Neutral pH composition of docetaxel and human serum albumin

Abstract

The present invention relates to a non-covalently bound complex comprising docetaxel and human serum albumin, and to a composition comprising the complex. The present invention also relates to a composition comprising docetaxel and human serum albumin, wherein the weight ratio of the docetaxel to the human serum albumin in the composition is about 1:50 to about 1:1000, and wherein the pH of the composition is about 5 to about 8; the composition is an aqueous preparation, and the aqueous preparation is a clear aqueous solution; the preparation method of the composition comprises the following steps: (i) obtaining an organic solution in which docetaxel is dissolved in a polar water-soluble organic solvent; (ii) obtaining a first aqueous solution of human serum albumin; and (iii) mixing the organic solution of docetaxel with the first aqueous solution of human serum albumin to obtain a second aqueous solution comprising a composition comprising docetaxel and human serum albumin, wherein the mixing is performed at room temperature.

Description

Technical Field

[0001] The present invention relates to complexes and compositions for treating proliferative diseases, and more particularly to complexes and compositions comprising docetaxel and human serum albumin, wherein the pH of the composition is neutral. Background Art

[0002] Many drugs used parenterally are insoluble in water and are therefore formulated with solubilizers, surfactants, solvents and / or emulsifiers that are irritating, allergic or toxic when administered to a patient. See, for example, Briggs et al., Anesthesis 37, 1099 (1982) and Waugh et al., Am. J. Hosp. Pharmacists, 48, 1520 (1991). In addition, many of these drugs, especially those administered intravenously, can cause adverse side effects such as venous irritation, phlebitis, burning and pain during injection, venous thrombosis, extravasation and other side effects associated with administration. In addition, free drug present in the formulation often induces pain or irritation when administered.

[0003] Taxanes play an important role in the treatment of various solid tumors. As a second-generation semisynthetic taxane derivative, docetaxel is about twice as potent as paclitaxel in participating in microtubule depolymerization and has a unique ability to alter certain types of microtubules, which is different from most spindle toxins currently used in clinical practice. However, docetaxel has extremely poor water solubility. Commercially available docetaxel Clinical intravenous administration of docetaxel is prepared in a high concentration solution containing 40 mg docetaxel and 1040 mg polysorbate 80 per ml. This concentrated solution must be carefully diluted with a solvent containing 13% ethanol in saline before administration and must be used within 4 hours due to its limited stability. These characteristics limit the administration of docetaxel. In addition, docetaxel administration has been reported to be associated with an incidence of unpredictable (acute) allergic 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 have been attributed in part to the presence of polysorbate 80.

[0004] US 2005 / 0282734 describes a complex of paclitaxel with albumin. A successful formulation as described in the present invention requires an acidic pH.

[0005] WO 2014 / 121033 describes complexes of camptothecin with albumin.

[0006] US 2012 / 0076862 describes nanoparticles of taxanes and albumin.

[0007] US 2010 / 0076008 describes paclitaxel non-covalently bound to HSA.

[0008] WO 2016 / 187147 describes a complex of docetaxel with albumin.

[0009] Therefore, there is a need in the art for stable and non-toxic docetaxel formulations. The compositions and methods described in this application help to meet this need. Summary of the invention

[0010] Provided herein are non-covalently bound complexes comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin is about 0.1: 1 to about 5: 1. In some embodiments, the pH of the composition comprising the non-covalently bound complex comprising docetaxel and human serum albumin is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.4, about 6.5, about 6.6, about 7, about 7.5, or about 8).

[0011] In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.1: 1 to about 3: 1, about 0.5: 1 to about 2: 1, about 0.75: 1 to about 1.5: 1, or about 0.8: 1 to about 1.3: 1. In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.5: 1, about 0.6: 1, about 0.7: 1, about 0.8: 1, about 0.9: 1, about 1: 1, about 1.1: 1, about 1.2: 1, about 1.3: 1, about 1.4: 1, or about 1.5: 1.

[0012] In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin. In some embodiments, the human serum albumin is fatty acid-free human serum albumin. In some embodiments, the human serum albumin is substantially free of fatty acids.

[0013] Also provided herein is a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin is from about 0.1:1 to about 5:1.

[0014] The present application also provides a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the complex is about 0.1:1 to about 5:1.

[0015] In some embodiments, the molar ratio of docetaxel to human serum albumin in the complex is about 0.1: 1 to about 3: 1, about 0.5: 1 to about 2: 1, about 0.75: 1 to about 1.5: 1, or about 0.8: 1 to about 1.3: 1. In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.5: 1, about 0.6: 1, about 0.7: 1, about 0.8: 1, about 0.9: 1, about 1: 1, about 1.1: 1, about 1.2: 1, about 1.3: 1, about 1.4: 1, or about 1.5: 1.

[0016] In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin. In some embodiments, the human serum albumin is fatty acid-free human serum albumin. In some embodiments, the human serum albumin is substantially free of fatty acids.

[0017] Also provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 0.1: 1 to about 5: 1. In some embodiments, the molar ratio of docetaxel to human serum albumin is from about 0.1: 1 to about 3: 1, from about 0.5: 1 to about 3: 1, from about 0.5: 1 to about 2: 1, from about 0.75: 1 to about 1.5: 1, or from about 0.8: 1 to about 1.3: 1. In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, or about 2.5:1. In some embodiments, the pH of the composition comprising the non-covalently bound complex comprising docetaxel and human serum albumin is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0018] In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin. In some embodiments, the human serum albumin is fatty acid-free human serum albumin. In some embodiments, the human serum albumin is substantially free of fatty acids.

[0019] In some embodiments, composition is solid preparation.For example, solid preparation can be prepared uniformly by lyophilization.Those skilled in the art will recognize that other methods can also prepare solid preparation, such as rotary evaporation.In some embodiments, the pH of solid preparation is neutral (for example, the pH of composition is about 5 to about 8, about 5.5 to about 7.5 or about 6 to about 7, or the pH of composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5 or about 8).

[0020] In some embodiments, the composition is an aqueous preparation. In some embodiments, the aqueous preparation is substantially free of solvents other than water. In some embodiments, the aqueous preparation is free of solvents other than water. In some embodiments, the aqueous preparation includes water and a water-soluble organic solvent, and the water-soluble organic solvent includes at least one of polyethylene glycol 300, polyethylene glycol 400, ethanol, methanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide and dimethyl sulfoxide. For example, the water-soluble organic solvent may include ethanol. In some embodiments, the aqueous preparation includes water and ethanol. In some embodiments, the water-soluble organic solvent may be a mixture of water-soluble organic solvents.

[0021] In some embodiments, the aqueous formulation may be free of surfactants such as Surfactants and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of surfactants, such as Surfactants and polysorbate 80. In some embodiments, the aqueous formulation does not contain Surfactants and polysorbate 80 surfactants.

[0022] In some embodiments, aqueous preparations are clear aqueous solutions.For example, preparations can be clear and stable aqueous solutions reconstituted by sterile lyophilized powder.In some embodiments, aqueous preparations are clear aqueous solutions, wherein the aqueous preparations are substantially free of solvents other than water.In some embodiments, aqueous preparations are clear aqueous solutions, wherein the aqueous preparations are free of solvents other than water.In some embodiments, the pH of aqueous preparations (for example, clear aqueous solutions) is neutral (for example, the pH of the composition is about 5 to about 8, about 5.5 to about 7.5 or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5 or about 8).

[0023] Also provided herein is a pharmaceutical composition comprising the composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0024] Also provided herein is a method for treating cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0025] In some embodiments, cancer is a solid tumor cancer. In some embodiments, cancer is selected from breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer, ovarian cancer, pancreatic cancer and Kaposi's sarcoma. In some embodiments, cancer is breast cancer. In some embodiments, cancer is non-small cell lung cancer. In some embodiments, cancer is prostate cancer. In some embodiments, cancer is gastric cancer. In some embodiments, cancer is head and neck cancer. In some embodiments, cancer is ovarian cancer. In some embodiments, cancer is pancreatic cancer. In some embodiments, cancer is Kaposi's sarcoma.

[0026] Also provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the composition has a solubility of at least 10 mg / ml in an aqueous solution. In some aspects of these embodiments, the pH of the composition is neutral (e.g., the pH of the composition is from about 5 to about 8, from about 5.5 to about 7.5, or from about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0027] In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.1:1 to about 3:1, about 0.2:1 to about 3:1, about 0.2:1 to about 2:1, about 0.5:1 to about 2:1, about 0.75:1 to about 1.5:1, or about 0.8:1 to about 1.3:1. In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, or about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, or about 2.5:1.

[0028] In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin. In some embodiments, the human serum albumin is fatty acid-free human serum albumin. In some embodiments, the human serum albumin is substantially free of fatty acids.

[0029] In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution for at least 6 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution for at least 24 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution for at least 3 days. In some embodiments, the aqueous solution is substantially free of solvents other than water. In some embodiments, the aqueous solution does not contain solvents other than water.

[0030] In some embodiments, composition is solid preparation.For example, solid preparation can be prepared uniformly by lyophilization.Those skilled in the art will recognize that other methods can also prepare solid preparation, such as rotary evaporation.In some aspects of these embodiments, the pH of solid preparation is neutral (for example, the pH of composition is about 5 to about 8, about 5.5 to about 7.5 or about 6 to about 7, or the pH of composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5 or about 8).

[0031] In some embodiments, the composition is an aqueous preparation. In some embodiments, the aqueous preparation is substantially free of solvents other than water. In some embodiments, the aqueous preparation is free of solvents other than water. In some embodiments, the aqueous preparation includes water and a water-soluble organic solvent, and the water-soluble organic solvent includes at least one of polyethylene glycol 300, polyethylene glycol 400, ethanol, methanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide and dimethyl sulfoxide. For example, the water-soluble organic solvent may include ethanol. In some embodiments, the aqueous preparation includes water and ethanol. In some embodiments, the water-soluble organic solvent may be a mixture of water-soluble organic solvents.

[0032] In some embodiments, the aqueous formulation may be free of surfactants such as Surfactants and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of surfactants, such as Surfactants and polysorbate 80. In some embodiments, the aqueous formulation does not contain Surfactants and polysorbate 80 surfactants.

[0033] In some embodiments, aqueous preparations are clear aqueous solutions. For example, preparations can be clear and stable aqueous solutions reconstituted by sterile lyophilized powder. In some embodiments, aqueous preparations are clear aqueous solutions, wherein the aqueous preparations are substantially free of solvents other than water. In some embodiments, aqueous preparations are clear aqueous solutions, wherein the aqueous preparations are free of solvents other than water. In some embodiments, the solution remains clear for at least about 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 20 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days or a week. In some embodiments, the pH of the aqueous formulation is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0034] Also provided herein is a pharmaceutical composition comprising the composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0035] Also provided herein is a method for treating cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0036] In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi's sarcoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is Kaposi's sarcoma.

[0037] Also provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is from about 1:50 to about 1:1000, and wherein the pH of the composition is from about 5 to about 8; The composition is an aqueous preparation, which is a clear aqueous solution; the preparation method of the composition comprises the following steps: Steps: (i) obtaining an organic solution containing docetaxel dissolved in a polar water-soluble organic solvent; (ii) obtaining human serum albumin and (iii) mixing the organic solution of docetaxel with the first aqueous solution of human serum albumin To obtain a second aqueous solution comprising a composition including docetaxel and human serum albumin, the mixing is carried out at room temperature OK.

[0038] In some embodiments, the pH of the composition is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0039] In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:60 to about 1:300. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:250. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:200. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:120. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:100 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:100 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:130, about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about 1:190, about 1:200, about 1:210, about 1:220, about 1:230, about 1:240, or about 1:250.

[0040] In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin. In some embodiments, the human serum albumin is substantially free of fatty acids. In some embodiments, the human serum albumin is free of fatty acids.

[0041] In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution. In some embodiments, the aqueous solution is substantially free of solvents other than water.

[0042] In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution for at least 3 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution for at least 6 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution for at least 24 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution for at least 3 days. In some embodiments, the aqueous solution is substantially free of solvents other than water. In some embodiments, the pH of the aqueous solution is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0043] In some embodiments, the composition is a solid formulation. In some embodiments, the composition is an aqueous formulation. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of surfactants, such as Surfactant and polysorbate 80. In some embodiments, the aqueous formulation is a clear aqueous solution. In some embodiments, the aqueous formulation does not contain a Surfactants and surfactants of polysorbate 80. In some embodiments, the pH of the solid formulation or aqueous formulation is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0044] Also provided herein is a pharmaceutical composition comprising the composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0045] Also provided herein is a method for treating cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0046] In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi's sarcoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is Kaposi's sarcoma.

[0047] Also provided herein is a composition consisting essentially of docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is from about 1:50 to about 1:1000.

[0048] In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:60 to about 1:300. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:250. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:200. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:120. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:100 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:100 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:130, about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about 1:190, about 1:200, about 1:210, about 1:220, about 1:230, about 1:240, or about 1:250.

[0049] Instruction Manual

[0050] Figure 1 is a graph showing the mean plasma concentration of docetaxel over time after intravenous (IV) administration of 680 mg / kg of a composition comprising docetaxel and HSA in SD rats. Specific implementation plan

[0051] Provided herein are non-covalently bound complexes comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin is about 0.1: 1 to about 5: 1. In some embodiments, the pH of the composition comprising the non-covalently bound complex comprising docetaxel and human serum albumin is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0052] In some embodiments, the present disclosure provides a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in each complex is from about 0.1:1 to about 5:1.

[0053] In some embodiments, the present disclosure provides a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the complex is from about 0.1:1 to about 5:1.

[0054] In some embodiments, the molar ratio of docetaxel to human serum albumin in the complex is about 0.1: 1 to about 3: 1, about 0.5: 1 to about 2: 1, about 0.75: 1 to about 1.5: 1, or about 0.8: 1 to about 1.3: 1. In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.5: 1, about 0.6: 1, about 0.7: 1, about 0.8: 1, about 0.9: 1, about 1: 1, about 1.1: 1, about 1.2: 1, about 1.3: 1, about 1.4: 1, or about 1.5: 1.

