprises about 1 g to about 50 g of human serum albumin. In some embodiments, the second aqueous composition comprises about 1 g to about 20 g of human serum albumin. In some embodiments, the second aqueous composition comprises about 2 g to about 10 g of human serum albumin. In some embodiments, the volume of the second aqueous composition is about 100 ml to about 1 L.In some embodiments, the volume of the second aqueous composition is from about 250 ml to about 1 L. In some embodiments, the volume of the second aqueous composition is from about 250 ml to about 500 ml.

[0056] As used herein, the term "docetaxel" refers to the compound having the CAS number 114977-28-5 and the following chemical structure, or a pharmaceutically acceptable salt thereof. [ka]

[0057] Docetaxel is a white to almost white powder that is highly lipophilic and practically insoluble in water.

[0058] Furthermore, docetaxel is a microtubule inhibitor with applications in breast cancer, non-small cell lung cancer, hormone-refractory prostate cancer, gastric adenocarcinoma, and squamous cell carcinoma of the head and neck.

[0059] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. In some embodiments, pharmaceutically acceptable salts may be preferred over the respective free bases or acids, as such salts may provide greater stability or solubility to the molecule, thereby facilitating formulation into dosage forms. Basic compounds can generally form pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids.Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, and the like. Acid salts, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxybenzoate p-Toluenesulfonate, Benzene sulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate (tosylate), Naphthalene-2-sulfonate, Ethanedisulfonate, Hydrogen disulfide, Bitartrate, Gluconate, Glucuronate, Parabromophenylsulfonate, Carbonate, Pyrosulfate, Sulfite, Bisulfite, Monohydrogen phosphate, Dihydrogen phosphate, Metaphosphate, Pyrophosphate, Chloride, Bromide Suitable bases include pharmaceutically acceptable inorganic bases and pharmaceutically acceptable organic bases.Representative pharmaceutically acceptable base addition salts include hydroxides of alkali metals such as sodium, potassium, lithium, and the like; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; organic amines such as ammonia, unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine, tributylamine, pyridine; N-methylamine, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamines such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

[0060] In some embodiments, docetaxel or a pharmaceutically acceptable salt thereof can be docetaxel having 1, 2, or 3 equivalents of water solvation. In some embodiments, docetaxel or a pharmaceutically acceptable salt thereof can be docetaxel having 3 equivalents of water solvation. In some embodiments, docetaxel is docetaxel trihydrate or a pharmaceutically acceptable salt thereof. In some embodiments, docetaxel is docetaxel monohydrate or a pharmaceutically acceptable salt thereof. In some embodiments, docetaxel is anhydrous docetaxel or a pharmaceutically acceptable salt thereof. In some embodiments, docetaxel can be docetaxel having 1 equivalent of acetone solvation. In some embodiments, docetaxel can be, for example, any one of the docetaxel solvates disclosed in WO2010091650 or US2012007167, which are incorporated herein by reference in their entireties, or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, docetaxel or its pharmaceutically acceptable salt is crystalline.In some embodiments, docetaxel or its pharmaceutically acceptable salt is any one of the crystalline forms disclosed in, for example, WO2012115402, US8410294, US20100197944, US20100099897, US8357811, US20100160653 or US20070142457, which are incorporated herein by reference in their entirety.

[0062] In some embodiments, docetaxel or a pharmaceutically acceptable salt thereof is amorphous. In some embodiments, docetaxel is, for example, any one of the amorphous forms disclosed in WO2008102374, which is incorporated herein by reference in its entirety, or a pharmaceutically acceptable salt thereof.

[0063] As used herein, the term "human serum albumin" refers to natural and recombinant human serum albumin. In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin.

[0064] Suitable human serum albumin solutions include, but are not limited to, commercially available solutions of human serum albumin for injection.Commercially available solutions of human serum albumin for injection contain pharmaceutically acceptable excipients such as sodium N-acetyltryptophan, sodium caprylate, sodium chloride, sodium bicarbonate, sodium hydroxide, or acetic acid, or their mixtures.In some embodiments, human serum albumin solutions can be prepared by diluting commercially available solutions of human serum albumin for injection with parenterally acceptable vehicles.

[0065] Alternatively, a human serum albumin solution can be prepared by mixing human serum albumin powder in water along with other pharmaceutically acceptable excipients available in commercial albumin products.

[0066] In some embodiments, the human serum albumin solution is a commercially available solution of human serum albumin USP for injection. In some embodiments, the human serum albumin solution is a commercially available solution of human serum albumin USP for injection. In some embodiments, the human serum albumin solution comprises a commercially available solution of human serum albumin USP for injection. In some embodiments, a commercially available solution of human serum albumin USP for injection is used as a source of human serum albumin solution. In some embodiments, the solution of human serum albumin for injection is a 5% solution (w / v) of human serum albumin USP. In some embodiments, the solution of human serum albumin for injection is a 20% solution (w / v) of human serum albumin USP. In some embodiments, the solution of human serum albumin for injection is a 25% solution (w / v) of human serum albumin USP. In some embodiments, the human serum albumin solution is an aqueous solution prepared by diluting a commercially available solution of human serum albumin for injection.

[0067] The term "parenteral" refers to a route selected from subcutaneous (SC), intravenous (IV), intramuscular (IM), internal (ID), intraperitoneal (IP), and the like.

[0068] Also provided herein is a clear parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof, comprising human serum albumin and said docetaxel or a pharmaceutically acceptable salt thereof, but free of precipitate, wherein the concentration of docetaxel in a parenterally acceptable vehicle is from about 0.05 mg / ml to about 1 mg / ml, wherein said parenteral injection solution is obtained by injecting a first liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and ethanol into an infusion bag or bottle containing a second aqueous composition comprising human serum albumin in a parenterally acceptable vehicle, wherein no mixing or stirring is required during the injection process, and said injection solution does not contain polysorbate 80. In some embodiments, the parenterally acceptable vehicle is normal saline or dextrose solution.

[0069] In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof does not contain a lipid (e.g., soybean oil). In some embodiments, the first liquid composition does not contain a lipid (e.g., soybean oil). In some embodiments, the lipid is soybean oil.

[0070] In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof does not contain a surfactant. In some embodiments, the first liquid composition does not contain a surfactant. In some embodiments, the second aqueous composition does not contain a surfactant.

[0071] In the present disclosure, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is a clear solution, not a nanoparticle suspension. When measured by dynamic light scattering (DLS), the parenteral injection composition (solution) has a substantially identical DLS profile compared to a related human serum albumin saline solution. Detailed DLS data is described in the Examples section. In some embodiments, at least 30% of the docetaxel in the parenteral injection composition (solution) is free (unbound) docetaxel. In some embodiments, at least 40% of the docetaxel in the parenteral injection composition (solution) is free (unbound) docetaxel. In some embodiments, at least 50% of the docetaxel in the parenteral injection composition (solution) is free (unbound) docetaxel. In some embodiments, at least 60% of the docetaxel in the parenteral injection composition (solution) is free (unbound) docetaxel. In some embodiments, at least 70% of the docetaxel in the parenteral injection composition (solution) is free (unbound) docetaxel. Free (unbound) docetaxel refers to the fraction of docetaxel in the parenteral injection composition (solution) that is not bound to human serum albumin. The concentration of free (unbound) docetaxel in the parenteral injection composition (solution) is measured by ultrafiltration using a 30 kDa membrane. Experimental details for measuring free (unbound) docetaxel are described in the Examples section.

[0072] In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 10% (v / v) or less. In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 5% (v / v) or less. In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 2% (v / v) or less. In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 1.75% (v / v) or less. In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 1.6% (v / v) or less. In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 1.5% (v / v) or less. In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 1.4% (v / v) or less. In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 30 ml or less. In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 20 ml or less. In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 15 ml or less. In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 10 ml or less. In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 8 ml or less. In some embodiments, the amount of ethanol in the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is 5 ml or less.

[0073] In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is prepared less than about 24 hours before being injected or administered to a patient. In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is prepared less than about 12 hours before being injected or administered to a patient. In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is prepared less than about 8 hours before being injected or administered to a patient. In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is prepared less than about 6 hours before being injected or administered to a patient. In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is prepared less than about 4 hours before being injected or administered to a patient. In some embodiments, the parenteral injection composition of docetaxel or a pharmaceutically acceptable salt thereof is prepared less than about 1 hour before being injected or administered to a patient.

[0074] In some embodiments, the pH value of the parenteral injection composition is from about 4 to about 9.5. In some embodiments, the pH value of the parenteral injection composition is from about 5 to about 9. In some embodiments, the pH value of the parenteral injection composition is from about 6 to about 8. In some embodiments, the pH value of the parenteral injection composition is from about 6.5 to about 7.5. In some embodiments, the pH value of the parenteral injection composition is from about 4 to about 9. In some embodiments, the pH value of the parenteral injection composition is from about 5 to about 8.5. In some embodiments, the pH value of the parenteral injection composition is from about 6 to about 7.5.

[0075] In some embodiments, 1 ml of the parenteral injection composition contains no more than 50 particles greater than 10 μm in size. In some embodiments, 1 ml of the parenteral injection composition contains no more than 100 particles greater than 10 μm in size. In some embodiments, 1 ml of the parenteral injection composition contains no more than 150 particles greater than 10 μm in size. In some embodiments, 1 ml of the parenteral injection composition contains no more than 200 particles greater than 10 μm in size.

[0076] In some embodiments, 1 ml of the parenteral injection composition contains no more than 5 particles greater than 25 μm in size. In some embodiments, 1 ml of the parenteral injection composition contains no more than 25 particles greater than 10 μm in size. In some embodiments, 1 ml of the parenteral injection composition contains no more than 5 particles greater than 15 μm in size. In some embodiments, 1 ml of the parenteral injection composition contains no more than 20 particles greater than 25 μm in size.