[0055] In some embodiments, the non-covalent interaction between docetaxel and human serum albumin in the complex comprises hydrogen bonding. In some embodiments, the non-covalent interaction between docetaxel and human serum albumin in the complex comprises electrostatic interaction. In some embodiments, the non-covalent interaction between docetaxel and human serum albumin in the complex comprises hydrophobic interaction. In some embodiments, the non-covalent interaction between docetaxel and human serum albumin in the complex comprises van der Waals force.

[0056] As used herein, the term "human serum albumin" refers to natural human serum albumin and recombinant human serum albumin. Natural human serum albumin and other plasma proteins can be precipitated from human plasma by changing the pH and adding ethanol, which is called Cohn fractionation process (Cohn EJ et al., J.Am.Chem.Soc.1946; 68: 459-475). By controlling the pH and ethanol content, semi-purified fractions of plasma proteins can be produced. One of the last proteins precipitated in the Cohn process is natural human serum albumin. After precipitation, a wet paste of crude natural human serum albumin is obtained. Subsequent bioprocessing steps (purification, filtration, pasteurization, etc.) can be used to produce purified, stable forms of natural human serum albumin for commercial use (Lin JJ et al., Pharmaceutical Research 2000; 17: 391-6). Recombinant human serum albumin is a highly purified product free of animals, viruses and prions as a substitute for natural human serum albumin, which is structurally equivalent to natural human serum albumin (Bosse D et al., J. Clin. Pharmacol. 2005; 45: 57-67). Recombinant human serum albumin has been produced by various hosts of prokaryotes and eukaryotes (Chen Z et al., Biochimica et Biophysica Acta 2013; 1830: 5515-5525). Human serum albumin free of fatty acids can be prepared by treating human serum albumin with charcoal at low pH. Similarly, treating human serum albumin with charcoal at low pH can be used to remove fatty acids from human serum albumin (Chen RF, J. Biol. Chem. 1967; 242: 173-181).

[0057] Human serum albumin (HSA) is r65K highly soluble globular protein and composed of 585 amino acids. HSA is the most abundant protein in plasma and accounts for 70-80% of the colloid osmotic pressure in human plasma. The amino acid sequence of HSA contains a total of 17 disulfide bonds, a free thiol (Cys 34) and a single tryptophan (Trp 214). Intravenous use of HSA solution has been shown to be used for the prevention and treatment of hypovolemic shock (see, e.g., Tullis, JAMA, 237, 355-360, 460-463, (1977) and Houser et al., Surgery, Gynecology and Obstetrics, 150, 811-816 (1980)), and in combination with exchange transfusion therapy for the treatment of neonatal hyperbilirubinemia (see, e.g., Finlayson, Seminars in Thrombosis and Hemostasis, 6, 85-120, (1980)).

[0058] Human serum albumin (HSA) has multiple hydrophobic binding sites (seven in total for medium-chain and long-chain fatty acids, the endogenous ligands of HSA), and binds a variety of drugs, especially neutral and negatively charged hydrophobic compounds (Goodman et al., The Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill New York (1996)). Two high-affinity binding sites have been proposed in subdomains IIA and IIIA of HSA, which are highly elongated hydrophobic pockets with charged lysine and arginine residues near the surface, serving as attachment points for polar ligand features (see, e.g., Fehske et al., Biochem. Pharmcol., 30, 687-92 (1981), Vorum, Dan. Med. Bull., 46, 379-99 (1999), Kragh-Hansen, Dan. Med. Bull., 1441, 131-40 (1990), Curry et al., Nat. Struct. Biol., 5, 827-35 (1998), Sugio et al., Protein. Eng., 12, 439-46 (1999), He et al., Nature, 358, 209-15 (1992) and Carter et al., Adv. Protein. Chem., 45, 153-203 (1994)).

[0059] In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin. In some embodiments, the human serum albumin is human serum albumin free of fatty acids. In some embodiments, the human serum albumin is substantially free of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than two moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than one mole of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.5 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.1 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.05 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.01 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.001 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.0005 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.0001 moles of fatty acids.

[0060] As used herein, the term "non-covalently bound complex" refers to a complex in which the bonds between the components of the complex are non-covalent bonds (e.g., weak bonds such as hydrogen bonds, electrostatic effects, π effects, hydrophobic effects, and van der Waals forces). In addition, human serum albumin (HSA) has multiple hydrophobic binding sites (a total of seven for medium-chain and long-chain fatty acids, the endogenous ligands of HSA), and binds to a variety of drugs, especially neutral and negatively charged hydrophobic compounds (Goodman et al., The Pharmacological Basis of Therapeutics, 9th edition, McGraw-Hill New York (1996)). In addition, after the drug molecule is bound to HSA, the drug molecule forms a drug and protein complex with HSA that is non-covalently bound through the binding site of HSA. This concept is generally understood by those skilled in the art to which the present disclosure belongs. An example of a non-covalently bound complex is a non-covalently bound complex of HSA and fatty acids, wherein the fatty acids are bound to HSA through multiple binding sites of HSA.

[0061] As used herein, the term "stable" refers to a non-covalently bound complex that is not easily separated and aggregated into its individual parts, such as a non-covalently bound complex that is not easily separated and aggregated within a period of more than 6 hours, 12 hours, 24 hours, or 3 days. For example, a solution comprising a stable non-covalently bound complex often appears transparent, while a solution comprising an unstable non-covalently bound complex appears translucent or turbid. In addition, one of ordinary skill in the art will appreciate that after a period of time, a stable non-covalently bound complex can separate and aggregate into its individual parts. Therefore, a solution comprising a stable non-covalently bound complex can become translucent or turbid after a period of time (e.g., 6 hours, 12 hours, 24 hours, or 3 days).

[0062] In vitro studies have shown that docetaxel is approximately 94% protein bound primarily to alpha 1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, in vitro binding to plasma proteins was found to be approximately 97%. See Docetaxel Prescribing Information.

[0063] As used herein, the term "substantially free of fatty acids" refers to proteins (eg, serum albumin) containing less than about 0.02% by weight of fatty acids. For example, substantially free of fatty acids human serum albumin may contain less than 0.02% by weight of fatty acids.

[0064] As used herein, the term "fatty acid" refers to non-esterified fatty acids (eg, linoleic acid, α-linoleic acid, γ-linoleic acid).

[0065] As used herein, the term docetaxel is a compound having CAS No. 114977-28-5 and the following chemical structure:

[0066]

[0067] Docetaxel is a white to almost white powder that is highly lipophilic and practically insoluble in water.

[0068] In addition, docetaxel is a microtubule inhibitor indicated for breast cancer, non-small cell lung cancer, hormone-resistant prostate cancer, gastric adenocarcinoma, and squamous cell carcinoma of the head and neck.

[0069] In some embodiments, docetaxel can be a pharmaceutically acceptable salt of docetaxel.

[0070] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compounds of the invention and exhibits minimal adverse toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound with a suitable base or acid in its free acid or free base form, respectively. In some embodiments, pharmaceutically acceptable salts may be superior to respective free bases or free acids because these salts impart greater stability or solubility to the molecule, thereby facilitating the formulation to form a dosage form. Basic compounds are generally capable of forming 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, methylnitrate, 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, benzoate, o-acetoxybenzoate, chlorobenzoate, benzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, propionate, estolate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-aminobenzenesulfonate, p-toluenesulfonate, naphthalene-2-sulfonate, ethanedisulfonate, hydrogen disulfide (hydrogen Suitable bases include pharmaceutically acceptable inorganic bases and pharmaceutically acceptable organic bases.Representative pharmaceutically acceptable base addition salts include alkali metal hydroxides, including sodium, potassium and lithium; alkaline earth metal hydroxides, such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines, such as unsubstituted or hydroxy-substituted mono-, di- or tri-alkylamines, dicyclohexylamine; tributylamine; pyridine; N-methylamine, N-ethylamine; diethylamine; triethylamine; mono-, di- or tri-(2-OH-(C1-C6)-alkylamines), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids, such as arginine, lysine, and the like.

[0071] In some embodiments, docetaxel may be docetaxel with 1, 2 or 3 equivalents of water solvate. In some embodiments, docetaxel may be docetaxel with three equivalents of water solvate. In some embodiments, docetaxel is docetaxel trihydrate. In some embodiments, docetaxel is docetaxel monohydrate. In some embodiments, docetaxel is anhydrous docetaxel. In some embodiments, docetaxel may be docetaxel with one equivalent of acetone solvate. In some embodiments, docetaxel may be any of the docetaxel solvates disclosed, for example, in WO2010091650 or US2012007167, the disclosures of which are incorporated herein by reference in their entirety.

[0072] In some embodiments, docetaxel is crystalline. In some embodiments, docetaxel is any of the crystalline forms disclosed, for example, in WO2012115402, US8410294, US20100197944, US20100099897, US8357811, US20100160653 or US20070142457, the disclosures of which are incorporated herein by reference in their entirety.

[0073] In some embodiments, docetaxel is amorphous. In some embodiments, docetaxel is any of the amorphous forms disclosed, for example, in WO2008102374, the disclosure of which is incorporated herein by reference in its entirety.

[0074] Also provided herein is a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin is from about 0.1:1 to about 5:1.

[0075] In some embodiments, the present disclosure provides a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the complex is from about 0.1:1 to about 5:1.

[0076] In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.1: 1 to about 3: 1, about 0.5: 1 to about 2: 1, about 0.75: 1 to about 1.5: 1, or about 0.8: 1 to about 1.3: 1. In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.5: 1, about 0.6: 1, about 0.7: 1, about 0.8: 1, about 0.9: 1, about 1: 1, about 1.1: 1, about 1.2: 1, about 1.3: 1, about 1.4: 1, or about 1.5: 1.

[0077] In some embodiments, the molar ratio of docetaxel to human serum albumin in the complex is about 0.1: 1 to about 3: 1, about 0.5: 1 to about 2: 1, about 0.75: 1 to about 1.5: 1, or about 0.8: 1 to about 1.3: 1. In some embodiments, the molar ratio of docetaxel to human serum albumin in the complex is about 0.5: 1, about 0.6: 1, about 0.7: 1, about 0.8: 1, about 0.9: 1, about 1: 1, about 1.1: 1, about 1.2: 1, about 1.3: 1, about 1.4: 1, or about 1.5: 1.

[0078] In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin. In some embodiments, the human serum albumin is human serum albumin free of fatty acids. In some embodiments, the human serum albumin is substantially free of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than two moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than one mole of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.5 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.1 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.05 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.01 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.001 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.0005 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.0001 moles of fatty acids.

[0079] Also provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 0.1: 1 to about 5: 1. In some embodiments, the present disclosure provides a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the complex is from about 0.1: 1 to about 5: 1. In some embodiments, the pH of the composition comprising the non-covalently bound complex comprising docetaxel and human serum albumin is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0080] In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.1:1 to about 3:1, about 0.5:1 to about 3:1, about 0.5:1 to about 2:1, about 0.75:1 to about 1.5:1, or about 0.8:1 to about 1.3:1. In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, or about 2.5:1.

[0081] In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin. In some embodiments, the human serum albumin is human serum albumin free of fatty acids. In some embodiments, the human serum albumin is substantially free of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than two moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than one mole of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.5 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.1 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.05 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.01 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.001 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.0005 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.0001 moles of fatty acids.

[0082] In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution. In some embodiments, the aqueous solution is substantially free of solvents other than water. In some embodiments, the aqueous solution is free of solvents other than water.

[0083] In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8.

[0084] In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of from about 6 to about 7.5.

[0085] In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.2:1 to about 0.3:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8.

[0086] In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.2:1 to about 0.3:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of from about 6 to about 7.5.

[0087] In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.1:1 to about 0.5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8.

[0088] In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.1:1 to about 0.5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of from about 6 to about 7.5.

[0089] In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is free of solvents other than water.

[0090] In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.2:1 to about 0.3:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.2:1 to about 0.3:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is free of solvents other than water.

[0091] In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.1:1 to about 0.5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.1:1 to about 0.5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is free of solvents other than water.

[0092] In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is free of solvents other than water.

[0093] In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 1.2: 1 to about 0.3: 1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 1.2: 1 to about 0.3: 1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is free of solvents other than water.

[0094] In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 1.1:1 to about 0.5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 1.1:1 to about 0.5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is free of solvents other than water.

[0095] In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 5 to about 8. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 5.5 to about 7.8. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6 to about 7.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6.5 to about 7.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6 to about 6.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6.5 to about 7. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 7 to about 7.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of solvents other than water.

[0096] In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution for at least 3 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution for at least 6 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution for at least 24 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution for at least 3 days. In some embodiments, the aqueous solution is substantially free of solvents other than water. In some embodiments, the aqueous solution does not contain solvents other than water.

[0097] Preparations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injections that may contain antioxidants, buffers, antibacterial agents and solutes that make the preparations compatible with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that may include suspending agents, solubilizers, thickeners, stabilizers and preservatives. The preparations may be present in unit dose or multi-dose sealed containers, such as ampoules or vials, and may be stored under freeze-drying (lyophilized) conditions, requiring only the immediate addition of sterile liquid excipients (e.g., water) prior to use for injection. Ready-to-use injections and suspensions may be prepared from sterile powders, granules and tablets.

[0098] In some embodiments, composition is solid preparation.For example, solid preparation can be prepared uniformly by lyophilization.Those skilled in the art will recognize that other methods can also prepare solid preparation, such as rotary evaporation.In some embodiments, the pH of solid preparation is neutral (for example, the pH of composition is about 5 to about 8, about 5.5 to about 7.5 or about 6 to about 7, or the pH of composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5 or about 8).