[0077] In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the parenteral injection composition is about 0.1 mg / ml to about 0.8 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the parenteral injection composition is about 0.1 mg / ml to about 0.5 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the parenteral injection composition is about 0.15 mg / ml to about 0.4 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the parenteral injection composition is about 0.2 mg / ml to about 0.35 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the parenteral injection composition is about 0.1 mg / ml to about 0.3 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the parenteral infusion composition is 0.2 mg / ml to about 0.3 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the parenteral infusion composition is about 0.25 mg / ml. In some embodiments, the weight ratio of human serum albumin to docetaxel or a pharmaceutically acceptable salt thereof is about 20:1 to about 200:1. In some embodiments, the weight ratio of human serum albumin to docetaxel or a pharmaceutically acceptable salt thereof is about 20:1 to about 100:1. In some embodiments, the weight ratio of human serum albumin to docetaxel or a pharmaceutically acceptable salt thereof is about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 100:1, or about 150:1. In some embodiments, the concentration of human serum albumin in the parenteral injection composition is about 0.1% to about 20% (w / v). In some embodiments, the concentration of human serum albumin in the parenteral injection composition is about 0.5% to about 20% (w / v). In some embodiments, the concentration of human serum albumin in the parenteral injection composition is about 0.5% to about 10% (w / v). In some embodiments, the concentration of human serum albumin in the parenteral injection composition is about 0.5% to about 5% (w / v).In some embodiments, the concentration of human serum albumin in the parenteral infusion composition is about 1% to about 10% (w / v). In some embodiments, the concentration of human serum albumin in the parenteral infusion composition is about 1% to about 5% (w / v). In some embodiments, the concentration of human serum albumin in the parenteral infusion composition is about 0.5% to about 3% (w / v). In some embodiments, the concentration of human serum albumin in the parenteral infusion composition is about 1% to about 3% (w / v).

[0078] In some embodiments, the ethanol in the first liquid composition is absolute ethanol. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and another organic solvent (e.g., an alcohol such as propylene glycol or polyethylene glycol 300). In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and propylene glycol. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and polyethylene glycol 300. In some embodiments, the first liquid composition further comprises an acid. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and an organic acid. The most preferred acid for use in accordance with the present invention is citric acid. In some embodiments, the citric acid is anhydrous citric acid. In some embodiments, the ethanol is absolute ethanol. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and citric acid. In some embodiments, the first liquid composition comprises docetaxel or a pharmaceutically acceptable salt thereof, ethanol, propylene glycol, and citric acid. In some embodiments, the first liquid composition is an ethanol solution comprising docetaxel or a pharmaceutically acceptable salt thereof. In some embodiments, the first liquid composition is an ethanol solution comprising docetaxel or a pharmaceutically acceptable salt thereof and citric acid. In some embodiments, the first liquid composition is an ethanol / propylene glycol solution comprising docetaxel or a pharmaceutically acceptable salt thereof and citric acid.

[0079] In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 2000:1 to about 100:1.In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 1000:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 500:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5:1 to about 20:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first liquid composition is about 5:1, about 10:1, about 15:1, or about 20:1. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.005 mg / ml to about 10 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.01 mg / ml to about 2 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.01 mg / ml to about 1 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.02 mg / ml to about 0.5 mg / ml. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.02 mg / ml to about 0.2 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first liquid composition is about 1 mg / ml to about 200 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first liquid composition is about 5 mg / ml to about 100 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first liquid composition is about 10 mg / ml to about 50 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first liquid composition is about 20 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first liquid composition is about 10 mg / ml to about 30 mg / ml.In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the first liquid composition is about 10 mg / ml, about 20 mg / ml, or about 30 mg / ml.

[0080] In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof in ethanol. In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof and citric acid in ethanol. In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof in ethanol and propylene glycol. In some embodiments, the first liquid composition is prepared by dissolving docetaxel or a pharmaceutically acceptable salt thereof and citric acid in ethanol and propylene glycol.

[0081] In some embodiments, the second aqueous composition is prepared by adding a human serum albumin solution to a parenterally acceptable vehicle. In some embodiments, the second aqueous composition is prepared by adding a human serum albumin solution to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a solution of human serum albumin for injection to a parenterally acceptable vehicle. In some embodiments, the second aqueous composition is prepared by adding a solution of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 20% solution (w / v) of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 25% solution (w / v) of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the second aqueous composition is prepared by adding a 5% solution (w / v) of human serum albumin for injection to normal saline or dextrose solution. In some embodiments, the concentration of human serum albumin in the second aqueous composition is about 0.1% to about 20% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is about 0.5% to about 10% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is 0.5% to 5% (w / v). In some embodiments, the concentration of human serum albumin in the second aqueous composition is 1% to 3% (w / v). In some embodiments, the second aqueous composition comprises about 1 g to about 50 g of human serum albumin. In some embodiments, the second aqueous composition comprises about 1 g to about 20 g of human serum albumin. In some embodiments, the second aqueous composition comprises about 2 g to about 10 g of human serum albumin.

[0082] Injection of the first liquid composition into an infusion bag or bottle containing the second aqueous composition is rapid. In some embodiments, the injection time is 60 seconds or less. In some embodiments, the injection time is 30 seconds or less. In some embodiments, the injection time is 15 seconds or less. In some embodiments, the injection time is 10 seconds or less. In some embodiments, the injection time is 5 seconds or less. In some embodiments, the injection time is 3 seconds or less. In some embodiments, the injection time is 3 seconds or less. In some embodiments, the injection of the first liquid composition into an infusion bag or bottle containing the second aqueous composition is carried out at a temperature of about 15°C to about 30°C. In some embodiments, the injection of the first liquid composition into an infusion bag or bottle containing the second aqueous composition is carried out at a temperature of about 15°C to about 25°C. In some embodiments, the injection of the first liquid composition into an infusion bag or bottle containing the second aqueous composition is carried out at a temperature of about 18°C ​​to about 25°C. In some embodiments, the injection of the first liquid composition into an infusion bag or bottle containing the second aqueous composition is carried out at a temperature of about 20°C to about 25°C.

[0083] During the process of injecting the first liquid composition into the infusion bag or bottle containing the second aqueous composition, mixing (e.g., manual mixing using a stirrer) or stirring is not required. After the injection of the first liquid composition into the infusion bag or bottle is complete, the first liquid composition and the second aqueous composition are thoroughly mixed (e.g., by gently inverting the bag containing the compositions by hand) to obtain a clear infusion solution free of precipitates. In some embodiments, the infusion bag or bottle containing the second aqueous composition is kept stationary during the injection process. In some embodiments, the first liquid composition is injected below the liquid surface of the second aqueous composition during the injection process. In some embodiments, after the injection is complete, the infusion bag or bottle is gently inverted repeatedly to thoroughly mix the first liquid composition and the second aqueous composition. In some embodiments, after the injection is complete, the infusion bag or bottle is gently inverted until a clear solution free of precipitates is obtained. In some embodiments, after the injection is complete, the infusion bag or bottle is gently inverted for about 5 seconds to about 10 minutes. In some embodiments, after the infusion is complete, the infusion bag or bottle is gently inverted for about 10 seconds to about 5 minutes. In some embodiments, after the infusion is complete, the infusion bag or bottle is gently inverted for about 0.5 minutes to about 3 minutes. In some embodiments, after the infusion is complete, the first liquid composition and the second aqueous composition are thoroughly mixed until a clear infusion solution without sediment is obtained.

[0084] Following injection of the first liquid composition into an infusion bag or bottle containing a second aqueous composition, after the first liquid composition and the second aqueous composition are thoroughly mixed, a clear infusion solution is obtained that contains human serum albumin, docetaxel or a pharmaceutically acceptable salt thereof, and ethanol in a parenterally acceptable vehicle, but is free of precipitate. In some embodiments, the clear infusion solution further contains citric acid. In some embodiments, the parenterally acceptable vehicle is normal saline or dextrose solution. In some embodiments, the clear infusion solution remains clear and free of precipitate for at least 1 hour. In some embodiments, the clear infusion solution remains clear and free of precipitate for at least 2 hours. In some embodiments, the clear infusion solution remains clear and free of precipitate for at least 3 hours. In some embodiments, the clear infusion solution remains clear and free of precipitate for at least 4 hours. In some embodiments, the clear infusion solution remains clear and free of precipitate for at least 6 hours. In some embodiments, the clear infusion solution remains clear and free of precipitate for at least 8 hours. In some embodiments, the clear infusion solution remains clear and precipitate-free for at least 1, 2, 3, 4, or 6 hours when the clear solution is kept at about 18° C. to about 25° C. In some embodiments, the clear infusion solution remains clear and precipitate-free for at least 1, 2, 3, 4, or 6 hours when the clear solution is kept at about 20° C. to about 25° C. In some embodiments, the clear infusion solution remains clear and precipitate-free for at least 2, 4, 6, 8, or 12 hours when the clear solution is kept at about 2-8° C.

[0085] In some embodiments, the present disclosure provides a method for preparing a precipitate-free, clear parenteral injection composition of docetaxel as described herein. A non-limiting preferred method is as follows:

[0086] 1) dissolving docetaxel and an acid (e.g., citric acid) in ethanol or a mixed solvent containing ethanol (e.g., a mixed solvent of ethanol and PEG300, or ethanol and PEG400) to prepare a first liquid composition;

[0087] 2) preparing a second aqueous composition by adding a human serum albumin solution (e.g., a clinically used 20%, 25%, or 5% solution (w / v) of human serum albumin for injection) to an infusion bag or bottle containing a parenterally acceptable vehicle (e.g., normal saline or dextrose solution);

[0088] 3) injecting the first liquid composition into an infusion bag or bottle containing the second aqueous composition, wherein the infusion bag or bottle is held stationary during the injection process and no mixing or agitation is required;

[0089] 4) After the injection of the first liquid composition into the infusion bag or bottle is complete, thoroughly mix the first liquid composition and the second aqueous composition (e.g., by gently inverting the infusion bag or bottle containing the compositions by hand) to obtain a clear infusion solution free of sediment.

[0090] One embodiment of this method is as follows, for example, the method includes:

[0091] 1) preparing a first liquid composition by dissolving docetaxel and an acid (e.g., citric acid) in ethanol or a mixed solvent containing ethanol (e.g., a mixed solvent of ethanol and PEG300, or ethanol and PEG400) (e.g., this method includes obtaining a first liquid composition containing an ethanol solution of docetaxel and an acid or a mixed solvent containing ethanol);

[0092] 2) adding a human serum albumin solution (e.g., a clinically used 20%, 25%, or 5% solution (w / v) of human serum albumin for injection) to an infusion bag or bottle containing a parenterally acceptable vehicle (e.g., normal saline or dextrose solution) to prepare a second aqueous composition (e.g., the method includes obtaining an infusion bag or bottle containing a second aqueous composition comprising a solution of HSA and a parenterally acceptable vehicle);

[0093] 3) injecting the first liquid composition into an infusion bag or bottle containing the second aqueous composition, wherein the infusion bag or bottle is held stationary and no mixing or agitation is required during the infusion process (e.g., the method includes combining the first liquid composition and the second aqueous composition by injecting the first liquid composition into the infusion bag of a bottle containing the second aqueous composition without mixing the compositions and / or agitating the infusion bag or bottle (e.g., holding the infusion bag or bottle stationary); and

[0094] 4) After the injection of the first liquid composition into the infusion bag or bottle is complete, the first liquid composition and the second aqueous composition are thoroughly mixed (e.g., by gently inverting the infusion bag or bottle containing the compositions by hand) to obtain a clear infusion solution free of sediment (e.g., this method includes agitating the infusion bag or bottle containing the compositions to obtain a clear infusion solution).

[0095] The first and second steps of the adjustment can be performed in parallel or in any different order.

[0096] Also provided herein are kits for preparing parenteral infusion solutions, comprising a first container containing a composition comprising docetaxel or a pharmaceutically acceptable salt thereof and a second container containing a composition comprising human serum albumin. In some embodiments, the kit comprises a first container containing a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and a second container containing a liquid composition comprising human serum albumin. In some embodiments, the kit comprises a first container containing a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and ethanol, and a second container containing a liquid composition comprising human serum albumin. In some embodiments, the kit comprises a first container containing a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and ethanol, and a second container containing a liquid composition comprising human serum albumin. In some embodiments, the kit comprises a first container containing a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and ethanol, and a second container containing a liquid composition comprising human serum albumin. In some embodiments, the kit comprises a first container containing a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and absolute ethanol, and a second container containing a liquid composition comprising human serum albumin. In some embodiments, the kit includes a first container containing a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and ethanol, and a second container containing a solution of human serum albumin for injection (e.g., 20%, 25%, or 5% (w / v)).

[0097] In some embodiments, the first container does not contain a lipid (e.g., soybean oil). In some embodiments, the lipid is soybean oil. In some embodiments, the first container does not contain a surfactant. In some embodiments, the second container does not contain a surfactant.

[0098] In some embodiments, the ethanol contained in the first container is absolute ethanol.

[0099] In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, an acid, and ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, an organic acid, and ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and another organic solvent (e.g., an alcohol such as propylene glycol, polyethylene glycol 300, etc.). In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and propylene glycol. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, ethanol, and polyethylene glycol 300. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, citric acid. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and absolute ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel or a pharmaceutically acceptable salt thereof, citric acid, ethanol, and propylene glycol. In some embodiments, the ethanol in the first container is absolute ethanol. In some embodiments, the first container contains an ethanol solution comprising docetaxel or a pharmaceutically acceptable salt thereof. In some embodiments, the first container contains an ethanol solution comprising docetaxel or a pharmaceutically acceptable salt thereof, and citric acid. In some embodiments, the first container contains an absolute ethanol solution comprising docetaxel or a pharmaceutically acceptable salt thereof, and citric acid.In some embodiments, the first container contains an ethanol / propylene glycol solution containing docetaxel or a pharmaceutically acceptable salt thereof and citric acid. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 5000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 2000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 1000:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 500:1 to about 1:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 5000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 2000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 1000:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 500:1 to about 5:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 5000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 2000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 1000:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 500:1 to about 10:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 2000:1 to about 100:1.In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 1000:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 500:1 to about 100:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 5:1 to about 20:1. In some embodiments, the weight ratio of docetaxel or a pharmaceutically acceptable salt thereof to citric acid in the first container is about 5:1, about 10:1, about 15:1, or about 20:1. In some embodiments, the concentration of citric acid or a pharmaceutically acceptable salt thereof in the first container is about 0.005 mg / ml to about 10 mg / ml. In some embodiments, the concentration of citric acid in the first container is about 0.01 mg / ml to about 2 mg / ml. In some embodiments, the concentration of citric acid in the first container is about 0.01 mg / ml to about 1 mg / ml. In some embodiments, the concentration of citric acid in the first container is about 0.02 mg / ml to about 0.5 mg / ml. In some embodiments, the concentration of citric acid in the first container is about 0.02 mg / ml to about 0.2 mg / ml.

[0100] In some embodiments, the amount of docetaxel contained in the first container is about 10 mg to about 300 mg of docetaxel. In some embodiments, the amount of docetaxel contained in the first container is about 20 mg to about 200 mg of docetaxel. In some embodiments, the amount of docetaxel contained in the first container is about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, or about 160 mg of docetaxel. In some embodiments, the amount of docetaxel contained in the first container is about 80 mg or about 100 mg of docetaxel. In some embodiments, the amount of ethanol contained in the first container is about 0.5 ml to about 50 ml of ethanol. In some embodiments, the amount of ethanol contained in the first container is about 1 ml to about 20 ml of ethanol. In some embodiments, the amount of ethanol contained in the first container is about 1 ml to about 10 ml of ethanol. In some embodiments, the amount of ethanol contained in the first container is about 3 ml to about 6 ml of ethanol. In some embodiments, the amount of ethanol contained in the first container is about 1 ml to about 5 ml of ethanol. In some embodiments, the amount of ethanol contained in the first container is about 5 ml to about 10 ml of ethanol. In some embodiments, the concentration of docetaxel in the first container is about 1 mg / ml to about 200 mg / ml. In some embodiments, the concentration of docetaxel in the first container is about 5 mg / ml to about 100 mg / ml. In some embodiments, the concentration of docetaxel in the first container is about 10 mg / ml to about 50 mg / ml. In some embodiments, the concentration of docetaxel in the first container is about 20 mg / ml. In some embodiments, the concentration of docetaxel in the first container is about 10 mg / ml to about 30 mg / ml. In some embodiments, the concentration of docetaxel in the first container is about 10 mg / ml, about 20 mg / ml, or about 30 mg / ml.

[0101] In some embodiments, the first container contains a solid composition comprising docetaxel or a pharmaceutically acceptable salt thereof. In some embodiments, the first container contains a solid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and an organic acid. In some embodiments, the first container contains a solid composition comprising docetaxel or a pharmaceutically acceptable salt thereof and citric acid.

[0102] In some embodiments, the second container contains a liquid composition comprising human serum albumin. In some embodiments, the second container contains a human serum albumin solution. In some embodiments, the second container contains a human serum albumin solution for injection. In some embodiments, the second container contains a human serum albumin solution having a concentration of human serum albumin in the solution of about 1% to about 25% (w / v). In some embodiments, the second container contains a human serum albumin solution having a concentration of human serum albumin in the solution of about 5% to about 25% (w / v). In some embodiments, the second container contains a solution of human serum albumin for injection. In some embodiments, the second container contains a 20% solution (w / v) of human serum albumin for injection. In some embodiments, the second container contains a 25% solution (w / v) of human serum albumin for injection. In some embodiments, the second container contains a 5% solution (w / v) of human serum albumin for injection. In some embodiments, the second container contains a liquid composition comprising about 1 g to about 50 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 1 g to about 30 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 1 g to about 20 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 1 g to about 10 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 2 g to about 6 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 2 g, about 4 g, about 6 g, about 8 g, about 10 g, about 12 g, or about 16 g of human serum albumin.

[0103] In some embodiments, the first container contains about 80 mg of docetaxel. In some embodiments, the first container contains about 4 ml of ethanol. In some embodiments, the first container contains about 80 mg of docetaxel and about 4 ml of ethanol.

[0104] In some embodiments, the kit comprises a first container containing about 80 mg of docetaxel and a second container containing about 2 g to about 8 g of human serum albumin. In some embodiments, the kit comprises a first container containing about 80 mg of docetaxel and a second container containing about 3 g to about 6 g of human serum albumin. In some embodiments, the kit comprises a first container containing about 80 mg of docetaxel and a second container containing about 4 g to about 5 g of human serum albumin.

[0105] In some embodiments, the kit further comprises instructions for adding the composition comprising docetaxel or a pharmaceutically acceptable salt thereof to the composition comprising human serum albumin.

[0106] The currently marketed formulation of Taxotere contains polysorbate 80 and ethanol. All other docetaxel infusions currently marketed in the United States also contain polysorbate 80 and ethanol. Companies marketing docetaxel infusions in the United States include, but are not limited to, HOSPIRA INC., SUN PHARMA, ACCORD HLTHCARE, SANDOZ, JIANGSU HENGRUI MED, ACTAVIS LLC, DR. REDDYS LABS LTD, TEIKOKU PHARMA, DFB ONCOLOGY LTD, INGENUS PHAMS LLC, MYLAN LABS INC, SHILPA MEDCARE LTD, and AMNEAL. The applicant surprisingly discovered that by using the technical method disclosed in the present invention (e.g., adding / mixing a clinically used human serum albumin solution for injection with normal saline in an infusion bag / bottle before adding (injecting) the docetaxel infusion into the infusion bag / bottle to prepare the infusion solution), it is actually not necessary to add polysorbate 80 to the formulation of docetaxel infusion. In clinical use of currently available docetaxel infusions, large amounts of polysorbate 80 (approximately 3-5 g) are administered to patients per infusion. Polysorbate 80 causes severe hypersensitivity reactions, including fatal anaphylaxis, in some patients. Therefore, polysorbate 80-free docetaxel infusions exhibit significant clinical advantages in terms of safety over currently available docetaxel infusions formulated with polysorbate 80.