[0099] In some embodiments, the composition is an aqueous preparation. In some embodiments, the aqueous preparation is substantially free of solvents other than water. In some embodiments, the aqueous preparation is free of solvents other than water. In some embodiments, the aqueous preparation includes water and a water-soluble organic solvent, and the water-soluble organic solvent includes at least one of polyethylene glycol 300, polyethylene glycol 400, ethanol, methanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide and dimethyl sulfoxide. For example, the water-soluble organic solvent may include ethanol. In some embodiments, the aqueous preparation includes water and ethanol. In some embodiments, the water-soluble organic solvent may be a mixture of water-soluble organic solvents. In some embodiments, the pH of the aqueous formulation (e.g., a clear aqueous solution) is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0100] As used herein, "substantially free of solvent" with respect to an aqueous solution refers to an aqueous solution containing less than 0.5% by weight of any non-aqueous solvent. In some embodiments, the aqueous solution contains less than 0.1% by weight of any non-aqueous solvent. In some embodiments, the aqueous solution contains less than 0.05% by weight of any non-aqueous solvent.

[0101] In some embodiments, the aqueous formulation may be free of surfactants. In some embodiments, the aqueous formulation may be free of surfactants, such as Surfactants and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of surfactants, such as Surfactants and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of Surfactants and polysorbate 80 surfactants.

[0102] As used herein, the term "substantially free of surfactants" refers to formulations containing less than 0.0005%, less than 0.0003%, or less than 0.0001% surfactants and / or less than 0.0005%, less than 0.0003%, or less than 0.0001% surfactants.

[0103] In some embodiments, the aqueous formulation is a clear aqueous solution. For example, the formulation can be a clear and stable aqueous solution reconstituted from a sterile lyophilized powder. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation is free of solvents other than water.

[0104] As used herein, the term "clear aqueous solution" refers to a solution containing docetaxel and HSA in an aqueous solution, which is transparent upon visual observation and substantially free of visible particles or precipitates of undissolved docetaxel.

[0105] The term "substantially free of visible particles or precipitates of undissolved docetaxel" can be assessed as follows: after filtering the clear aqueous solution with a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 95% of the total amount of docetaxel in the aqueous solution before filtration. The total amount of docetaxel in the aqueous solution before filtration includes particles or precipitates of undissolved docetaxel in the aqueous solution or together with the aqueous solution. The amount of docetaxel in the aqueous solution can be measured by using a method of HPLC. The method of measuring the amount of docetaxel in the aqueous solution is described in the experimental examples described herein. The method is generally understood by a person of ordinary skill in the art to which the present disclosure belongs.

[0106] When visually observed, for example, the term "clear aqueous solution" does not include a milky aqueous solution. In addition, the term "clear aqueous solution" does not include a turbid or hazy aqueous solution.

[0107] As used herein, the term "micron" refers to a unit of measurement of one thousandth of a millimeter. In some embodiments, the term "micron" refers to a micrometer.

[0108] In some embodiments, the aqueous preparation is a clear aqueous solution reconstituted in water by a solid preparation (e.g., a sterile lyophilized powder). In some embodiments, the aqueous preparation is a clear aqueous solution reconstituted in 0.9% saline solution by a solid preparation (e.g., a sterile lyophilized powder). In some embodiments, the aqueous preparation is a clear aqueous solution reconstituted in 5% glucose aqueous solution by a solid preparation (e.g., a sterile lyophilized powder).

[0109] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in water, wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 0.9% saline solution, wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 5% dextrose aqueous solution, wherein the aqueous formulation has a pH of about 5 to about 8.

[0110] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in water, wherein the pH of the water is about 7, and wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 0.9% saline solution, wherein the pH of the 0.9% saline solution is about 5.4, and wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 5% glucose aqueous solution, wherein the pH of the 5% glucose solution is about 4.4, and wherein the aqueous formulation has a pH of about 5 to about 8. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or 200 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 10 mg per 1 ml of aqueous solvent to about 500 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 25 mg per 1 ml of aqueous solvent to about 250 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 30 mg per 1 ml of aqueous solvent to about 200 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 40 mg per 1 ml of aqueous solvent to about 150 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 50 mg per 1 ml of aqueous solvent to about 125 mg per 1 ml of aqueous solvent.

[0111] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in water by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the water is about 7, and wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 0.9% saline solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the 0.9% saline solution is about 5.4, and wherein the aqueous formulation has a pH of about 6.7 to about 7.1. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 5% glucose aqueous solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the 5% glucose solution is about 4.4, and wherein the aqueous formulation has a pH of about 6.7 to about 7.1. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or 200 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 10 mg per 1 ml of aqueous solvent to about 500 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 25 mg per 1 ml of aqueous solvent to about 250 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 30 mg per 1 ml of aqueous solvent to about 200 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 40 mg per 1 ml of aqueous solvent to about 150 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 50 mg per 1 ml of aqueous solvent to about 125 mg per 1 ml of aqueous solvent.

[0112] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in water by a solid formulation (e.g., a sterile lyophilized powder), wherein the aqueous formulation has a pH value of about 6 to about 7.5. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 0.9% saline solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the aqueous formulation has a pH value of about 6 to about 7.5. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 5% glucose aqueous solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the aqueous formulation has a pH value of about 6 to about 7.5.

[0113] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in water by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the water is about 7, and wherein the aqueous formulation has a pH of about 6 to about 7.5. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 0.9% saline solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the 0.9% saline solution is about 5.4, and wherein the aqueous formulation has a pH of about 6 to about 7.5. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 5% glucose aqueous solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the 5% glucose solution is about 4.4, and wherein the aqueous formulation has a pH of about 6 to about 7.5.

[0114] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in water, wherein the pH of the water is about 7, and wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 0.9% saline solution, wherein the pH of the 0.9% saline solution is about 5.4, and wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 5% dextrose aqueous solution, wherein the pH of the 5% dextrose solution is about 4.4, and wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8.

[0115] In some embodiments, the aqueous formulation has a pH value of about 5 to about 8. In some embodiments, the aqueous formulation has a pH value of about 5.5 to about 7.8. In some embodiments, the aqueous formulation has a pH value of about 6 to about 7.5. In some embodiments, the aqueous formulation has a pH value of about 6.5 to about 7.5. In some embodiments, the aqueous formulation has a pH value of about 6 to about 6.5. In some embodiments, the aqueous formulation has a pH value of about 6 to about 6.5. In some embodiments, the aqueous formulation has a pH value of about 6.5 to about 7. In some embodiments, the aqueous formulation has a pH value of about 7 to about 7.5. In some embodiments, the aqueous formulation has a pH value of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4 or about 7.5. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation does not contain solvents other than water.

[0116] In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 5 to about 8, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 5 to about 8, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 5.5 to about 7.8, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 5.5 to about 7.8, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 7.5, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 7.5, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 7.5, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6.5 to about 7.5, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6.5 to about 7.5, and wherein the aqueous formulation is free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 6.5, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 6.5, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6.5 to about 7, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 6.5 to about 7, and wherein the aqueous formulation does not contain a solvent other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 7 to about 7.5, and wherein the aqueous formulation is substantially free of a solvent other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 7 to about 7.5, and wherein the aqueous formulation does not contain a solvent other than water.In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5, and wherein the aqueous formulation is free of solvents other than water.

[0117] In some embodiments, after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 97% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 98% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 99% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 99.5% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, the aqueous formulation is substantially free of solvents other than water.

[0118] In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution does not contain solvents other than water. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution does not contain solvents other than water.

[0119] In some embodiments, the aqueous formulation is a clear aqueous solution for at least 3 hours at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C. In some embodiments, the aqueous formulation is a clear aqueous solution for at least 6 hours at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C for at least 24 hours. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 20°C, about 35°C, or about 35°C for at least 3 days. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of solvents other than water.

[0120] In some embodiments, the aqueous formulation is an aqueous solution, wherein after the aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 80% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, the aqueous formulation is an aqueous solution, wherein after the aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 85% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, the aqueous formulation is an aqueous solution, wherein after the aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 90% of the total amount of docetaxel in the aqueous solution before filtration.

[0121] Also provided herein is a pharmaceutical composition comprising the composition comprising a non-covalently bound complex of docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0122] In some embodiments, the pharmaceutical composition further comprises at least one anti-cancer drug (eg, any anti-cancer drug as described herein).

[0123] As used herein, the term "pharmaceutically acceptable carrier" means any solution used to dissolve a medicament and deliver the medicament to a subject. A desirable pharmaceutically acceptable carrier is normal saline. Other pharmaceutically acceptable carriers and formulations thereof are known to those skilled in the art and are described, for example, in Remington's Pharmaceutical Sciences. (20th edition), editor A. Gennaro, 2003, Lippincon Williams & Wilkins.

[0124] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (other than HSA), buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, and cellulose-based substances.

[0125] In some embodiments, the pharmaceutical composition does not contain a surfactant, such as Surfactants and polysorbate 80.

[0126] In some embodiments, the pharmaceutical composition is substantially free of surfactants, such as Surfactants and polysorbate 80. In some embodiments, the pharmaceutical composition does not contain Surfactants and polysorbate 80 surfactants.

[0127] Also provided herein is a method of treating a proliferative disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.

[0128] As used herein, the terms "individual," "patient," or "subject" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0129] As used herein, the term "proliferative disease" refers to a disease caused by excessive cell proliferation and cell matrix renewal. Non-limiting examples of proliferative diseases include cancer, atherosclerosis, arthritis (e.g., rheumatoid arthritis), psoriasis, fibrosis (e.g., pulmonary fibrosis, idiopathic pulmonary fibrosis), scleroderma, and cirrhosis (e.g., cirrhosis of the liver).

[0130] Also provided herein is a method for treating cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0131] In some embodiments, the cancer is selected from bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary tract cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, and testicular cancer.

[0132] In some embodiments, the cancer is selected from sarcoma, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, teratoma, non-small cell lung cancer (NSCLC), bronchial lung cancer squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, small bronchoalveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal cancer, esophageal cancer, squamous cell carcinoma, adenocarcinoma, smooth muscle tumor, lymphoma, gastric cancer, carcinoma, lymphoma, leiomyosarcoma, pancreatic cancer, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilator peptide tumor, small intestine cancer, adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, colorectal cancer or colon cancer, tubular adenoma, villous adenoma, hamartoma, leiomyoma, genitourinary tract cancer, renal adenocarcinoma, Wilm's tumor tumor), lymphoma, leukemia, bladder cancer, urethral cancer, squamous cell carcinoma, transitional cell carcinoma, prostate cancer, testicular cancer, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma, liver cancer, hepatocellular carcinoma, bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, bone cancer, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma (Ewing's sarcoma), malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor of bone, chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma giant cell tumor of bone, nervous system cancer, skull cancer, osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningeal cancer, meningioma, meningeal sarcoma, glioma, brain cancer, astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord cancer, neurofibroma, meningioma, glioma, sarcoma, gynecological cancer, uterine cancer, endometrial cancer, cervical cancer (cancer of the cervix / cervicalcarcinoma), preneoplastic cervical dysplasia, ovarian cancer (cancer of the ovaries / ovariancarcinoma), serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecoma cell tumor, Sertoli-Leydig cell tumortumor), dysgerminoma, malignant teratoma, vulvar cancer, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, vaginal cancer, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tube cancer, hematologic 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, 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, moles dysplastic nevi), lipoma, hemangioma, dermatofibroma, keloid, psoriasis, adrenal carcinoma, and neuroblastoma.

[0133] As used herein, an "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" with respect to a compound or composition of the invention refers to an amount sufficient to induce a desired biological, pharmacological, or therapeutic result in a subject. The result may be a reduction, alleviation, delay, shortening of the time required for resolution, alleviation of a sign or symptom, or exertion of a medically beneficial effect or any other desirable change to a biological system based on an expected or observed side effect, toxicity, underlying pathophysiology or pathogenesis of a disorder or condition. In cancer treatment, the results will generally include reduction, alleviation, limitation, and / or delay of harmful physiological manifestations, growth, or metastasis of a neoplasm.

[0134] In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi's sarcoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is Kaposi's sarcoma.

[0135] In some embodiments, a method of treating cancer (e.g., any of the cancers described herein) comprises the step of administering to a subject in need thereof a therapeutically effective amount of a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin as described herein and a therapeutically effective amount of an inhibitor of at least one of the following kinases for treating cancer: PIM, Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R , IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TR KC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf.

[0136] In some embodiments, a method of treating cancer (e.g., any of the cancers described herein) comprises the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin as described herein and a therapeutically effective amount of at least one anti-cancer drug. Examples of anticancer drugs include abiraterone, abiraterone acetate, abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bavituximab, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral oral), calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin / denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, enzalutamide, epirubicin, erlotinib, estramustine, etoposide phosphatephosphate), etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab, ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon α2a, irinotecan, lapatinib ditosylate ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexeddisodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0137] In some embodiments, a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin as described herein is administered concurrently with an anti-cancer drug.

[0138] In some embodiments, a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin as described herein is administered consecutively with an anti-cancer drug.

[0139] The compositions described herein comprising a non-covalently bound complex comprising docetaxel and human serum albumin can be administered to an individual (such as a human) via various routes, such as parenteral, including intravenous, intraarterial, intraperitoneal, intrapulmonary, oral, inhalation, intracapsular, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal or transdermal routes. For example, the composition can be administered by inhalation to treat respiratory conditions. The composition can be used to treat respiratory conditions such as pulmonary fibrosis, bronchiolitis obliterans, lung cancer, bronchoalveolar carcinoma, etc. In some embodiments, the nanoparticle composition is administered intravenously.

[0140] The methods described herein may be performed alone or in combination with another treatment such as surgery, radiation, chemotherapy, immunotherapy, gene therapy, etc. Additionally, persons at greater risk of developing a proliferative disease may receive treatment to inhibit and / or delay the development of the disease.