[0107] Also provided herein is an injectable pharmaceutical composition comprising docetaxel or a pharmaceutically acceptable salt thereof and ethanol, wherein the injectable pharmaceutical composition comprises about 5 mg to 500 mg of docetaxel or a pharmaceutically acceptable salt thereof, the injectable pharmaceutical composition does not contain polysorbate 80, and the injectable pharmaceutical composition is further mixed with an aqueous composition comprising human serum albumin to form a parenteral infusion solution prior to injection or administration to a patient. In some embodiments, the injectable pharmaceutical composition further comprises citric acid. In some embodiments, the injectable pharmaceutical composition and the aqueous composition comprising human serum albumin are mixed in an infusion bag or bottle.

[0108] In some embodiments, mixing the injectable pharmaceutical composition with the aqueous composition containing human serum albumin involves two steps. In the first step, the injectable pharmaceutical composition is injected into an infusion bag or bottle containing the aqueous composition containing human serum albumin. During the injection process, the infusion bag or bottle is kept stationary and no mixing or stirring is required. In the second step, after the injection of the injectable pharmaceutical composition into the infusion bag or bottle is complete, the injectable pharmaceutical composition and the aqueous composition are thoroughly mixed (e.g., by gently inverting the infusion bag or bottle containing the composition by hand) to obtain a clear infusion solution free of sediment.

[0109] In the process of injecting an injectable pharmaceutical composition into an infusion bag or bottle containing an aqueous composition containing human serum albumin, the infusion bag or bottle is kept stationary and no mixing or stirring is required during the injection process. Surprisingly, it has been found that simply inverting the infusion bag or bottle gently (e.g., 5 to 30 times) can result in a clear infusion solution free of precipitates.

[0110] In some embodiments, the parenteral infusion solution of docetaxel, or a pharmaceutically acceptable salt thereof, is a clear solution rather than a nanoparticle suspension. In some embodiments, at least 30% of the docetaxel in the parenteral infusion solution is free (unbound) docetaxel. In some embodiments, at least 40% of the docetaxel in the parenteral infusion solution is free (unbound) docetaxel. In some embodiments, at least 50% of the docetaxel in the parenteral infusion solution is free (unbound) docetaxel. In some embodiments, at least 60% of the docetaxel in the parenteral infusion solution is free (unbound) docetaxel. In some embodiments, at least 70% of the docetaxel in the parenteral infusion solution is free (unbound) docetaxel. Free (unbound) docetaxel refers to the fraction of docetaxel in the parenteral infusion solution that is not bound to human serum albumin. The concentration of free (unbound) docetaxel in the parenteral infusion solution is measured by ultrafiltration through a 30 kDa membrane. Experimental details for the measurement of free (unbound) docetaxel are described in the Examples section.

[0111] In some embodiments, provided herein is a docetaxel infusion solution comprising docetaxel and ethanol, but not including polysorbate 80. In some embodiments, provided herein is a docetaxel infusion solution comprising docetaxel, citric acid, and ethanol, but not including polysorbate 80. In some embodiments, provided herein is a docetaxel infusion solution consisting essentially of docetaxel, citric acid, and ethanol, but not including polysorbate 80.

[0112] In some embodiments, the injectable pharmaceutical composition contains about 10 mg to about 300 mg of docetaxel or a pharmaceutically acceptable salt thereof. In some embodiments, the injectable pharmaceutical composition contains about 20 mg to about 200 mg of docetaxel or a pharmaceutically acceptable salt thereof. In some embodiments, the injectable pharmaceutical composition contains 20 mg, 40 mg, 80 mg, 120 mg, or 160 mg of docetaxel. In some embodiments, the injectable pharmaceutical composition contains about 20 mg, about 40 mg, about 80 mg, about 120 mg, or about 160 mg of docetaxel.

[0113] In some embodiments, the injectable pharmaceutical composition does not include a lipid (e.g., soybean oil). In some embodiments, the injectable pharmaceutical composition does not include a surfactant. In some embodiments, the injectable pharmaceutical composition includes, in addition to ethanol, one or more other organic solvents (e.g., propylene glycol, polyethylene glycol 300, polyethylene glycol 400, etc.). In some embodiments, the injectable pharmaceutical composition includes more than 50% ethanol (v / v). In some embodiments, the injectable pharmaceutical composition includes more than 70% ethanol (v / v). In some embodiments, the injectable pharmaceutical composition includes more than 80% ethanol (v / v).

[0114] In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the injectable pharmaceutical composition is about 5 mg / ml to about 40 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the injectable pharmaceutical composition is about 10 mg / ml to about 20 mg / ml. In some embodiments, the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the injectable pharmaceutical composition is about 10 mg / ml, 15 mg / ml, or about 20 mg / ml.

[0115] In some embodiments, the injectable pharmaceutical composition further comprises an acid. In some embodiments, the acid is an organic acid. The most preferred acid for use in accordance with the present invention is citric acid.

[0116] In some embodiments, the pH value of the injectable pharmaceutical composition is from about 3 to about 9. In some embodiments, the pH value of the injectable pharmaceutical composition is from about 3 to about 8. In some embodiments, the pH value of the injectable pharmaceutical composition is from about 3 to about 7. In some embodiments, the pH value of the injectable pharmaceutical composition is from about 3 to about 6.5. In some embodiments, the pH value of the injectable pharmaceutical composition is from about 3.5 to about 6.5. In some embodiments, the pH value of the injectable pharmaceutical composition is from about 3.5 to about 6. In some embodiments, the pH value of the injectable pharmaceutical composition is from about 3.5 to about 5.5. In some embodiments, the pH value of the injectable pharmaceutical composition is from about 4 to about 5. To measure the pH value of an injectable pharmaceutical dosage form, the injectable pharmaceutical dosage form is mixed with normal saline in a 1:1 ratio (v / v) to obtain an aqueous solution, and then the pH value of the aqueous solution is tested.

[0117] According to yet another embodiment, the docetaxel injectable pharmaceutical composition is formulated into an injectable pharmaceutical dosage form. In some embodiments, the injectable pharmaceutical dosage form contains about 20 mg, about 40 mg, about 80 mg, about 120 mg, or about 160 mg of docetaxel or a pharmaceutically acceptable salt thereof, citric acid, and ethanol, wherein the concentration of docetaxel or a pharmaceutically acceptable salt thereof in the injectable pharmaceutical dosage form is 5 mg / ml to 40 mg / ml (e.g., about 20 mg / ml, about 10 mg / ml). In some embodiments, the injectable pharmaceutical dosage form has a pH value of about 3 to about 6.5. The preferred pH of the injectable pharmaceutical dosage form is about 3.5 to about 5.5.

[0118] Also provided herein are methods of treating cancer, comprising administering to a subject a therapeutically effective amount of any of the compositions or formulations described herein. In some embodiments, the methods comprise parenterally administering to the subject a therapeutically effective amount of a liquid injection composition of the present disclosure.

[0119] In some embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, reproductive cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, and testicular cancer.

[0120] In some embodiments, the cancer is selected from the group consisting of sarcoma, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, non-small cell lung cancer (NSCLC), bronchogenic carcinoma squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma, alveolar bronchogenic carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal cancer, esophageal cancer, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, gastric cancer, carcinoma, lymphoma, leiomyosarcoma, pancreatic cancer, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma, small intestine cancer, adenocarcinoma, lymphoma, carcinoma. Tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, cancer of the large intestine or colon, tubular adenoma, villous adenoma, hamartoma, leiomyoma, genitourinary cancer, cancer of the kidney, Wilms' tumor (nephroblastoma), lymphoma, leukemia, bladder cancer, urethral cancer, squamous cell carcinoma, transitional cell carcinoma, prostate cancer, cancer of the testes, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, bone cancer, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, carcinoma Osteosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, bone chronic tumor (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid giant cell tumor, nervous system cancer, skull cancer, osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningeal cancer, meningeal sarcoma, gliomatosis, brain cancer, astrocytoma, medulloblastoma, glioma, ependymoma, embryonal tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cancer, neurofibroma, meningioma, glioma, sarcoma, gynecological cancer, uterine cancer, endometrial cancer, foetal cancer Cancer of the cervix, cervical cancer, neoplastic pre-cervical dysplasia, cancer of the ovary, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumor, Sertoli-Leydig cell tumor, germinoma, malignant teratoma, vulvar cancer, squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma, cancer of the vagina, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, embryonal rhabdomyosarcoma, cancer of the fallopian tubes, blood cancer, cancer of the blood, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma,The cancer is selected from the group consisting of myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma), Waldenstrom's macroglobulinemia, skin cancer, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentil dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, adrenal adenocarcinoma, and neuroblastoma.

[0121] In some embodiments, the cancer is selected from breast cancer, non-small cell lung cancer, hormone-refractory prostate cancer, gastric adenocarcinoma, and squamous cell carcinoma of the head and neck.

[0122] Also provided herein are parenteral pharmaceutical formulations comprising two compositions mixed prior to injection or administration to a patient, the two compositions comprising (a) a first liquid composition comprising a substantially water-insoluble pharmaceutically active agent or a pharmaceutically acceptable salt thereof, and (b) a second aqueous composition comprising human serum albumin and a parenterally acceptable vehicle, wherein the substantially water-insoluble pharmaceutically active agent is the API (active pharmaceutical ingredient) of the parenteral pharmaceutical formulation. In some embodiments, the first liquid composition comprises the substantially water-insoluble pharmaceutically active agent, or a pharmaceutically acceptable salt thereof, and an organic solvent (e.g., alcohol or other suitable solvent such as DMSO). In some embodiments, the first liquid composition comprises the substantially water-insoluble pharmaceutically active agent, or a pharmaceutically acceptable salt thereof, the agent, and alcohol. In some embodiments, the first liquid composition comprises the substantially water-insoluble pharmaceutically active agent, or a pharmaceutically acceptable salt thereof, and ethanol. In some embodiments, the mixing of the first liquid composition and the second aqueous composition is performed in an infusion bag or bottle. In some embodiments, the second aqueous composition is contained in an infusion bag or bottle. In some embodiments, the first liquid composition is injected into an infusion bag or bottle containing the second aqueous composition. In some embodiments, the first liquid composition and the second aqueous composition are mixed in a hospital or clinic before being injected or administered to a patient.