[0141] As is understood by those of ordinary skill in the art, the appropriate dose of docetaxel will be approximately the dose that has been used in clinical treatments where docetaxel is administered alone or in combination with other chemotherapeutic agents. Depending on the condition being treated, the dose may vary. As will be appreciated by those of ordinary skill in the art, the appropriate effective dose will also vary depending on the severity of the disease, the route of administration, the sex, age and general health of the subject, the use of excipients, the possibility of co-use with other treatments (such as the use of other agents), and the judgment of the treating physician. For example, the prescribing information for docetaxel may be referenced to determine guidelines for selecting an effective dose.

[0142] Also provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the composition has a solubility of at least 10 mg / ml in an aqueous solution. In some aspects of these embodiments, the pH of the composition is neutral (e.g., the pH of the composition is from about 5 to about 8, from about 5.5 to about 7.5, or from about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0143] In some embodiments, the present disclosure provides a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 0.1: 1 to about 5: 1, wherein when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, and wherein the solubility of the composition in the aqueous solution is at least 10 mg / ml. In some aspects of these embodiments, the pH of the composition is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0144] In some embodiments, the composition has a solubility in aqueous solution of about 10 mg / ml, about 20 mg / ml, about 30 mg / ml, about 40 mg / ml, about 50 mg / ml, 60 mg / ml, about 70 mg / ml, about 80 mg / ml, about 90 mg / ml, about 100 mg / ml, about 110 mg / ml, about 120 mg / ml, about 130 mg / ml, about 140 mg / ml, about 150 mg / ml, or about 200 mg / ml.

[0145] In some embodiments, the solubility of the composition in aqueous solution is at least about 10 mg / ml, at least about 20 mg / ml, at least about 30 mg / ml, at least about 40 mg / ml, at least about 50 mg / ml, at least 60 mg / ml, at least about 70 mg / ml, at least about 80 mg / ml, at least about 90 mg / ml, at least about 100 mg / ml, at least about 150 mg / ml, or at least about 200 mg / ml.

[0146] As used herein, the term "aqueous solution" refers to a solution in which at least one solvent is water and the weight % of water in a solvent mixture is at least 50%, at least 60%, at least 70% or at least 90%. In some embodiments, an aqueous solution is a solution in which water is the only solvent. In some embodiments, an aqueous solution is a buffer (e.g., a phosphate buffer or a carbonate buffer). In some embodiments, the buffer is a physiological buffer or a pharmaceutically acceptable buffer. In some embodiments, the buffer is, for example, any buffer described in Y.-C.Lee et al., International Journal of Pharmaceutics 253 (2003) 111-119, the disclosure of which is incorporated herein by reference as a whole. In some embodiments, the buffer comprises maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate or a mixture thereof. In some embodiments, the pH range of the buffer is about 3 to about 9, about 4 to about 8, about 5 to about 7, about 6 to about 7, about 3 to about 5, about 3 to about 7, about 4 to about 6 or about 6 to about 6. In some embodiments, the pH of the buffer is about 4, about 5, about 6, about 6.4, about 6.5, about 6.6, about 7, about 7.5, or about 8. In other embodiments, the aqueous solution is 0.9% saline (wherein the pH of 0.9% saline is about 4 to about 6, about 4.5 to about 6, or about 5 to about 6, or wherein the pH of 0.9% saline is about 5, about 5.2, about 5.4, about 5.5, or about 6). In still other embodiments, the aqueous solution is 5% glucose solution (wherein the pH of 5% glucose solution is about 3 to about 5, about 3.5 to about 5, or about 4 to about 5, or wherein the pH of 5% glucose solution is about 4, about 4.2, about 4.4, about 4.5, or about 5).

[0147] As used herein, the term "aqueous solvent" refers to a liquid comprising at least 50%, at least 60%, at least 70%, at least 90%, or at least 95% water. In some embodiments, the aqueous solvent is water.

[0148] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8.

[0149] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is free of solvents other than water.

[0150] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5.

[0151] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is free of solvents other than water.

[0152] In some embodiments, the molar ratio of docetaxel to human serum albumin in the composition is about 0.1:1 to about 3:1, about 0.2:1 to about 3:1, about 0.2:1 to about 2:1, about 0.5:1 to about 2:1, about 0.75:1 to about 1.5:1, or about 0.8:1 to about 1.3:1. In some embodiments, the molar ratio of docetaxel to human serum albumin in the composition is about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, or about 2.5:1.

[0153] In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin. In some embodiments, the human serum albumin is human serum albumin free of fatty acids. In some embodiments, the human serum albumin is substantially free of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than two moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than one mole of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.5 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.1 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.05 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.01 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.001 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.0005 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.0001 moles of fatty acids.

[0154] In some embodiments, docetaxel may be a pharmaceutically acceptable salt of docetaxel. In some embodiments, docetaxel may be docetaxel having three equivalents of water solvate. In some embodiments, docetaxel may be any one of the crystalline form, amorphous form, solvate and hydrate as described herein.

[0155] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 1.2:1 to about 0.3:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8.

[0156] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.2:1 to about 0.3:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.2:1 to about 0.3:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is free of solvents other than water.

[0157] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 1.2:1 to about 0.3:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5.

[0158] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 1.2:1 to about 0.3:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 1.2:1 to about 0.3:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is free of solvents other than water.

[0159] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.1:1 to about 0.5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of from about 5 to about 8.

[0160] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.1:1 to about 0.5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.1:1 to about 0.5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is free of solvents other than water.

[0161] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.1:1 to about 0.5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of from about 6 to about 7.5.

[0162] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.1:1 to about 0.5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 1.1:1 to about 0.5:1, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is free of solvents other than water.

[0163] In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 5 to about 8. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 5.5 to about 7.8. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6 to about 7.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6.5 to about 7.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6 to about 6.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6.5 to about 7. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 7 to about 7.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of solvents other than water.

[0164] In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99% or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99% or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution does not contain solvents other than water. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution does not contain solvents other than water.

[0165] In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution for at least 6 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution for at least 24 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution for at least 3 days. In some embodiments, the aqueous solution is substantially free of solvents other than water. In some embodiments, the aqueous solution does not contain solvents other than water.

[0166] In some embodiments, the composition is a solid formulation. For example, the solid formulation can be uniformly prepared by lyophilization. Those skilled in the art will recognize that other methods can also prepare solid formulations, such as rotary evaporation.

[0167] In some embodiments, the composition is an aqueous preparation. In some embodiments, the aqueous preparation is substantially free of solvents other than water. In some embodiments, the aqueous preparation is free of solvents other than water. In some embodiments, the aqueous preparation includes water and a water-soluble organic solvent, and the water-soluble organic solvent includes at least one of polyethylene glycol 300, polyethylene glycol 400, ethanol, methanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide and dimethyl sulfoxide. For example, the water-soluble organic solvent may include ethanol. In some embodiments, the aqueous preparation includes water and ethanol. In some embodiments, the water-soluble organic solvent may be a mixture of water-soluble organic solvents.

[0168] In some embodiments, the aqueous formulation may be free of surfactants, such as Surfactants and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of surfactants, such as Surfactants and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of Surfactants and polysorbate 80 surfactants.

[0169] In some embodiments, the aqueous formulation is a clear aqueous solution. For example, the formulation can be a clear and stable aqueous solution reconstituted from a sterile lyophilized powder. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation is free of solvents other than water.

[0170] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in water by a solid formulation (e.g., a sterile lyophilized powder). In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in 0.9% saline by a solid formulation (e.g., a sterile lyophilized powder). In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in 5% glucose solution by a solid formulation (e.g., a sterile lyophilized powder).

[0171] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in water, wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in 0.9% saline, wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in 5% glucose solution, wherein the aqueous formulation has a pH of about 5 to about 8.

[0172] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in water, wherein the pH of the water is about 7, and wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 0.9% saline solution, wherein the pH of the 0.9% saline solution is about 5.4, and wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 5% glucose aqueous solution, wherein the pH of the 5% glucose solution is about 4.4, and wherein the aqueous formulation has a pH of about 5 to about 8. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or 200 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 10 mg per 1 ml of aqueous solvent to about 500 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 25 mg per 1 ml of aqueous solvent to about 250 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 30 mg per 1 ml of aqueous solvent to about 200 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 40 mg per 1 ml of aqueous solvent to about 150 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 50 mg per 1 ml of aqueous solvent to about 125 mg per 1 ml of aqueous solvent.

[0173] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in water by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the water is about 7, and wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 0.9% saline solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the 0.9% saline solution is about 5.4, and wherein the aqueous formulation has a pH of about 6.7 to about 7.1. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 5% glucose aqueous solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the 5% glucose solution is about 4.4, and wherein the aqueous formulation has a pH of about 6.7 to about 7.1. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or 200 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 10 mg per 1 ml of aqueous solvent to about 500 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 25 mg per 1 ml of aqueous solvent to about 250 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 30 mg per 1 ml of aqueous solvent to about 200 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 40 mg per 1 ml of aqueous solvent to about 150 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 50 mg per 1 ml of aqueous solvent to about 125 mg per 1 ml of aqueous solvent.

[0174] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in water by a solid formulation (e.g., a sterile lyophilized powder), wherein the aqueous formulation has a pH value of about 6 to about 7.5. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in 0.9% saline by a solid formulation (e.g., a sterile lyophilized powder), wherein the aqueous formulation has a pH value of about 6 to about 7.5. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in 5% glucose solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the aqueous formulation has a pH value of about 6 to about 7.5.

[0175] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in water by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the water is about 7, and wherein the aqueous formulation has a pH of about 6 to about 7.5. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 0.9% saline solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the 0.9% saline solution is about 5.4, and wherein the aqueous formulation has a pH of about 6 to about 7.5. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 5% glucose aqueous solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the 5% glucose solution is about 4.4, and wherein the aqueous formulation has a pH of about 6 to about 7.5.

[0176] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in water, wherein the pH of the water is about 7, and wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 0.9% saline solution, wherein the pH of the 0.9% saline solution is about 5.4, and wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 5% dextrose aqueous solution, wherein the pH of the 5% dextrose solution is about 4.4, and wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8.

[0177] In some embodiments, the aqueous formulation has a pH value of about 5 to about 8. In some embodiments, the aqueous formulation has a pH value of about 5.5 to about 7.8. In some embodiments, the aqueous formulation has a pH value of about 6 to about 7.5. In some embodiments, the aqueous formulation has a pH value of about 6.5 to about 7.5. In some embodiments, the aqueous formulation has a pH value of about 6 to about 6.5. In some embodiments, the aqueous formulation has a pH value of about 6 to about 6.5. In some embodiments, the aqueous formulation has a pH value of about 6.5 to about 7. In some embodiments, the aqueous formulation has a pH value of about 7 to about 7.5. In some embodiments, the aqueous formulation has a pH value of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4 or about 7.5. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation does not contain solvents other than water.

[0178] In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 5 to about 8, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 5 to about 8, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 5.5 to about 7.8, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 5.5 to about 7.8, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 7.5, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 7.5, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 7.5, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6.5 to about 7.5, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6.5 to about 7.5, and wherein the aqueous formulation is free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 6.5, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 6.5, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6.5 to about 7, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 6.5 to about 7, and wherein the aqueous formulation does not contain a solvent other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 7 to about 7.5, and wherein the aqueous formulation is substantially free of a solvent other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 7 to about 7.5, and wherein the aqueous formulation does not contain a solvent other than water.In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5, and wherein the aqueous formulation is free of solvents other than water.

[0179] In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 97% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 98% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 99% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 99.5% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of solvents other than water.

[0180] In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution does not contain solvents other than water. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution does not contain solvents other than water.

[0181] In some embodiments, the aqueous formulation is a clear aqueous solution for at least 3 hours at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C. In some embodiments, the aqueous formulation is a clear aqueous solution for at least 6 hours at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C for at least 24 hours. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 20°C, about 35°C, or about 35°C for at least 3 days. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of solvents other than water.

[0182] Also provided herein is a pharmaceutical composition comprising the composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0183] In some embodiments, the pharmaceutical composition does not contain a surfactant, such as Surfactants and polysorbate 80.

[0184] In some embodiments, the pharmaceutical composition is substantially free of surfactants, such as Surfactants and polysorbate 80.

[0185] Also provided herein is a method of treating a proliferative disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0186] Also provided herein is a method for treating cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0187] In some embodiments, the cancer is any one of the cancers described herein.

[0188] In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi's sarcoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is Kaposi's sarcoma.

[0189] In some embodiments, a method of treating cancer (e.g., any of the cancers described herein) comprises the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a therapeutically effective amount of at least one kinase inhibitor for treating a cancer described herein.

[0190] In some embodiments, a method of treating cancer (e.g., any of the cancers described herein) comprises the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a therapeutically effective amount of at least one anti-cancer drug described herein.

[0191] In some embodiments, a composition comprising docetaxel and human serum albumin as described herein is administered concurrently with an anti-cancer drug.

[0192] In some embodiments, a composition comprising docetaxel and human serum albumin as described herein is administered consecutively with an anti-cancer drug.

[0193] The compositions described herein comprising docetaxel and human serum albumin can be administered to an individual (such as a human) via various routes, such as parenteral, including intravenous, intraarterial, intraperitoneal, intrapulmonary, oral, inhaled, intracapsular, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal or transdermal. For example, the composition can be administered by inhalation to treat respiratory conditions. The composition can be used to treat respiratory conditions such as pulmonary fibrosis, bronchiolitis obliterans, lung cancer, bronchoalveolar carcinoma, etc. In some embodiments, the nanoparticle composition is administered intravenously.

[0194] The methods described herein may be performed alone or in combination with another treatment such as surgery, radiation, chemotherapy, immunotherapy, gene therapy, etc. Additionally, persons at greater risk of developing a proliferative disease may receive treatment to inhibit and / or delay the development of the disease.

[0195] As is understood by those of ordinary skill in the art, the appropriate dose of docetaxel will be approximately the dose that has been used in clinical treatments where docetaxel is administered alone or in combination with other chemotherapeutic agents. Depending on the condition being treated, the dose may vary. As will be appreciated by those of ordinary skill in the art, the appropriate effective dose will also vary depending on the severity of the disease, the route of administration, the sex, age and general health of the subject, the use of excipients, the possibility of co-use with other treatments (such as the use of other agents), and the judgment of the treating physician. For example, the prescribing information for docetaxel may be referenced to determine guidelines for selecting an effective dose.

[0196] Also provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1: 1000. In some embodiments, the pH of the composition is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0197] In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:60 to about 1:300. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:250. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:200. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:150. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:120. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:100 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:100 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:130, about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about 1:190, about 1:200, about 1:210, about 1:220, about 1:230, about 1:240, or about 1:250.

[0198] In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin. In some embodiments, the human serum albumin is human serum albumin free of fatty acids. In some embodiments, the human serum albumin is substantially free of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than two moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than one mole of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.5 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.1 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.05 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.01 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.001 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.0005 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.0001 moles of fatty acids.

[0199] In some embodiments, docetaxel may be a pharmaceutically acceptable salt of docetaxel. In some embodiments, docetaxel may be docetaxel having three equivalents of water solvate. In some embodiments, docetaxel may be any one of the crystalline form, amorphous form, solvate and hydrate as described herein.

[0200] In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution. In some embodiments, the aqueous solution is substantially free of solvents other than water. In some embodiments, the aqueous solution is free of solvents other than water.

[0201] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:1000, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8.

[0202] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:1000, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5.

[0203] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:250, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8.

[0204] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:250, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5.

[0205] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 150, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8.

[0206] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:150, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5.

[0207] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:1000, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:1000, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is free of solvents other than water.

[0208] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:250, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:250, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is free of solvents other than water.

[0209] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:150, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:150, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is free of solvents other than water.

[0210] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:1000, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:1000, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is free of solvents other than water.

[0211] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:250, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:250, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is free of solvents other than water.

[0212] In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:150, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, provided herein is a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:150, wherein when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, and wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is free of solvents other than water.

[0213] In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 5 to about 8. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 5.5 to about 7.8. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6 to about 7.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6.5 to about 7.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6 to about 6.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6.5 to about 7. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 7 to about 7.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of solvents other than water.

[0214] In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 97% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 98% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 99% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, the aqueous formulation is substantially free of solvents other than water.

[0215] In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99% or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99% or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99% or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution does not contain a solvent other than water. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after the clear aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99% or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution does not contain a solvent other than water.

[0216] In some embodiments, the composition is an aqueous solution, wherein after the aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 80% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, the composition is an aqueous solution, wherein after the aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 85% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, the composition is an aqueous solution, wherein after the aqueous solution is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 90% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of solvents other than water.

[0217] In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution for at least 3 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution for at least 6 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution for at least 24 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution for at least 3 days. In some embodiments, the aqueous solution is substantially free of solvents other than water. In some embodiments, the aqueous solution does not contain solvents other than water.

[0218] In some embodiments, composition is solid preparation.For example, solid preparation can be prepared uniformly by lyophilization.Those skilled in the art will recognize that other methods can also prepare solid preparation, such as rotary evaporation.In some embodiments, the pH of solid preparation is neutral (for example, the pH of composition is about 5 to about 8, about 5.5 to about 7.5 or about 6 to about 7, or the pH of composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5 or about 8).

[0219] In some embodiments, the composition is an aqueous preparation. In some embodiments, the aqueous preparation is substantially free of solvents other than water. In some embodiments, the aqueous preparation is free of solvents other than water. In some embodiments, the aqueous preparation includes water and a water-soluble organic solvent, and the water-soluble organic solvent includes at least one of polyethylene glycol 300, polyethylene glycol 400, ethanol, methanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide and dimethyl sulfoxide. For example, the water-soluble organic solvent may include ethanol. In some embodiments, the aqueous preparation includes water and ethanol. In some embodiments, the water-soluble organic solvent may be a mixture of water-soluble organic solvents. In some embodiments, the pH of the aqueous formulation (e.g., a clear aqueous solution) is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0220] In some embodiments, the aqueous formulation may be free of surfactants such as Surfactants and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of surfactants, such as Surfactants and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of Surfactants and polysorbate 80 surfactants.

[0221] In some embodiments, the aqueous formulation is a clear aqueous solution. For example, the formulation can be a clear and stable aqueous solution reconstituted from a sterile lyophilized powder. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation is free of solvents other than water.

[0222] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in water by a solid formulation (e.g., a sterile lyophilized powder). In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in 0.9% saline by a solid formulation (e.g., a sterile lyophilized powder). In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in 5% glucose solution by a solid formulation (e.g., a sterile lyophilized powder).

[0223] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in water, wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in 0.9% saline, wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in 5% glucose solution, wherein the aqueous formulation has a pH of about 5 to about 8.

[0224] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in water, wherein the pH of the water is about 7, and wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 0.9% saline solution, wherein the pH of the 0.9% saline solution is about 5.4, and wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 5% glucose aqueous solution, wherein the pH of the 5% glucose solution is about 4.4, and wherein the aqueous formulation has a pH of about 5 to about 8. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or 200 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 10 mg per 1 ml of aqueous solvent to about 500 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 25 mg per 1 ml of aqueous solvent to about 250 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 30 mg per 1 ml of aqueous solvent to about 200 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 40 mg per 1 ml of aqueous solvent to about 150 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 50 mg per 1 ml of aqueous solvent to about 125 mg per 1 ml of aqueous solvent.

[0225] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in water by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the water is about 7, and wherein the aqueous formulation has a pH of about 5 to about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 0.9% saline solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the 0.9% saline solution is about 5.4, and wherein the aqueous formulation has a pH of about 6.7 to about 7.1. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 5% glucose aqueous solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the 5% glucose solution is about 4.4, and wherein the aqueous formulation has a pH of about 6.7 to about 7.1. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or 200 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 10 mg per 1 ml of aqueous solvent to about 500 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 25 mg per 1 ml of aqueous solvent to about 250 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 30 mg per 1 ml of aqueous solvent to about 200 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 40 mg per 1 ml of aqueous solvent to about 150 mg per 1 ml of aqueous solvent. In some aspects of the foregoing embodiments, the concentration of the reconstituted solid in the aqueous formulation is about 50 mg per 1 ml of aqueous solvent to about 125 mg per 1 ml of aqueous solvent.

[0226] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in water by a solid formulation (e.g., a sterile lyophilized powder), wherein the aqueous formulation has a pH value of about 6 to about 7.5. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in 0.9% saline by a solid formulation (e.g., a sterile lyophilized powder), wherein the aqueous formulation has a pH value of about 6 to about 7.5. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in 5% glucose solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the aqueous formulation has a pH value of about 6 to about 7.5.

[0227] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in water by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the water is about 7, and wherein the aqueous formulation has a pH of about 6 to about 7.5. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 0.9% saline solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the 0.9% saline solution is about 5.4, and wherein the aqueous formulation has a pH of about 6 to about 7.5. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted in a 5% glucose aqueous solution by a solid formulation (e.g., a sterile lyophilized powder), wherein the pH of the 5% glucose solution is about 4.4, and wherein the aqueous formulation has a pH of about 6 to about 7.5.

[0228] In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in water, wherein the pH of the water is about 7, and wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 0.9% saline solution, wherein the pH of the 0.9% saline solution is about 5.4, and wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8. In some embodiments, the aqueous formulation is a clear aqueous solution reconstituted from a solid formulation (e.g., a sterile lyophilized powder) in a 5% dextrose aqueous solution, wherein the pH of the 5% dextrose solution is about 4.4, and wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8.

[0229] In some embodiments, the aqueous formulation has a pH value of about 5 to about 8. In some embodiments, the aqueous formulation has a pH value of about 5.5 to about 7.8. In some embodiments, the aqueous formulation has a pH value of about 6 to about 7.5. In some embodiments, the aqueous formulation has a pH value of about 6.5 to about 7.5. In some embodiments, the aqueous formulation has a pH value of about 6 to about 6.5. In some embodiments, the aqueous formulation has a pH value of about 6 to about 6.5. In some embodiments, the aqueous formulation has a pH value of about 6.5 to about 7. In some embodiments, the aqueous formulation has a pH value of about 7 to about 7.5. In some embodiments, the aqueous formulation has a pH value of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4 or about 7.5. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation does not contain solvents other than water.

[0230] In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 5 to about 8, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 5 to about 8, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 5.5 to about 7.8, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 5.5 to about 7.8, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 7.5, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 7.5, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 7.5, and wherein the aqueous formulation does not contain solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6.5 to about 7.5, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6.5 to about 7.5, and wherein the aqueous formulation is free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 6.5, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6 to about 6.5, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH value of about 6.5 to about 7, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 6.5 to about 7, and wherein the aqueous formulation does not contain a solvent other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 7 to about 7.5, and wherein the aqueous formulation is substantially free of a solvent other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 7 to about 7.5, and wherein the aqueous formulation does not contain a solvent other than water.In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5, and wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation has a pH of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5, and wherein the aqueous formulation is free of solvents other than water.

[0231] In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 97% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 98% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 99% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 99.5% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of solvents other than water.

[0232] In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution is substantially free of solvents other than water. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 5 to about 8, and wherein the clear aqueous solution does not contain solvents other than water. In some embodiments, after the aqueous formulation (e.g., clear aqueous solution) is filtered through a 0.22 micron filter, the amount of docetaxel in the filtered aqueous solution is at least 96%, 97%, 98%, 99%, or 99.5% of the total amount of docetaxel in the aqueous solution before filtration, wherein the clear aqueous solution has a pH of about 6 to about 7.5, and wherein the clear aqueous solution does not contain solvents other than water.

[0233] In some embodiments, the aqueous formulation is a clear aqueous solution for at least 3 hours. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C for at least 3 hours. In some embodiments, the aqueous formulation is a clear aqueous solution for at least 6 hours. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C for at least 6 hours. In some embodiments, the aqueous formulation is a clear aqueous solution for at least 24 hours. In some embodiments, the aqueous formulation is a clear aqueous solution for at least 24 hours at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C. In some embodiments, the aqueous formulation is a clear aqueous solution for at least 3 days. In some embodiments, when the aqueous formulation is dissolved in an aqueous solution at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C, it is a clear aqueous solution for at least 3 days. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of solvents other than water.

[0234] Also provided herein is a pharmaceutical composition comprising the composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0235] In some embodiments, the pharmaceutical composition does not contain a surfactant, such as Surfactants and polysorbate 80.

[0236] In some embodiments, the pharmaceutical composition is substantially free of surfactants, such as Surfactants and polysorbate 80.

[0237] Also provided herein is a method of treating a proliferative disease, comprising the step of administering to a subject in need thereof a pharmaceutical composition comprising the composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0238] Also provided herein is a method of treating cancer (e.g., any of the cancers described herein), comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0239] In some embodiments, the cancer is any one of the cancers described herein.

[0240] In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi's sarcoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is Kaposi's sarcoma.

[0241] In some embodiments, a method of treating cancer (e.g., any of the cancers described herein) comprises the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a therapeutically effective amount of at least one kinase inhibitor for treating a cancer described herein.

[0242] In some embodiments, a method of treating cancer (e.g., any of the cancers described herein) comprises the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a therapeutically effective amount of at least one anti-cancer drug described herein.

[0243] In some embodiments, a composition comprising docetaxel and human serum albumin as described herein is administered concurrently with an anti-cancer drug.

[0244] In some embodiments, a composition comprising docetaxel and human serum albumin as described herein is administered consecutively with an anti-cancer drug.

[0245] The compositions described herein comprising docetaxel and human serum albumin can be administered to an individual (such as a human) via various routes, such as parenteral, including intravenous, intraarterial, intraperitoneal, intrapulmonary, oral, inhaled, intracapsular, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal or transdermal. For example, the composition can be administered by inhalation to treat respiratory conditions. The composition can be used to treat respiratory conditions such as pulmonary fibrosis, bronchiolitis obliterans, lung cancer, bronchoalveolar carcinoma, etc. In some embodiments, the composition is administered intravenously.

[0246] The methods described herein may be performed alone or in combination with another treatment such as surgery, radiation, chemotherapy, immunotherapy, gene therapy, etc. Additionally, persons at greater risk of developing a proliferative disease may receive treatment to inhibit and / or delay the development of the disease.

[0247] As is understood by those of ordinary skill in the art, the appropriate dose of docetaxel will be approximately the dose that has been used in clinical treatments where docetaxel is administered alone or in combination with other chemotherapeutic agents. Depending on the condition being treated, the dose may vary. As will be appreciated by those of ordinary skill in the art, the appropriate effective dose will also vary depending on the severity of the disease, the route of administration, the sex, age and general health of the subject, the use of excipients, the possibility of co-use with other treatments (such as the use of other agents), and the judgment of the treating physician. For example, the prescribing information for docetaxel may be referenced to determine guidelines for selecting an effective dose.

[0248] Also provided herein is a composition consisting essentially of docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1: 1000. In some embodiments, the pH of the composition is neutral (e.g., the pH of the composition is about 5 to about 8, about 5.5 to about 7.5, or about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

[0249] In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:60 to about 1:300. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:250. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:200. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:150. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:120. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:100 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:100 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:130, about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about 1:190, about 1:200, about 1:210, about 1:220, about 1:230, about 1:240, or about 1:250.

[0250] In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin. In some embodiments, the human serum albumin is human serum albumin free of fatty acids. In some embodiments, the human serum albumin is substantially free of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than two moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than one mole of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.5 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.1 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.05 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.01 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.001 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.0005 moles of fatty acids. In some embodiments, one mole of human serum albumin in human serum albumin binds no more than 0.0001 moles of fatty acids.

[0251] In some embodiments, docetaxel may be a pharmaceutically acceptable salt of docetaxel. In some embodiments, docetaxel may be docetaxel having three equivalents of water solvate. In some embodiments, docetaxel may be any one of the crystalline form, amorphous form, solvate and hydrate as described herein.