[0123] As used herein, the term "water-insoluble" refers to the limited solubility of a pharmacologically active agent or its pharmaceutically acceptable salt in an aqueous solution (such as water, saline, or injectable dextrose solution). The United States Pharmacopeia / National Formulary (USP / NF) generally expresses solubility in terms of the volume of solvent required to dissolve 1 gram of pharmacologically active agent at a particular temperature (e.g., 1 g of aspirin in 300 mL of water or 5 mL of ethanol at 25°C). Other references may use more subjective terms to describe solubility, as shown in the following table from *Remington's Pharmaceutical Sciences* by Joseph Remington and Alfonso Gennaro, Mack Publishing Co., Easton, PA, 1995. [Table 1]

[0124] As used herein, the term "substantially water-insoluble pharmaceutically active agent" refers to an agent that is sparingly, slightly, or very slightly soluble, or substantially insoluble or insoluble, according to the definition of solubility provided in Table 1 above, or other agent that has a solubility in water of less than 1 mg / ml. For example, a substantially water-insoluble pharmaceutically active agent can be docetaxel or paclitaxel, or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the substantially water-insoluble pharmaceutically active agent, or pharmaceutically acceptable salt thereof, has a solubility of less than about 1 mg / mL, less than about 0.9 mg / mL, less than about 0.8 mg / mL, less than about 0.7 mg / mL, less than about 0.6 mg / mL, less than about 0.5 mg / mL, less than about 0.4 mg / mL, less than about 0.3 mg / mL, less than about 0.2 mg / mL, less than about 0.1 mg / mL, less than about 0.09 mg / mL, less than about 0.08 mg / mL, less than about 0.07 mg / mL, less than about 0.06 mg / mL, less than about 0.05 mg / mL, less than about 0.04 mg / mL, less than about 0.03 mg / mL, less than about 0.02 mg / mL, or less than about 0.01 mg / mL.

[0126] In some embodiments, the formulation does not include a lipid (e.g., soybean oil). In some embodiments, the first liquid composition does not include a lipid (e.g., soybean oil). In some embodiments, the lipid is soybean oil.

[0127] In some embodiments, the pharmaceutical formulation does not contain a surfactant. In some embodiments, the first liquid composition does not contain a surfactant. In some embodiments, the second aqueous composition does not contain a surfactant. [Example]

[0128] Example 1: 300.8 mg of docetaxel and 60.9 mg of citric acid were dissolved in 15 ml of absolute ethanol to obtain a docetaxel API solution. 25 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bottle containing 150 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally and 2.5 ml of docetaxel API solution was rapidly injected into the infusion bottle. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.78. The particulate matter content of the clear solution was also measured. 1 ml of the clear solution contained approximately 44 particles greater than 10 μm in size and approximately 3 particles greater than 25 μm in size. The solution was then divided into two portions. One portion of the clear solution was kept at 20°C to 25°C and remained clear and precipitate-free for 3 hours. The other portion of the clear solution was kept at 2 to 8°C for 2 hours and remained a clear solution without precipitate. After 2 hours, the solution was kept at 20 to 25°C and remained a clear solution without precipitate for another 2 hours.

[0129] Thirty milliliters of a 20% solution of human serum albumin for injection was added to a 250-ml infusion bottle containing 180 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally and 3 ml of docetaxel API solution was rapidly injected into the infusion bottle. The solution was then thoroughly mixed to obtain a clear, precipitate-free solution. The pH of the resulting clear solution was 6.77. The particulate matter content of 1 ml of the clear solution was also measured. The clear solution contained approximately 86 particles greater than 10 μm in size and approximately 5 particles greater than 25 μm in size. The solution was then divided into two portions. One portion of the clear solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for three hours. The other portion was kept at 2°C to 8°C for two hours and maintained as a clear, precipitate-free solution. After two hours, the solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for an additional two hours.

[0130] Example 2: 300.8 mg of docetaxel and 59.6 mg of citric acid were dissolved in 15 ml of absolute ethanol to obtain a docetaxel API solution. 20 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bottle containing 120 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally and 2 ml of docetaxel API solution was rapidly injected into the bottle. The solution was then thoroughly mixed to obtain a clear, precipitate-free solution. The particulate matter of the clear solution was measured. 1 ml of the clear solution contained approximately 96 particles greater than 10 μm in size and approximately 6 particles greater than 25 μm in size. The solution was then divided into two portions. One portion was kept at 20°C to 25°C for 2 hours, remaining as a clear, precipitate-free solution. The other portion was kept at 2°C to 8°C for 4 hours, remaining as a clear, precipitate-free solution. After 4 hours, the solution was kept at 20°C to 25°C and remained as a clear solution without precipitate for another 2 hours.

[0131] Fifteen milliliters of a 20% solution of human serum albumin for injection was added to a 250-ml infusion bottle containing 90 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally and 1.5 ml of docetaxel API solution was rapidly injected into the bottle. The solution was then thoroughly mixed to obtain a clear, precipitate-free solution. The particulate matter of 1 ml of the clear solution was measured. The clear solution contained approximately 49 particles greater than 10 μm in size and approximately 2 particles greater than 25 μm in size. The solution was then divided into two portions. One portion of the clear solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for four hours. The other portion was kept at 2°C to 8°C for two hours and maintained as a clear, precipitate-free solution. After two hours, the solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for an additional hour.

[0132] Example 3: A docetaxel API solution was obtained by dissolving 1.0005 g of docetaxel and 199.8 mg of citric acid in 50 ml of absolute ethanol. 50 ml of a 20% solution of human serum albumin for injection was added to a 500 ml infusion bottle containing 300 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally and 5 ml of the docetaxel API solution was rapidly injected into the bottle. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The particulate matter of the clear solution was measured. Each ml of the clear solution contained approximately 39 particles greater than 10 μm in size and approximately 2 particles greater than 25 μm in size. The solution was then divided into three portions. One portion of the clear solution was kept at 20°C to 25°C and maintained as a clear solution without precipitate for 4 hours. The second portion of the clear solution was kept at 2°C to 8°C for 7 hours and remained as a clear solution without precipitate. The third portion of the clear solution was kept at 2°C to 8°C for 4 hours and remained as a clear solution without precipitate. After 4 hours, the solution was kept at 20°C to 25°C and remained as a clear solution without precipitate for an additional 2.5 hours.

[0133] Example 4: 300 mg of docetaxel and 59.5 mg of citric acid were dissolved in 15 ml of absolute ethanol to obtain a docetaxel API solution. 65 ml of a 20% solution of human serum albumin for injection was added to a 500 ml infusion bottle containing 390 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally and 6.5 ml of docetaxel API solution was rapidly injected into the infusion bottle. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.78. The particulate matter content of the clear solution was also measured. Each ml of the clear solution contained approximately 53 particles greater than 10 μm in size and approximately 5 particles greater than 25 μm in size. The solution was then divided into three portions. One portion of the clear solution was kept at 20°C to 25°C and maintained as a clear solution without precipitate for 2 hours. The second portion of the clear solution was kept at 2°C to 8°C for 3 hours and remained as a clear solution without precipitate. After 3 hours, the solution was kept at 20°C to 25°C and remained as a clear solution without precipitate for an additional 1.5 hours. The third portion of the clear solution was kept at 2°C to 8°C for 4 hours and remained as a clear solution without precipitate. After 4 hours, the solution was kept at 20°C to 25°C and remained as a clear solution without precipitate for an additional 2 hours.

[0134] Example 5: 300.2 mg of docetaxel and 30.1 mg of citric acid were dissolved in 15 ml of absolute ethanol to obtain a docetaxel API solution. 19 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bottle containing 120 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally and 2 ml of docetaxel API solution was rapidly injected into the bottle. The solution was then thoroughly mixed to obtain a clear, precipitate-free solution. The particulate matter of the clear solution was measured. Each ml of the clear solution contained approximately 64 particles greater than 10 μm in size and approximately 2 particles greater than 25 μm in size. The solution was then divided into two portions. One portion was kept at 20°C to 25°C for 3.5 hours, remaining as a clear, precipitate-free solution. The other portion was kept at 2°C to 8°C for 4 hours, remaining as a clear, precipitate-free solution. After 4 hours, the solution was kept at 20°C to 25°C and remained as a clear solution without precipitate for another 1.5 hours.

[0135] Eighteen milliliters of a 20% solution of human serum albumin for injection was added to a 250-ml infusion bottle containing 120 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally and 2 ml of docetaxel API solution was rapidly injected into the bottle. The solution was then thoroughly mixed to obtain a clear, precipitate-free solution. The particulate matter of 1 ml of the clear solution was measured. The clear solution contained approximately 102 particles greater than 10 μm in size and approximately 2 particles greater than 25 μm in size. The solution was then divided into two portions. One portion of the clear solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for 1.5 hours. The other portion of the clear solution was kept at 2°C to 8°C for 4 hours and maintained as a clear, precipitate-free solution. After 4 hours, the solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for an additional 2 hours.

[0136] Sixty-five milliliters of a 20% solution of human serum albumin for injection was added to a 500-ml infusion bottle containing 390 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally and 6.5 ml of docetaxel API solution was rapidly injected into the bottle. The solution was then thoroughly mixed to obtain a clear, precipitate-free solution. The particulate matter of the clear solution was measured. Each ml of the clear solution contained approximately 51 particles greater than 10 μm in size and approximately 2 particles greater than 25 μm in size. The solution was then divided into three portions. One portion of the clear solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for three hours. The second portion of the clear solution was kept at 2°C to 8°C for four hours and maintained as a clear, precipitate-free solution. After four hours, the solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for an additional three hours. The third portion of the clear solution was kept at 2°C to 8°C for 6 hours and remained as a clear solution without precipitate. After 6 hours, the solution was kept at 20°C to 25°C and remained as a clear solution without precipitate for an additional 2 hours.