[0252] In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution. In some embodiments, the aqueous solution is substantially free of solvents other than water. In some embodiments, the aqueous solution is free of solvents other than water.

[0253] In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 5 to about 8. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 5.5 to about 7.8. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6 to about 7.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6.5 to about 7.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6 to about 6.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6.5 to about 7. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 7 to about 7.5. In some embodiments, when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, wherein the clear aqueous solution has a pH value of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of solvents other than water.

[0254] In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution for at least 3 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution for at least 6 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution for at least 24 hours. In some embodiments, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution for at least 3 days. In some embodiments, the aqueous solution is substantially free of solvents other than water. In some embodiments, the aqueous solution does not contain solvents other than water.

[0255] In some embodiments, the composition is a solid formulation. For example, the solid formulation can be uniformly prepared by lyophilization. Those skilled in the art will recognize that other methods can also prepare solid formulations, such as rotary evaporation.

[0256] In some embodiments, the composition is an aqueous formulation. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of solvents other than water.

[0257] In some embodiments, the aqueous formulation is a clear aqueous solution. For example, the formulation can be a clear and stable aqueous solution reconstituted from a sterile lyophilized powder. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is a clear aqueous solution, wherein the aqueous formulation is free of solvents other than water.

[0258] In some embodiments, the aqueous formulation has a pH value of about 5 to about 8. In some embodiments, the aqueous formulation has a pH value of about 5.5 to about 7.8. In some embodiments, the aqueous formulation has a pH value of about 6 to about 7.5. In some embodiments, the aqueous formulation has a pH value of about 6.5 to about 7.5. In some embodiments, the aqueous formulation has a pH value of about 6 to about 6.5. In some embodiments, the aqueous formulation has a pH value of about 6 to about 6.5. In some embodiments, the aqueous formulation has a pH value of about 6.5 to about 7. In some embodiments, the aqueous formulation has a pH value of about 7 to about 7.5. In some embodiments, the aqueous formulation has a pH value of about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4 or about 7.5. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation does not contain solvents other than water.

[0259] In some embodiments, the aqueous formulation is a clear aqueous solution for at least 3 hours. In some embodiments, the aqueous formulation is a clear aqueous solution for at least 6 hours. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C for at least 6 hours. In some embodiments, the aqueous formulation is a clear aqueous solution for at least 24 hours. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C for at least 24 hours. In some embodiments, the aqueous formulation is a clear aqueous solution for at least 3 days. In some embodiments, when the aqueous formulation is dissolved in an aqueous solution at a temperature of about 1°C to about 35°C, about 1°C to about 10°C, about 10°C to about 20°C, about 20°C to about 35°C, or about 1°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C, it is a clear aqueous solution for at least 3 days. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of solvents other than water.

[0260] Also provided herein is a pharmaceutical composition comprising a composition consisting essentially of docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

[0261] Also provided herein is a method of treating cancer (e.g., any of the cancers described herein), comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition consisting essentially of docetaxel and human serum albumin as described herein, and a pharmaceutically acceptable carrier.

[0262] In some embodiments, the cancer is any one of the cancers described herein.

[0263] In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi's sarcoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is Kaposi's sarcoma.

[0264] Reagent test kit

[0265] The present invention also includes, for example, a pharmaceutical kit for treating or preventing any of the diseases or conditions mentioned herein, comprising one or more containers containing a pharmaceutical composition comprising a composition of docetaxel and human serum albumin as described herein. As will be readily apparent to those skilled in the art, if desired, the kit may further include one or more of various conventional pharmaceutical kit components, such as a container containing one or more pharmaceutically acceptable carriers (e.g., water, 0.9% saline or 5% glucose), other containers, etc. The kit may also include instructions in the form of an insert or label, indicating the amount of the component to be administered (e.g., the dosage as described herein), guidelines for administration, and / or guidelines for mixing the components.

[0266] Preparation method

[0267] Also provided herein are several methods for preparing a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin as described herein, a composition comprising docetaxel and human serum albumin as described herein, or a composition consisting essentially of docetaxel and human serum albumin as described herein.

[0268] In some embodiments, the present disclosure provides a method for preparing a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the complex is about 0.1:1 to about 5:1.

[0269] In some embodiments, the present disclosure provides a method of preparing a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is from about 0.1:1 to about 5:1.

[0270] In some embodiments, the present disclosure provides a method of preparing a composition comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the composition is about 0.1:1 to about 5:1, wherein when the composition is dissolved in an aqueous solution, the composition forms a clear aqueous solution, and wherein the solubility of the composition in the aqueous solution is at least 10 mg / ml.

[0271] In some embodiments, the present disclosure provides a method for preparing a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:1000.

[0272] In some embodiments, the present disclosure provides a method of preparing a composition consisting essentially of docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:1000.

[0273] In some embodiments, the method comprises mixing an organic solution comprising docetaxel dissolved in a polar water-miscible organic solvent with a first aqueous solution comprising human serum albumin to form a second aqueous solution, wherein the second aqueous solution is a clear aqueous solution.

[0274] In some embodiments, the method further comprises removing the polar water-soluble organic solvent and water from the second aqueous solution.

[0275] A non-limiting preferred method is as follows.

[0276] Formation of organic solution

[0277] In some embodiments, docetaxel is dissolved in a polar organic solvent (eg, an alcohol such as methanol, ethanol, isopropanol, and / or n-butanol; THF, CH 3 CN, DMF, or a mixture thereof) to form an organic solution.

[0278] As used herein, the term "organic solution" refers to a solution in which at least one solvent is a non-aqueous solvent and the weight % of the non-aqueous solvent in the solvent mixture is at least 50%, at least 60%, at least 70%, or at least 90%. In some embodiments, the organic solution is a solution that does not contain water as a solvent.

[0279] In some embodiments, the terms "organic solvent" and "non-aqueous solvent" are used interchangeably and refer to a liquid comprising at least 50%, at least 60%, at least 70%, at least 90%, or at least 95% of a solvent other than water.

[0280] The polar organic solvent is miscible in water. In some embodiments, the polar organic solvent is an alcohol. In some embodiments, the polar organic solvent is ethanol or methanol or a mixture thereof. In some embodiments, the polar organic solvent may be ethanol. In some embodiments, the polar organic solvent is methanol.

[0281] In some embodiments, the amount of polar organic solvent is about 0.005 mL to about 10 mL per 1 mg of docetaxel. In some embodiments, the amount of polar organic solvent is about 0.01 mL to about 5 mL per 1 mg of docetaxel. In some embodiments, the amount of polar organic solvent is about 0.05 mL to about 5 mL per 1 mg of docetaxel. In some embodiments, the amount of polar organic solvent is about 0.1 mL to about 2.0 mL per 1 mg of docetaxel. In some embodiments, the amount of polar organic solvent is about 0.4 mL to about 2.0 mL per 1 mg of docetaxel. In some embodiments, the amount of polar organic solvent is about 0.5 mL to about 1.7 mL per 1 mg of docetaxel. In some embodiments, the amount of polar organic solvent is about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 1 mL, about 1.2 mL, about 1.25 mL, about 1.35 mL, about 1.4 mL, about 1.45 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, or about 2.0 mL per 1 mg of docetaxel.

[0282] Formation of the first aqueous solution

[0283] In some embodiments, a predetermined amount of human serum albumin is dissolved in an amount of water to form a first aqueous solution.

[0284] In some embodiments, the amount of aqueous solvent (e.g., water, saline, glucose solution, or buffer (e.g., any buffer described herein)) used to prepare the first aqueous solution is about 1 mL to about 1000 L, about 2 mL to about 100 L, about 3 mL to about 10 L, about 4 mL to about 1 L, about 5 mL to about 200 mL, about 6 mL to about 100 mL, about 10 mL to about 90 mL, about 4 mL to about 20 mL, or about 10 mL to about 20 mL. In some embodiments, the amount of water used to prepare the first aqueous solution is about 4 mL, about 4.5 mL, about 5 mL, about 6 mL, about 10 mL, about 16 mL, about 17 mL, about 90 mL, or about 100 mL.

[0285] In some embodiments, the amount of HSA used to prepare the first aqueous solution is about 100 mg to about 500 kg, about 150 mg to about 100 kg, about 200 mg to about 10 kg, about 300 mg to about 500 g, about 200 mg to about 100 g, or about 200 mg to about 10 g. In some embodiments, the amount of HSA used to prepare the first aqueous solution is about 100 mg, about 200 mg, about 300 mg, about 600 mg, about 700 mg, about 800 mg, about 850 mg, about 900 mg, about 4500 mg, or about 5000 mg.

[0286] In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL to about 10 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL to about 5 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL to about 1 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL to about 0.5 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL to about 0.1 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL to about 0.05 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.015 mL to about 0.04 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL, about 0.015 mL, about 0.02 mL, about 0.025 mL, about 0.03 mL, about 0.035 mL, about 0.04 mL, about 0.045 mL, or about 0.05 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.02 mL per 1 mg of human serum albumin.

[0287] In some embodiments, the resulting composition comprising docetaxel and human serum albumin can have any molar ratio or any weight ratio of docetaxel to human serum albumin as described herein. In some embodiments, the human serum albumin is fatty acid-free human serum albumin. In some embodiments, the human serum albumin is substantially free of fatty acids.

[0288] In some embodiments, preparing the organic solution and preparing the first aqueous solution are performed simultaneously.

[0289] In some embodiments, preparing the organic solution and preparing the first aqueous solution are performed sequentially. In some embodiments, preparing the organic solution is performed before preparing the first aqueous solution. In some embodiments, preparing the first aqueous solution is performed before preparing the organic solution.

[0290] In some embodiments, the pH of the first aqueous solution ranges from about 3 to about 9, about 4 to about 8, about 5 to about 8, about 5 to about 7, about 6 to about 7, about 3 to about 5, about 3 to about 7, about 4 to about 6, or about 6 to about 6.5. In some embodiments, the pH of the first aqueous solution is about 4, about 5, about 6, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.5, or about 8.

[0291] Formation of the Second Aqueous Solution

[0292] In some embodiments, the organic solution of docetaxel is mixed with the first aqueous solution of human serum albumin to form a second aqueous solution. In some embodiments, the second aqueous solution is a clear aqueous solution.

[0293] In some embodiments, the volume ratio of the amount of water to the amount of polar organic solvent is in the range of about 1:1 to about 1000:1. In some embodiments, the volume ratio of the amount of water to the amount of polar organic solvent is in the range of about 1.5:1 to about 100:1. In some embodiments, the volume ratio of the amount of water to the amount of polar organic solvent is in the range of about 1.5:1 to about 20:1. In some embodiments, the volume ratio of the amount of water to the amount of polar organic solvent is in the range of about 1.5:1 to about 10:1. In some embodiments, the volume ratio of the amount of water to the amount of polar organic solvent is in the range of about 2:1 to about 10:1. In some embodiments, the volume ratio of the amount of water to the amount of polar organic solvent is about 1.5:1, about 2:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1.

[0294] In some embodiments, an organic solution is added to a first aqueous solution to form a second aqueous solution. In some embodiments, an organic solution is added dropwise to a first aqueous solution to form a second aqueous solution. In some embodiments, a first aqueous solution is added to an organic solution to form a second aqueous solution. In some embodiments, mixing is performed with agitation. In some embodiments, mixing is performed with stirring. In some embodiments, mixing is performed with shaking.

[0295] In some embodiments, the addition is performed at a temperature of about 0°C to about 35°C. In some embodiments, the addition is performed at a temperature of about 0°C to about 25°C. In some embodiments, the addition is performed at a temperature of about 0°C to about 10°C. In some embodiments, the addition is performed at a temperature of about 0°C to about 5°C. In some embodiments, the addition is performed at a temperature of about 0°C. In some embodiments, the addition is performed at a temperature of about 5°C. In some embodiments, the addition is performed at a temperature of about 10°C.

[0296] In some embodiments, the addition time is in the range of about 0.1 min to about 24 hours. In some embodiments, the addition time is in the range of about 1 min to about 2 hours. In some embodiments, the addition time is in the range of about 1 min to about 1 hour. In some embodiments, the addition time is in the range of about 5 min to about 30 min.

[0297] In some embodiments, the pH of the second aqueous solution ranges from about 3 to about 9, about 4 to about 8, about 5 to about 8, about 5 to about 7, about 6 to about 7, about 3 to about 5, about 3 to about 7, about 4 to about 6, or about 6 to about 6.5. In some embodiments, the pH of the second aqueous solution is about 4, about 5, about 6, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.5, or about 8.

[0298] Removal of organic solvents

[0299] In some embodiments, after the organic solution and the first aqueous solution are mixed to form the second aqueous solution, the polar organic solvent is removed from the second aqueous solution.

[0300] In some embodiments, the polar organic solvent is removed under reduced pressure. In some embodiments, the polar organic solvent is removed using rotary evaporation. In some embodiments, the polar organic solvent is removed under vacuum.

[0301] In some embodiments, removal of the polar organic solvent produces a clear aqueous solution. In some embodiments, water is removed from the aqueous solution under vacuum. In some embodiments, water is removed from the aqueous solution using rotary evaporation. In some embodiments, water is removed from the aqueous solution by lyophilization.

[0302] In some embodiments, the solvent comprising water and an organic solvent is removed simultaneously from the second aqueous solution to provide a solid composition. In some embodiments, the solvent is removed under vacuum. In some embodiments, the solvent is removed using rotary evaporation. In some embodiments, the solvent is removed by lyophilization. In some embodiments, the second aqueous solution is filtered before removing the solvent.

[0303] Removing water from the second aqueous solution

[0304] In some embodiments, after removing the organic solvent from the second aqueous solution, water can be removed from the second aqueous solution to provide a solid.

[0305] In some embodiments, the second aqueous solution is filtered prior to removing the water. For example, the second aqueous solution can be filtered through a 0.22 micron filter prior to removing the water.

[0306] As used herein, the term "micrometer" refers to a unit of measurement that is one thousandth of a millimeter.

[0307] In some embodiments, water is removed under vacuum. In some embodiments, water is removed using rotary evaporation. In some embodiments, water is removed by lyophilization.

[0308] In some embodiments, the amount of docetaxel that is bound to HSA (e.g., non-covalently) in a solid composition comprising a composition comprising docetaxel and HSA (as described herein) is at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or about 100% of the total amount of docetaxel in the solid composition.

[0309] Reconstitution of solids

[0310] In some embodiments, a solid composition comprising docetaxel and human serum albumin (e.g., a solid composition prepared by removing an organic solvent from a second aqueous solution and removing water from a second aqueous solution) is mixed with an aqueous solution. In some embodiments, the aqueous solution is a physiological saline solution. In some embodiments, the aqueous solution is a 5% dextrose aqueous solution. In some embodiments, mixing is adding an aqueous solution to a solid. In some embodiments, mixing is adding a solid to an aqueous solution. In some embodiments, mixing re-dissolves the solid. In some embodiments, mixing produces a clear aqueous solution. In some embodiments, the pH range of the reconstituted solution is about 5 to about 8, about 5 to about 7, about 6 to about 7, about 6.5 to about 7.5, about 4 to about 6, or about 6 to about 6.5. In some embodiments, the pH of the reconstituted solution is about 5, about 6, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.5, or about 8.

[0311] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs. Methods and materials for use in the present disclosure are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, the present specification (including definitions) shall prevail.

[0312] The composition prepared by the method

[0313] In some embodiments, the present disclosure provides a composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:1000, which is produced by a method comprising the steps of:

[0314] (i) obtaining an organic solution containing docetaxel dissolved in a polar water-soluble organic solvent;

[0315] (ii) obtaining a first aqueous solution of human serum albumin; and

[0316] (iii) mixing the organic solution of docetaxel with the first aqueous solution of human serum albumin to obtain a second aqueous solution comprising a composition including docetaxel and human serum albumin.

[0317] In some embodiments, the pH of the first aqueous solution ranges from about 3 to about 9, about 4 to about 8, about 5 to about 8, about 5 to about 7, about 6 to about 7, about 3 to about 5, about 3 to about 7, about 4 to about 6, or about 6 to about 6.5. In some embodiments, the pH of the first aqueous solution is about 4, about 5, about 6, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.5, or about 8.

[0318] In some embodiments, the pH of the second aqueous solution ranges from about 3 to about 9, about 4 to about 8, about 5 to about 8, about 5 to about 7, about 6 to about 7, about 3 to about 5, about 3 to about 7, about 4 to about 6, or about 6 to about 6.5. In some embodiments, the pH of the second aqueous solution is about 4, about 5, about 6, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.5, or about 8.

[0319] In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:50 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:60 to about 1:300. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:250. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:200. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:120. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:100 to about 1:1000. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:70 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:80 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:90 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:100 to about 1:500. In some embodiments, the weight ratio of docetaxel to human serum albumin in the composition is about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:130, about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about 1:190, about 1:200, about 1:210, about 1:220, about 1:230, about 1:240, or about 1:250.

[0320] In some embodiments, docetaxel may be a pharmaceutically acceptable salt of docetaxel. In some embodiments, docetaxel may be docetaxel having three equivalents of water solvate. In some embodiments, docetaxel may be any one of the crystalline form, amorphous form, solvate and hydrate as described herein.

[0321] In some embodiments, the human serum albumin is substantially free of fatty acids.

[0322] In some embodiments, the composition comprises a non-covalently bound complex comprising docetaxel and human serum albumin.

[0323] In some embodiments, the amount of polar water-soluble organic solvent in the organic solution is from about 0.01 mL to about 5 mL per 1 mg of docetaxel.

[0324] In some embodiments, the amount of the polar water-soluble organic solvent in the organic solution is from about 0.1 mL to about 2.0 mL per 1 mg of docetaxel.

[0325] In some embodiments, the amount of polar water-soluble organic solvent in the organic solution is from about 0.4 mL to about 2.0 mL per 1 mg of docetaxel.

[0326] In some embodiments, the amount of polar water-soluble organic solvent in the organic solution is from about 0.5 mL to about 1.7 mL per 1 mg of docetaxel.

[0327] In some embodiments, the amount of organic solvent is about 0.005 mL to about 10 mL per 1 mg of docetaxel. In some embodiments, the amount of organic solvent is about 0.01 mL to about 5 mL per 1 mg of docetaxel. In some embodiments, the amount of organic solvent is about 0.05 mL to about 5 mL per 1 mg of docetaxel. In some embodiments, the amount of organic solvent is about 0.1 mL to about 2.0 mL per 1 mg of docetaxel. In some embodiments, the amount of organic solvent is about 0.4 mL to about 2.0 mL per 1 mg of docetaxel. In some embodiments, the amount of organic solvent is about 0.5 mL to about 1.7 mL per 1 mg of docetaxel. In some embodiments, the amount of organic solvent is about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 1 mL, about 1.2 mL, about 1.25 mL, about 1.35 mL, about 1.4 mL, about 1.45 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, or about 2.0 mL per 1 mg of docetaxel.

[0328] In some embodiments, the amount of the aqueous solvent in the first aqueous solution is from about 0.005 mL to about 0.05 mL per 1 mg of human serum albumin.

[0329] In some embodiments, the amount of the aqueous solvent in the first aqueous solution is from about 0.01 mL to about 0.05 mL per 1 mg of human serum albumin.

[0330] In some embodiments, the amount of the aqueous solvent in the first aqueous solution is from about 0.015 mL to about 0.04 mL per 1 mg of human serum albumin.

[0331] In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL to about 10 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL to about 5 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL to about 1 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL to about 0.5 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL to about 0.1 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL to about 0.05 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.015 mL to about 0.04 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.01 mL, about 0.015 mL, about 0.02 mL, about 0.025 mL, about 0.03 mL, about 0.035 mL, about 0.04 mL, about 0.045 mL, or about 0.05 mL per 1 mg of human serum albumin. In some embodiments, the amount of the aqueous solvent in the first aqueous solution is about 0.02 mL per 1 mg of human serum albumin.

[0332] In some embodiments, the polar water-soluble organic solvent is an alcohol selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, and mixtures thereof.

[0333] In some embodiments, the polar water-soluble organic solvent is selected from methanol, ethanol, and mixtures thereof.

[0334] In some embodiments, the polar water-soluble organic solvent is methanol.

[0335] In some embodiments, the aqueous solvent is water.

[0336] In some embodiments, mixing comprises adding the organic solution to the first aqueous solution. In some embodiments, wherein mixing comprises adding the first aqueous solution to the organic solution. In some embodiments, adding is performed dropwise. In some embodiments, adding is performed over a period of several minutes to several hours. In some embodiments, adding is performed over a period of 2 min to 24 hours. In some embodiments, adding is performed over a period of 2 minutes to 12 hours, 2 min to 6 hours, 3 min to 3 hours, 2 min to 1 hour, 2 min to 30 min, or 2 min to 25 min.

[0337] In some embodiments, mixing is performed at a temperature of about 0° C. to about 25° C. In some embodiments, mixing is performed at ambient temperature (e.g., about 25° C.). In some embodiments, mixing is performed at a temperature of about 0° C. to about 5° C. In some embodiments, mixing is performed at about 0° C.

[0338] In some embodiments, the volume ratio of the amount of aqueous solvent in the second aqueous solution to the amount of organic solvent is in the range of about 1:1 to about 1000:1. In some embodiments, the volume ratio of the amount of aqueous solvent in the second aqueous solution to the amount of organic solvent is in the range of about 1.5:1 to about 100:1. In some embodiments, the volume ratio of the amount of aqueous solvent in the second aqueous solution to the amount of organic solvent is in the range of about 1.5:1 to about 20:1. In some embodiments, the volume ratio of the amount of aqueous solvent in the second aqueous solution to the amount of organic solvent is in the range of about 1.5:1 to about 10:1. In some embodiments, the volume ratio of the amount of aqueous solvent in the second aqueous solution to the amount of organic solvent is in the range of about 2:1 to about 10:1. In some embodiments, the volume ratio of the amount of aqueous solvent to the amount of organic solvent in the second aqueous solution is about 1.5:1, about 2:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1. In some embodiments, the aqueous solvent is water. In some embodiments, the aqueous solvent is water and the organic solvent is an alcohol. In some embodiments, the aqueous solvent is water and the organic solvent is methanol,

[0339] In some embodiments, the composition is prepared by further comprising the step of removing the polar water-soluble organic solvent from the second aqueous solution to obtain a third aqueous solution comprising a composition comprising docetaxel and human serum albumin. In some embodiments, the composition is prepared by further comprising the step of removing the aqueous solvent from the third aqueous solution to obtain a composition comprising docetaxel and human serum albumin.

[0340] In some embodiments, the composition is prepared by further comprising a step of removing the organic solvent (eg, methanol) and the aqueous solvent (eg, water) from the second aqueous solution to obtain a composition comprising docetaxel and human serum albumin.

[0341] In some embodiments, the removal is performed in vacuo (eg, using a rotovap). In some embodiments, the removal is performed by lyophilization.

[0342] In some embodiments, when the composition is dissolved in an aqueous solvent, the composition forms a clear aqueous solution, and wherein the solubility of the composition in the aqueous solution is at least 10 mg / ml.

[0343] In some embodiments, the composition is a solid dosage form.

[0344] In some embodiments, the composition is an aqueous formulation. In some embodiments, the aqueous formulation is substantially free of solvents other than water. In some embodiments, the aqueous formulation is free of surfactants. In some embodiments, the surfactant is selected from Surfactant and polysorbate 80. In some embodiments, the aqueous formulation is a clear aqueous solution. In some embodiments, the aqueous formulation is a clear aqueous solution for at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 24 hours, at least 48 hours, or at least 72 hours.

[0345] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a composition as prepared by the method described herein and a pharmaceutically acceptable carrier.

[0346] In some embodiments, the present disclosure provides a method of treating cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.

[0347] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer, ovarian cancer, pancreatic cancer, and Kaposi's sarcoma.

[0348] Example

[0349] Materials and methods

[0350] HPLC analysis: The HPLC system used in this paper is a SHIMADZU LC-10AT vp series system, which is composed of a SHIMADZU L-10AT vp pump, a manual injector, a SHIMADZU CTO-10AS vp column oven, a SHIMADZU SPD-10Avp wavelength detector, and a SHIMADZU LC solution workbench. Waters XTERRARP10 column (4.6mm x 150mm, 5μm) is used as an analytical HPLC column. The temperature of the column oven is 30°C. The mobile phase is composed of methanol and water (70:30, v / v) and is pumped at a flow rate of 1 ml / min. The effluent is detected using a UV detector at a wavelength of 233nm. The sample injection volume is 20μl.

[0351] Example 1: Composition comprising docetaxel and human serum albumin (HSA).

[0352] The molar ratio of docetaxel to HSA was prepared to be about 1:1.

[0353] Docetaxel (10 mg) was dissolved in methanol (10 ml) in a flask to produce a clear solution. Powdered HSA (824 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm of fatty acids) was dissolved in 20 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask with rapid stirring. The addition took about 25 minutes to complete. After the addition was completed, a clear solution was obtained. Methanol was removed under vacuum until the solution volume was about 18 ml to produce a clear solution. The resulting aqueous solution was lyophilized overnight to produce a white solid.

[0354] A 50 mg sample of freeze-dried solid was reconstituted by adding 1 mL of water to produce a clear solution. This clear aqueous solution remained clear without any solid precipitation after 24 hours.

[0355] A 50 mg sample of freeze-dried solid was reconstituted by adding 1 mL of 2% aqueous ethanol (2% ethanol in water) to produce a clear solution. This 2% aqueous ethanol solution remained clear without any solid precipitation after 24 hours.

[0356] Example 2: Compositions comprising docetaxel and human serum albumin (HSA)

[0357] The molar ratio of docetaxel to HSA was prepared to be about 1.3:1.

[0358] Docetaxel (3 mg) was dissolved in methanol (3 ml) in a glass vial to produce a clear solution. Powdered HSA (190 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm of fatty acids) was dissolved in 6 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask with rapid stirring. The addition took about 8 minutes to complete. After the addition was completed, a clear solution was obtained. Methanol was removed under vacuum until the solution volume was about 5 ml to produce a clear solution. The resulting aqueous solution was lyophilized overnight to produce a white solid.

[0359] A 50 mg sample of freeze-dried solid was reconstituted by adding 1 mL of water to produce a clear solution. This clear aqueous solution remained clear without any solid precipitation after 24 hours at room temperature.

[0360] Example 3: Compositions comprising docetaxel and human serum albumin (HSA)

[0361] The molar ratio of docetaxel to HSA was prepared to be about 1.5:1.

[0362] Docetaxel (3 mg) was dissolved in methanol (3 ml) in a glass vial to produce a clear solution. Powdered HSA (165 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm of fatty acids) was dissolved in 6 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask with rapid stirring. The addition took about 8 minutes to complete. After the addition was completed, a clear solution was obtained. Methanol was removed under vacuum until the solution volume was about 5 ml to produce a clear solution. The resulting aqueous solution was lyophilized overnight to produce a white solid.

[0363] A 50 mg sample of lyophilized solid was reconstituted by adding 1 mL of water to produce a slightly turbid solution.

[0364] Example 4: Compositions comprising docetaxel and human serum albumin (HSA)

[0365] The molar ratio of docetaxel to HSA was prepared to be about 1.2:1.

[0366] Docetaxel (10 mg) was dissolved in methanol (5 ml) in a glass vial to produce a clear solution. Powdered HSA (687 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm of fatty acids) was dissolved in 15 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask with rapid stirring. The addition took about 15 minutes to complete. After the addition was completed, a clear solution was obtained. Methanol was removed under vacuum until the solution volume was about 13 ml to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The clear aqueous solution obtained was lyophilized overnight to produce a white solid.