[0137] Example 6: A docetaxel API solution was obtained by dissolving 100.3 mg of docetaxel and 5.1 mg of citric acid in 5 ml of absolute ethanol. Twenty ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bottle containing 120 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally and 2 ml of docetaxel API solution was rapidly injected into the bottle. The solution was then thoroughly mixed to obtain a clear, precipitate-free solution. The particulate matter of the clear solution was measured. Each ml of the clear solution contained approximately 63 particles greater than 10 μm in size and approximately 1 particle greater than 25 μm in size. The solution was then divided into two portions. One portion was kept at 20°C to 25°C for 4.5 hours, remaining as a clear, precipitate-free solution. The other portion was kept at 2°C to 8°C for 6 hours, remaining as a clear, precipitate-free solution. After 6 hours, the solution was kept at 20°C to 25°C and remained as a clear solution without precipitate for another 1.5 hours.

[0138] Example 7: 20 mg of citric acid was dissolved in 20 ml of absolute ethanol to obtain a citric acid solution (1 mg / ml). 100.4 mg of docetaxel was dissolved in 3 ml of absolute ethanol, followed by the addition of 2 ml of citric acid solution (1 mg / ml) to obtain a docetaxel API solution. 19 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bag containing 120 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally and 2 ml of docetaxel API solution was rapidly injected into the infusion bag. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 7.05. The particulate matter content of the clear solution was also measured. 1 ml of the clear solution contained approximately 66 particles greater than 10 μm in size and approximately 1 particle greater than 25 μm in size. The solution was then divided into two portions. One portion of the clear solution was kept at 20-25°C and remained clear and precipitate-free for 3 hours. The other portion was kept at 2-8°C for 4 hours and remained clear and precipitate-free. After 4 hours, the solution was kept at 20-25°C and remained clear initially, but became cloudy due to precipitation within about 1 hour.

[0139] Example 8: A citric acid solution was obtained by dissolving 19.8 mg of citric acid in 20 ml of absolute ethanol. 200 mg of docetaxel was dissolved in 9 ml of absolute ethanol, followed by the addition of 1 ml of the prepared citric acid solution to obtain the docetaxel API solution. 65 ml of a 20% solution of human serum albumin for injection was added to a 500 ml infusion bag containing 390 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally and 6.5 ml of docetaxel API solution was rapidly injected into the infusion bag. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.95. The particulate matter content of the clear solution was also measured. 1 ml of the clear solution contained approximately 29 particles larger than 10 μm and approximately 2 particles larger than 25 μm. The solution was then divided into three portions. One portion of the clear solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for 3 hours. A second portion of the clear solution was kept at 2°C to 8°C for 4 hours and maintained as a clear, precipitate-free solution. After 4 hours, the solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for an additional 0.5 hours. A third portion of the clear solution was kept at 2°C to 8°C for 6 hours and maintained as a clear, precipitate-free solution. After 6 hours, the solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for an additional 1.5 hours.

[0140] 100.1 mg of docetaxel was dissolved in 2.5 ml of absolute ethanol, followed by the addition of 0.5 ml of the prepared citric acid solution to obtain a docetaxel API solution. 20 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bag containing 120 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally and 1.2 ml of docetaxel API solution was rapidly injected into the infusion bag. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.99. The particulate matter content of the clear solution was also measured. 1 ml of the clear solution contained approximately 64 particles greater than 10 μm in size and approximately 1 particle greater than 25 μm in size. The solution was then divided into two portions. One portion of the clear solution was kept at 20 to 25°C and maintained as a clear solution without precipitate for 4 hours. The other portion of the clear solution was kept at 2 to 8°C for 6 hours and remained a clear solution without precipitate. After 6 hours, the solution was kept at 20 to 25°C, and it initially remained a clear solution but became cloudy with precipitate in about 0.5 hours.

[0141] 100.4 mg of docetaxel was dissolved in 3.5 ml of absolute ethanol, followed by the addition of 0.5 ml of the prepared citric acid solution and 1 ml of propylene glycol to obtain a docetaxel API solution. 20 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bag containing 120 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally and 2 ml of the docetaxel API solution was rapidly injected into the infusion bag. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The particulate matter content of the clear solution was measured. 1 ml of the clear solution contained approximately 32 particles greater than 10 μm in size and approximately 1 particle greater than 25 μm in size. The solution was then divided into two portions. One portion of the clear solution was kept at 20°C to 25°C and maintained as a clear solution without precipitate for 5 hours. The other portion of the clear solution was kept at 2 to 8°C for 6 hours and remained as a clear solution without precipitate. After 6 hours, the solution was kept at 20 to 25°C and remained as a clear solution without precipitate for another 2 hours.

[0142] Example 9: 20 mg of citric acid was dissolved in 20 ml of absolute ethanol to obtain a citric acid solution. 300.9 mg of docetaxel was dissolved in 14.4 ml of absolute ethanol, followed by the addition of 0.6 ml of the prepared citric acid solution to obtain the docetaxel API solution. 18 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bag containing 120 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally and 2 ml of the docetaxel API solution was rapidly injected into the infusion bag. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.96. The particulate matter content of the clear solution was also measured. 1 ml of the clear solution contained approximately 49 particles larger than 10 μm in size and approximately 6 particles larger than 25 μm in size. The solution was then divided into two portions. One portion of the clear solution was kept at 20-25°C and remained clear and precipitate-free for 4.5 hours. The other portion of the clear solution was kept at 2-8°C for 6 hours and remained clear and precipitate-free. After 6 hours, the solution was kept at 20-25°C and remained clear and precipitate-free for an additional hour.

[0143] Twenty milliliters of a 20% solution of human serum albumin for injection was added to a 250-ml infusion bag containing 120 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally and 2 ml of docetaxel API solution was rapidly injected into the infusion bag. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.96. The particulate matter of the clear solution was also measured. Each ml of the clear solution contained approximately 55 particles greater than 10 μm in size and approximately 3 particles greater than 25 μm in size. The solution was then divided into two portions. One portion of the clear solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for 4 hours. The other portion was kept at 2°C to 8°C for 6 hours and maintained as a clear, precipitate-free solution. After 6 hours, the solution was kept at 20°C to 25°C and initially remained a clear solution, which became cloudy with precipitation in about 0.5 hours.

[0144] 35 ml of a 20% solution of human serum albumin for injection was added to a 500 ml infusion bag containing 210 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was placed horizontally and 3.5 ml of docetaxel API solution was rapidly injected into the infusion bag. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.96. The particulate matter of the clear solution was also measured. Each ml of the clear solution contained approximately 83 particles greater than 10 μm in size and approximately 7 particles greater than 25 μm in size. The solution was then divided into three portions. One portion of the clear solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for 3.5 hours. The second portion of the clear solution was kept at 2°C to 8°C for 4 hours and maintained as a clear, precipitate-free solution. After 4 hours, the solution was kept at 20-25°C and maintained as a clear solution without precipitate for an additional hour. The third portion of the clear solution was kept at 2-8°C for 6 hours and maintained as a clear solution without precipitate. After 6 hours, the solution was kept at 20-25°C and maintained as a clear solution without precipitate for an additional hour.

[0145] Fifty milliliters of a 20% solution of human serum albumin for injection was added to a 500-ml infusion bag containing 300 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally and 5 ml of docetaxel API solution was rapidly injected into the infusion bag. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.96. The particulate matter content of the clear solution was also measured. Each ml of the clear solution contained approximately 95 particles greater than 10 μm in size and approximately 3 particles greater than 25 μm in size. The solution was then divided into three portions. One portion of the clear solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for four hours. The second portion of the clear solution was kept at 2°C to 8°C for four hours and maintained as a clear, precipitate-free solution. After four hours, the solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for an additional hour. The third portion of the clear solution was kept at 2°C to 8°C for 6 hours and remained as a clear solution without precipitate. After 6 hours, the solution was kept at 20°C to 25°C and remained as a clear solution without precipitate for an additional 1.5 hours.

[0146] Example 10: 19.8 mg of citric acid was dissolved in 20 ml of absolute ethanol to obtain a citric acid solution. 299.5 mg of docetaxel was dissolved in 14.4 ml of absolute ethanol, followed by the addition of 0.6 ml of the prepared citric acid solution to obtain a docetaxel API solution. 17.5 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bag containing 105 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally and 1.75 ml of docetaxel API solution was rapidly injected into the infusion bag. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.96. The particulate matter content of the clear solution was also measured. 1 ml of the clear solution contained approximately 57 particles greater than 10 μm in size and approximately 1 particle greater than 25 μm in size. The clear solution was kept at 20°C to 25°C and remained as a clear precipitate-free solution for 4.5 hours.

[0147] Thirty milliliters of a 20% solution of human serum albumin for injection was added to a 250-ml infusion bag containing 180 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally and 3 ml of docetaxel API solution was rapidly injected into the infusion bag. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.97. The particulate matter content of the clear solution was also measured. 1 ml of the clear solution contained approximately 29 particles greater than 10 μm in size and approximately 0 particles greater than 25 μm in size. The clear solution was kept at 20°C to 25°C and remained clear and precipitate-free for 3.5 hours.

[0148] Example 11: 20.9 mg of citric acid was dissolved in 20 ml of absolute ethanol to obtain a citric acid solution. 100.3 mg of docetaxel was dissolved in 4.5 ml of absolute ethanol, followed by the addition of 0.5 ml of the prepared citric acid solution to obtain a docetaxel API solution. 9.5 ml of a 20% solution of human serum albumin for injection was added to a 100 ml vial containing 60 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the vial was held horizontally and 1 ml of docetaxel API solution was rapidly injected into the vial. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.96. The particulate matter of the clear solution was also measured. Each ml of the clear solution contained approximately 42 particles greater than 10 μm in size and approximately 1 particle greater than 25 μm in size. The clear solution was kept at 20°C to 25°C and remained clear and free of precipitate for 4 hours.

[0149] Nine milliliters of a 20% solution of human serum albumin for injection was added to a 100-ml vial containing 60 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the vial was held horizontally and 1 ml of docetaxel API solution was rapidly injected into the vial. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.96. The particulate matter content of the clear solution was also measured. Each ml of the clear solution contained approximately 101 particles greater than 10 μm in size and approximately 3 particles greater than 25 μm in size. The clear solution was kept at 20°C to 25°C and remained clear and precipitate-free for 2.5 hours.

[0150] 8.5 ml of a 20% solution of human serum albumin for injection was added to a 100 ml vial containing 60 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the vial was held horizontally and 1 ml of docetaxel API solution was rapidly injected into the vial. The solution was then thoroughly mixed to obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.95. The particulate matter content of the clear solution was also measured. Each ml of the clear solution contained approximately 17 particles greater than 10 μm in size and approximately 1 particle greater than 25 μm in size. The clear solution was kept at 20°C to 25°C and remained clear and precipitate-free for 2 hours.

[0151] Example 12: 19.4 mg of citric acid was dissolved in 20 ml of absolute ethanol to obtain a citric acid solution. 200.5 mg of docetaxel was dissolved in 9.6 ml of absolute ethanol, followed by the addition of 0.4 ml of the prepared citric acid solution to obtain the docetaxel API solution. 25 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bag containing 150 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally, and 2.5 ml of the docetaxel API solution was rapidly injected into the infusion bag by injecting it below the surface of the albumin solution (the injection process took approximately 1-2 seconds). The infusion bag was then immediately gently inverted approximately 20-30 times to thoroughly mix the solution and obtain a clear solution without precipitate. The pH of the resulting clear solution was 6.98. The particulate matter content of the clear solution was also measured. One milliliter of the clear solution contained approximately 161 particles greater than 10 μm in size and approximately 13 particles greater than 25 μm in size. The solution was then divided into two portions. One portion of the clear solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for two hours. The other portion of the clear solution was kept at 2°C to 8°C for four hours and maintained as a clear, precipitate-free solution. After four hours, the solution was kept at 20°C to 25°C and maintained as a clear, precipitate-free solution for an additional 1.5 hours.

[0152] 17.5 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bag containing 105 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally, and 1.75 ml of docetaxel API solution was rapidly injected into the infusion bag by injecting it below the surface of the albumin solution (the injection process took approximately 2 seconds). The infusion bag was then immediately gently inverted approximately 20-30 times to thoroughly mix the solution and obtain a clear solution without precipitate. The particulate matter of the clear solution was measured. 1 ml of the clear solution contained approximately 81 particles greater than 10 μm in size and approximately 1 particle greater than 25 μm in size. The solution was then divided into two portions. One portion of the clear solution was kept at 20-25°C and maintained as a clear solution without precipitate for 5 hours. The other portion was kept at 2-8°C for 4 hours and maintained as a clear solution without precipitate. After 4 hours, the solution was kept at 20°C to 25°C, and it initially remained a clear solution, becoming cloudy in about 0.5 hours.

[0153] Example 13: Docetaxel API solution was obtained by dissolving 100.3 mg of docetaxel in 5 ml of absolute ethanol. After adding 35 ml of normal saline (0.5% NaCl solution) to a 50 ml vial, 0.5 ml of docetaxel API solution was rapidly injected into the vial by holding the vial horizontally and injecting it below the surface of the saline (the injection process took approximately 2 seconds). The vial was then immediately gently inverted approximately 10 times, initially resulting in a clear solution. A precipitate appeared in the solution within approximately 10 minutes.

[0154] Five milliliters of a 20% solution of human serum albumin for injection was added to a 50-ml vial containing 30 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the vial was held horizontally, and 0.5 ml of docetaxel API solution was rapidly injected into the vial by injecting it below the surface of the albumin solution (the injection process took approximately 2 seconds). The vial was then immediately and gently inverted approximately 10 times to thoroughly mix the solution, resulting in a clear solution without precipitate. The solution remained clear and precipitate-free for 4.5 hours.

[0155] Four milliliters of a 20% solution of human serum albumin for injection was added to a 50-ml vial containing 31 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the vial was held horizontally, and 0.5 ml of docetaxel API solution was rapidly injected into the vial by injecting it below the surface of the albumin solution (the injection process took approximately 2 seconds). The vial was then immediately gently inverted approximately 10 times to thoroughly mix the solution, resulting in a clear solution without precipitate. The solution remained clear and precipitate-free for 4.5 hours.

[0156] 2.5 ml of a 20% solution of human serum albumin for injection was added to a 50 ml vial containing 32.5 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the vial was held horizontally, and 0.5 ml of docetaxel API solution was rapidly injected into the vial by injecting it below the surface of the albumin solution (the injection process took approximately 2 seconds). The vial was then immediately gently inverted approximately 10 times to thoroughly mix the solution, resulting in a clear solution without precipitate. The solution remained clear and precipitate-free for 3.5 hours.

[0157] Example 14: A docetaxel API solution was obtained by dissolving 100.3 mg of docetaxel in 5 ml of absolute ethanol. 15 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bag containing 90 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally, and 1.5 ml of docetaxel API solution was rapidly injected into the infusion bag by injecting it below the surface of the albumin solution (the injection process took approximately 3 seconds). The infusion bag was then immediately gently inverted approximately 20 times to thoroughly mix the solution, resulting in a clear solution without precipitate. The particulate matter content of the clear solution was measured. 1 ml of the clear solution contained approximately 78 particles greater than 10 μm in size and approximately 3 particles greater than 25 μm in size. The solution remained clear and free of precipitate for 3 hours.

[0158] Twelve milliliters of a 20% solution of human serum albumin for injection was added to a 250-ml infusion bag containing 93 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally, and 1.5 ml of docetaxel API solution was rapidly injected into the infusion bag by injecting it below the surface of the albumin solution (the injection process took approximately 3 seconds). The infusion bag was then immediately gently inverted approximately 20 times to thoroughly mix the solution and obtain a clear solution without precipitate. The particulate matter in the clear solution was measured. 1 ml of the clear solution contained approximately 90 particles greater than 10 μm in size and approximately 4 particles greater than 25 μm in size. The solution remained clear and free of precipitate for 3.5 hours.

[0159] 7.5 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bag containing 97.5 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bag was held horizontally, and 1.5 ml of docetaxel API solution was rapidly injected into the infusion bag by injecting it below the surface of the albumin solution (the injection process took approximately 3 seconds). The infusion bag was then immediately gently inverted approximately 20 times to thoroughly mix the solution and obtain a clear solution without precipitate. The particulate matter in the clear solution was measured. 1 ml of the clear solution contained approximately 63 particles greater than 10 μm in size and approximately 2 particles greater than 25 μm in size. The solution remained clear and free of precipitate for 3 hours.

[0160] Example 15: 20.1 mg of citric acid was dissolved in 20 ml of absolute ethanol to obtain a citric acid solution. 300.7 mg of docetaxel was dissolved in 14.4 ml of absolute ethanol, followed by the addition of 0.6 ml of the prepared citric acid solution to obtain a docetaxel API solution. 7.5 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bottle containing 97.5 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally, and 1.5 ml of docetaxel API solution was rapidly injected into the infusion bottle by injecting it below the surface of the albumin solution (the injection process took approximately 2 seconds). The infusion bottle was then immediately gently inverted approximately 20 times to thoroughly mix the solution and obtain a clear solution without precipitate. The particulate matter content of the clear solution was measured. In 1 ml of the clear solution, there are approximately 88 particles greater than 10 μm in size and approximately 8 particles greater than 25 μm in size. The solution remained clear and free of precipitate for 2.5 hours.

[0161] Six milliliters of a 20% solution of human serum albumin for injection was added to a 250-ml infusion bottle containing 99 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally, and 1.5 ml of docetaxel API solution was rapidly injected into the infusion bottle by injecting it below the surface of the albumin solution (the injection process took approximately 2 seconds). The infusion bottle was then immediately gently inverted approximately 20 times to thoroughly mix the solution and obtain a clear solution without precipitate. The particulate matter of the clear solution was measured. 1 ml of the clear solution contained approximately 37 particles greater than 10 μm in size and approximately 0 particles greater than 25 μm in size. The solution remained clear and free of precipitate for 3 hours.

[0162] 4.5 ml of a 20% solution of human serum albumin for injection was added to a 250 ml infusion bottle containing 100.5 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally, and 1.5 ml of docetaxel API solution was rapidly injected into the infusion bottle by injecting it below the surface of the albumin solution (the injection process took approximately 2 seconds). The infusion bottle was then immediately gently inverted approximately 20 times to thoroughly mix the solution and obtain a clear solution without precipitate. The particulate matter of the clear solution was measured. 1 ml of the clear solution contained approximately 65 particles greater than 10 μm in size and approximately 2 particles greater than 25 μm in size. The solution remained clear and free of precipitate for 3 hours.

[0163] Thirty milliliters of a 20% solution of human serum albumin for injection was added to a 500-ml infusion bottle containing 390 ml of normal saline (0.5% NaCl solution). After thoroughly mixing the albumin solution with the saline, the infusion bottle was held horizontally, and 6 ml of docetaxel API solution was rapidly injected into the infusion bottle by injecting it below the surface of the albumin solution (the injection process took approximately 2 seconds). The infusion bottle was then immediately gently inverted approximately 20-30 times to thoroughly mix the solution and obtain a clear, precipitate-free solution. The particulate matter content of the clear solution was measured. 1 ml of the clear solution contained approximately 60 particles greater than 10 μm in size and approximately 4 particles greater than 25 μm in size. The solution was then divided into three portions. One portion of the clear solution was kept at 20-25°C and maintained as a clear, precipitate-free solution for 5.5 hours. The second portion of the clear solution was kept at 2-8°C and maintained as a clear, precipitate-free solution for 7 hours. The third portion of the clear solution was maintained at 2°C to 85°C for 5 hours and remained as a clear solution without precipitate. After 5 hours, the solution was maintained at 20°C to 25°C and remained as a clear solution without precipitate for an additional 1.5 hours.

[0164] Example 16: 44.84 g of docetaxel was weighed and dissolved in 671.98 g of absolute ethanol in a 2-L beaker. The docetaxel solution was then transferred to a 5-L beaker. The 2-L beaker was rinsed with 822.63 g of absolute ethanol in three portions, and the rinsed ethanol was also transferred to the 5-L beaker. 87.7 mg of citric acid was dissolved in 42.05 g of absolute ethanol in a 100-mL beaker. Next, while stirring the docetaxel solution in the 5-L beaker, the citric acid solution was transferred to the 5-L beaker. Next, the 100-mL beaker was rinsed with 92.56 g of absolute ethanol in three portions, and the rinsed ethanol was also transferred to the 5-L beaker. The resulting docetaxel solution in the 5-L beaker was stirred for approximately 1 minute and then filtered through a 0.22 μm filter. The filtered docetaxel solution was filled into 10-mL glass vials using an automated filling machine. A total of 470 vials containing 4.4 ml of docetaxel solution (10% overfill) in 10 ml vials were obtained. The stability of the resulting docetaxel solution (docetaxel product) was tested under long-term conditions (2-8°C) and accelerated conditions (25 ± 2°C / 60% ± 5% RH). The results of the stability test are shown in Tables 1 and 2. The stability test data indicate that the resulting docetaxel solution was stable under both long-term and accelerated conditions. [Table 2] [Table 3]

[0165] Example 17: Four different formulations of docetaxel solution were prepared by dissolving docetaxel and citric acid in absolute ethanol. The compositions of the four formulations are as follows: Formulation A (20 mg / ml docetaxel and 0.01 mg / ml citric acid), Formulation B (20 mg / ml docetaxel and 0.02 mg / ml citric acid), Formulation C (20 mg / ml docetaxel and 0.1 mg / ml citric acid), and Formulation D (20 mg / ml docetaxel and 0.2 mg / ml citric acid).

[0166] The pH values ​​of the four formulations of docetaxel solution were measured along with the docetaxel solution obtained in Example 16 (Formulation E: 20 mg / ml docetaxel and 0.04 mg / ml citric acid). The results of the pH test are shown in Table 3. [Table 4]

[0167] Example 18: A batch of docetaxel infusion solution (88 mg / 4.4 mL) containing docetaxel (88 mg) and citric acid (0.176 mg) in absolute ethanol (4.4 mL) was obtained according to the same manufacturing process and procedure as described in Example 16. A reconstituted parenteral infusion solution of docetaxel (160 mL) was prepared according to the following procedure: 15 mL of 20% human albumin infusion solution was mixed with 143 mL of 0.9% sodium chloride and injected into an infusion bottle. Then, 2 mL of docetaxel infusion solution (40 mg / docetaxel) was rapidly injected into the albumin saline solution in the infusion bottle and mixed well with the albumin saline solution to obtain a clear docetaxel infusion solution. The resulting docetaxel infusion solution was examined for particle size distribution using dynamic light scattering (DLS). For comparison, albumin saline was also examined for particle size distribution using DLS. To prepare the albumin saline solution, the same preparation procedure as for the docetaxel infusion solution was used, except that the same amount (2 mL) of absolute ethanol was used (infusion) instead of the 2 mL of docetaxel infusion in the final step of preparation. The DLS test results for the docetaxel infusion solution and albumin saline are shown in Figure 1. The docetaxel infusion solution has a nearly identical particle size distribution profile compared to the albumin saline solution. The DLS data indicated that the docetaxel infusion solution is the same simple solution as the albumin saline solution. See Figures 1A and 1B.

[0168] Example 19: The percentage of free (unbound) docetaxel in the reconstituted docetaxel infusion solution prepared using the docetaxel infusion solution (88 mg / 4.4 mL) obtained in Example 16 was tested. The docetaxel infusion solution was prepared using the same procedure as described in Example 18. The percentage of free (unbound) docetaxel in the docetaxel infusion solution was measured by ultrafiltration using a 30 kDa membrane. The percentage of free (unbound) docetaxel in the docetaxel infusion solution ranged from 62.8% to 67%. The results of the percentage of free (unbound) docetaxel in the reconstituted docetaxel infusion solution are shown in Table 4. [Table 5]

[0169] Example 20: The percentage of free (unbound) docetaxel in two reconstituted docetaxel infusion solutions was studied by varying the amount of human serum albumin in the docetaxel infusion solutions. Docetaxel infusion solution-A, which has a lower amount of albumin, and docetaxel infusion solution-B, which has a higher amount of albumin compared to the docetaxel infusion solution of Example 19, were prepared.

[0170] Preparation of docetaxel infusion solution-A: 5 mL of 20% human albumin infusion solution was mixed with 74 mL of 0.9% sodium chloride for injection and injected into an infusion bottle first, and then 1 mL (20 mg) of docetaxel infusion solution (prepared in Example 16) was rapidly injected into the albumin saline solution in the infusion bottle and mixed thoroughly with the albumin saline solution to obtain docetaxel infusion solution-A as a clear solution.

[0171] Preparation of Docetaxel Injection Solution-B: 10 mL of 20% human albumin injection solution was mixed with 69 mL of 0.9% sodium chloride for injection and injected into an infusion bottle first, and then 1 mL (20 mg) of Docetaxel Injection Solution (prepared in Example 16) was rapidly injected into the albumin saline solution in the infusion bottle and mixed thoroughly with the albumin saline solution to obtain Docetaxel Injection Solution-B as a clear solution.

[0172] The percentage of free (unbound) docetaxel in Docetaxel Infusion Solution-A and Docetaxel Infusion Solution-B is measured by ultrafiltration through a 30 kDa membrane. The results of the percentage of free (unbound) docetaxel in the reconstituted Docetaxel Infusion Solutions are shown in Table 5. [Table 6]

[0173] Example 21: 10 mL of 20% human albumin injection solution was first mixed with 148 mL of 0.9% sodium chloride in a 250 mL infusion bottle, and then 2 mL (40 mg) of docetaxel injection solution (prepared in Example 16) was rapidly injected into the albumin saline solution in the infusion bottle, and the infusion bottle was inverted to thoroughly mix with the albumin saline solution to obtain a clear infusion solution. The infusion solution remained clear without precipitate for 6 hours.

[0174] Example 22: Preparation of docetaxel infusion solution containing polysorbate 80: 201.5 mg of docetaxel was dissolved in 5 mL of absolute ethanol, followed by the addition of 5 mL of polysorbate 80 to obtain a clear solution of docetaxel infusion solution containing polysorbate 80. 295.5 mL of 0.9% sodium chloride for injection was first prepared in a 500 mL infusion bottle. Next, 4.5 mL of docetaxel infusion solution containing polysorbate 80 and ethanol (1:1, v / v) (prepared as described above) was rapidly injected into the saline solution in the infusion bottle. The infusion bottle was inverted and mixed well with the saline solution to obtain a clear infusion solution. The infusion solution remained clear for 6 hours without any precipitate.

[0175] Example 23: A batch of docetaxel injection solution (88 mg / 4.4 mL) containing docetaxel (88 mg) and citric acid (0.176 mg) in absolute ethanol (4.4 mL) was obtained according to the same manufacturing process and procedure as described in Example 16.

[0176] 37.5 mL of 20% human albumin infusion solution was first mixed with 357.5 mL of 0.9% sodium chloride for injection in a 500 mL infusion bottle. Then, while the infusion bottle was held stationary, 5 mL of the docetaxel infusion solution (prepared above) was rapidly injected into the albumin saline solution in the infusion bottle. After inverting the infusion solution bottle approximately 20 times to thoroughly mix the solution, a clear infusion solution was obtained. The infusion solution remained clear for 7 hours without any precipitate.

[0177] First, 22.5 mL of 20% human albumin infusion solution and 214.5 mL of 0.9% sodium chloride for infusion were mixed in a 250 mL infusion bottle. Then, while the infusion solution bottle was kept stationary, 3 mL of docetaxel infusion solution (prepared above) was rapidly injected into the albumin saline solution in the infusion solution bottle. After inverting the infusion solution bottle approximately 30 times to thoroughly mix the solution, a clear infusion solution was obtained. The infusion solution remained clear and free of precipitate for 8 hours.

[0178] More examples While the present invention has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to illustrate, but not to limit, the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. 1. An injectable pharmaceutical composition comprising docetaxel or a pharmaceutically acceptable salt thereof and ethanol, wherein the injectable pharmaceutical composition does not contain polysorbate 80, and the injectable pharmaceutical composition is further mixed with an aqueous composition comprising human serum albumin to form a parenteral infusion solution before being injected or administered to a patient.

2. 10. The injectable pharmaceutical composition of claim 1, comprising about 5 mg to about 500 mg of docetaxel or a pharmaceutically acceptable salt thereof.

3. 10. The injectable pharmaceutical composition of claim 1, comprising about 20 mg, about 40 mg, about 80 mg, about 120 mg, or about 160 mg of docetaxel or a pharmaceutically acceptable salt thereof.

4. 10. The injectable pharmaceutical composition of claim 1, which is surfactant-free.

5. 2. The injectable pharmaceutical composition of claim 1, wherein the concentration of docetaxel or its pharmaceutically acceptable salt is from about 5 mg / mL to about 40 mg / mL.

6. 2. The injectable pharmaceutical composition of claim 1, wherein the concentration of docetaxel or its pharmaceutically acceptable salt is about 10 mg / mL, about 15 mg / mL, or about 20 mg / mL.

7. 10. The injectable pharmaceutical composition of claim 1, further comprising an acid.

8. The injectable pharmaceutical composition of claim 7 , wherein the acid is an organic acid.

9. 9. The injectable pharmaceutical composition of claim 8, wherein the organic acid is citric acid.

10. 10. The injectable pharmaceutical composition of claim 1, wherein the pH value is from about 3 to about 9.

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