[0367] A 50 mg sample of lyophilized solid was reconstituted by adding 1 mL of water to produce a clear solution. The clear aqueous solution remained clear, with no precipitation of docetaxel after 6 hours at room temperature. The clear aqueous solution remained clear, with no precipitation of docetaxel after 24 hours at room temperature. The clear aqueous solution remained clear, with no precipitation of docetaxel after 3 days at room temperature.

[0368] 70 mg of the lyophilized solid sample was reconstituted by adding 1 mL of water to produce a clear solution. The clear aqueous solution remained clear, and no docetaxel precipitated after 6 hours at room temperature. The clear aqueous solution remained clear, and no docetaxel precipitated after 24 hours at room temperature. The clear aqueous solution remained clear, and no docetaxel precipitated after 3 days at room temperature.

[0369] A 50 mg sample of lyophilized solid was reconstituted by adding 1 mL of water to produce a clear solution. This clear aqueous solution remained clear, with no precipitation of docetaxel after 6 hours at 4°C. This clear aqueous solution remained clear, with no precipitation of docetaxel after 24 hours at 4°C. This clear aqueous solution remained clear, with no precipitation of docetaxel after 3 days at 4°C.

[0370] 50 mg of the lyophilized solid sample was reconstituted by adding 1 mL of saline to produce a clear solution. This clear saline solution remained clear, and no docetaxel precipitated after 6 hours at room temperature. This clear saline solution remained clear, and no docetaxel precipitated after 24 hours at room temperature. This clear saline solution remained clear, and no docetaxel precipitated after 3 days at room temperature.

[0371] Example 5: Compositions comprising docetaxel and human serum albumin (HSA)

[0372] The molar ratio of docetaxel to HSA was prepared to be about 1.2:1.

[0373] Docetaxel (3 mg) was dissolved in methanol (1.5 ml) in a glass vial to produce a clear solution. Powdered HSA (206 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm of fatty acids) was dissolved in 4.5 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask with rapid stirring. The addition took about 4 minutes to complete. After the addition was completed, a clear solution was obtained. The clear solution was filtered through a 0.22 micron aqueous phase filter. The resulting clear aqueous solution containing methanol was directly lyophilized overnight to produce a white solid.

[0374] A 50 mg sample of lyophilized solid was reconstituted by adding 1 mL of water to produce a clear solution. The clear aqueous solution remained clear, with no precipitation of docetaxel after 6 hours at room temperature. The clear aqueous solution remained clear, with no precipitation of docetaxel after 24 hours at room temperature. The clear aqueous solution remained clear, with no precipitation of docetaxel after 3 days at room temperature.

[0375] Example 6: Compositions comprising docetaxel and human serum albumin (HSA)

[0376] The molar ratio of docetaxel to HSA was prepared to be about 0.5:1.

[0377] Docetaxel (2 mg) was dissolved in methanol (1 ml) in a glass vial to produce a clear solution. Powdered HSA (329 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm of fatty acids) was dissolved in 6 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask with rapid stirring. The addition took about 2-3 minutes to complete. After the addition was completed, a clear solution was obtained. Methanol was removed under vacuum until the solution volume was about 5 ml to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The clear aqueous solution obtained was lyophilized overnight to produce a white solid.

[0378] A 50 mg sample of lyophilized solid was reconstituted by adding 1 mL of water to produce a clear solution. The clear aqueous solution remained clear, with no precipitation of docetaxel after 6 hours at room temperature. The clear aqueous solution remained clear, with no precipitation of docetaxel after 24 hours at room temperature. The clear aqueous solution remained clear, with no precipitation of docetaxel after 3 days at room temperature.

[0379] Example 7: Composition comprising docetaxel and human serum albumin (recombinant human serum albumin)

[0380] The molar ratio of docetaxel to recombinant human serum albumin was prepared to be about 1:1.

[0381] Docetaxel (10 mg) was dissolved in methanol (7 ml) in a glass vial to produce a clear solution. Powdered recombinant human serum albumin (823 mg) (recombinant human serum albumin without fatty acids purchased from Wuhan Healthgen Biotechnology Corp., www.oryzogen.com (no fatty acids detected)) was dissolved in 16 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the recombinant human serum albumin solution flask with rapid stirring. After the addition was completed, a clear solution was obtained. Methanol was removed under vacuum until the solution volume was about 14 ml to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The clear aqueous solution obtained was lyophilized overnight to produce a white solid.

[0382] A 50 mg sample of lyophilized solid was reconstituted by adding 1 mL of water to produce a clear solution. The clear aqueous solution remained clear, with no precipitation of docetaxel after 6 hours at room temperature. The clear aqueous solution remained clear, with no precipitation of docetaxel after 24 hours at room temperature. The clear aqueous solution remained clear, with no precipitation of docetaxel after 3 days at room temperature.

[0383] Example 8: Compositions comprising docetaxel and human serum albumin (HSA)

[0384] The weight ratio of docetaxel to HSA was prepared to be about 1:85.

[0385] Docetaxel (10 mg) was dissolved in methanol (7 ml) in a glass vial to produce a clear solution. Powdered HSA (850 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm of fatty acids) was dissolved in 17 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The resulting clear aqueous solution was lyophilized overnight to produce a white solid.

[0386] A 100 mg freeze-dried solid sample was reconstituted by adding 2 mL of water to produce a clear solution. This clear aqueous solution remained clear, and no docetaxel precipitated after 6 hours at room temperature. This clear aqueous solution remained clear, and no docetaxel precipitated after 24 hours at room temperature.

[0387] Example 9: Compositions comprising docetaxel and human serum albumin (HSA)

[0388] The weight ratio of docetaxel to HSA was prepared to be about 1:90.

[0389] Docetaxel (50 mg) was dissolved in methanol (30 ml) in a glass vial to produce a clear solution. Powdered HSA (4500 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm of fatty acids) was dissolved in 90 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. 8.5 ml of methanol was added to the solution. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The resulting clear aqueous solution was lyophilized overnight to produce a white solid.

[0390] A 100 mg freeze-dried solid sample was reconstituted by adding 2 mL of water to produce a clear solution. This clear aqueous solution remained clear, and no docetaxel precipitated after 6 hours at room temperature. This clear aqueous solution remained clear, and no docetaxel precipitated after 24 hours at room temperature.

[0391] Example 10: Compositions comprising docetaxel and human serum albumin (HSA)

[0392] The weight ratio of docetaxel to HSA was prepared to be about 1:100.

[0393] Docetaxel (50 mg) was dissolved in methanol (30 ml) in a glass vial to produce a clear solution. Powdered HSA (5000 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm of fatty acids) was dissolved in 100 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. 13 ml of methanol was added to the solution. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The resulting clear aqueous solution was lyophilized overnight to produce a white solid.

[0394] A 100 mg freeze-dried solid sample was reconstituted by adding 2 mL of water to produce a clear solution. This clear aqueous solution remained clear, and no docetaxel precipitated after 6 hours at room temperature. This clear aqueous solution remained clear, and no docetaxel precipitated after 24 hours at room temperature.

[0395] Example 11: Composition comprising docetaxel and human serum albumin (HSA)

[0396] The weight ratio of docetaxel to HSA was prepared to be about 1:100.

[0397] Docetaxel (5 mg) was dissolved in methanol (4.3 ml) in a glass vial to produce a clear solution. Powdered HSA (500 mg) (natural fatty acid-free human serum albumin purchased from Golden West Biologicals, Inc., CAT#: HA1020) was dissolved in 10 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The resulting clear aqueous solution was lyophilized overnight to produce a white solid.

[0398] 100 mg of the lyophilized solid sample was reconstituted by adding 2 mL of water to produce a clear solution. The clear aqueous solution remained clear, and no docetaxel precipitated after 3 hours at room temperature. The clear aqueous solution remained clear, and no docetaxel precipitated after 6 hours at room temperature. The clear aqueous solution remained clear, and no docetaxel precipitated after 24 hours at room temperature.

[0399] Example 12: Compositions comprising docetaxel and human serum albumin (HSA)

[0400] The weight ratio of docetaxel to HSA was prepared to be about 1:200.

[0401] Docetaxel (1 mg) was dissolved in methanol (1.7 ml) in a glass vial to produce a clear solution. Powdered HSA (200 mg) (native human serum albumin purchased from Golden West Biologicals, Inc., CAT#: HA1000) was dissolved in 4 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The resulting clear aqueous solution was lyophilized overnight to produce a white solid.

[0402] A 100 mg lyophilized solid sample was reconstituted by adding 2 mL of water to produce a clear solution without docetaxel precipitation.

[0403] Example 13: Compositions comprising docetaxel and human serum albumin (HSA)

[0404] The weight ratio of docetaxel to HSA was prepared to be about 1:150.

[0405] Docetaxel (1 mg) was dissolved in methanol (1 ml) in a glass vial to produce a clear solution. Powdered HSA (150 mg) (native human serum albumin purchased from Golden West Biologicals, Inc., CAT#: HA1000) was dissolved in 3 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The resulting clear aqueous solution was lyophilized overnight to produce a white solid.

[0406] A 100 mg lyophilized solid sample was reconstituted by adding 2 mL of water to produce a clear solution without docetaxel precipitation.

[0407] Example 14: Compositions comprising docetaxel and human serum albumin (HSA)

[0408] The weight ratio of docetaxel to HSA was prepared to be about 1:150.

[0409] Docetaxel (2 mg) was dissolved in methanol (2.5 ml) in a glass vial to produce a clear solution. HSA solution (300 mg, 1.5 ml) (20% human serum albumin solution for infusion (product name: AlbuRx), from CSL Behring) was added to 4.5 ml of water in a round-bottom flask to produce an HSA solution (6 ml). The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The obtained clear aqueous solution was lyophilized overnight to produce a white solid.

[0410] A 100 mg sample of lyophilized solid was reconstituted by adding 2 mL of water to produce a clear solution.

[0411] Example 15: Compositions comprising docetaxel and human serum albumin (HSA)

[0412] The weight ratio of docetaxel to HSA was prepared to be about 1:160.

[0413] Docetaxel (2 mg) was dissolved in methanol (2.7 ml) in a glass vial to produce a clear solution. HSA solution (320 mg, 1.6 ml) (20% human serum albumin solution for infusion (product name: AlbuRx), from CSL Behring) was added to 4.8 ml of water in a round-bottom flask to produce an HSA solution (6.4 ml). The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The clear aqueous solution obtained was lyophilized overnight to produce a white solid.

[0414] A 100 mg sample of lyophilized solid was reconstituted by adding 2 mL of water to produce a clear solution.

[0415] Example 16: Compositions comprising docetaxel and human serum albumin (HSA)

[0416] The weight ratio of docetaxel to HSA was prepared to be about 1:170.

[0417] Docetaxel (2 mg) was dissolved in methanol (2.9 ml) in a glass vial to produce a clear solution. HSA solution (340 mg, 1.7 ml) (20% human serum albumin solution for infusion (product name: AlbuRx), from CSL Behring) was added to 5.1 ml of water in a round-bottom flask to produce an HSA solution (6.8 ml). The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The clear aqueous solution obtained was lyophilized overnight to produce a white solid.

[0418] A 100 mg sample of lyophilized solid was reconstituted by adding 2 mL of water to produce a clear solution.

[0419] Example 17: Compositions comprising docetaxel and human serum albumin (HSA)

[0420] The weight ratio of docetaxel to HSA was prepared to be about 1:180.

[0421] Docetaxel (2 mg) was dissolved in methanol (3.1 ml) in a glass vial to produce a clear solution. HSA solution (360 mg, 1.8 ml) (20% human serum albumin solution for infusion (product name: AlbuRx), from CSL Behring) was added to 5.4 ml of water in a round-bottom flask to produce an HSA solution (7.2 ml). The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The clear aqueous solution obtained was lyophilized overnight to produce a white solid.

[0422] A 100 mg sample of lyophilized solid was reconstituted by adding 2 mL of water to produce a clear solution.

[0423] Example 18: Compositions comprising docetaxel and human serum albumin (HSA)

[0424] The weight ratio of docetaxel to HSA was prepared to be about 1:200.

[0425] Docetaxel (2 mg) was dissolved in methanol (3.4 ml) in a glass vial to produce a clear solution. HSA solution (400 mg, 2 ml) (20% human serum albumin solution for infusion (product name: AlbuRx), from CSL Behring) was added to 6 ml of water in a round-bottom flask to produce an HSA solution (8 ml). The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The clear aqueous solution obtained was lyophilized overnight to produce a white solid.

[0426] A 100 mg sample of lyophilized solid was reconstituted by adding 2 mL of water to produce a clear solution.

[0427] Example 19: Measurement of the correlation between HPLC peak area and docetaxel concentration.

[0428] Seven different concentrations of docetaxel methanol solutions were prepared: 0.025 mg / ml, 0.05 mg / ml, 0.075 mg / ml, 0.1 mg / ml, 0.15 mg / ml, 0.2 mg / ml and 0.25 mg / ml. The seven docetaxel methanol solutions were analyzed by HPLC. Linear regression was used to correlate the peak area with the docetaxel concentration. The linear regression data are shown below.

[0429] Y(peak area)=61390+2.571E7*X(concentration), R=0.9999, P<0.0001.

[0430] Example 20: Docetaxel concentrations in clear aqueous solutions were measured before and after filtration at 0 hours and after filtration at 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 ​​hours and 72 hours.

[0431] 2.5g of the lyophilized solid of the composition comprising docetaxel and HSA (weight ratio of about 1:100) from Example 10 was dissolved in 50ml water to produce a clear aqueous solution, which was kept at about 20°C. After the lyophilized solid was dissolved in water, 6ml of clear aqueous solution was taken out from the 50ml solution immediately. Then 1ml of solution was taken out from the 6ml clear aqueous solution to produce solution DC-0-0h, and the remaining 5ml solution was filtered through the same 0.22 micron aqueous phase filter, 1ml each time to produce solutions DC-1-0h, DC-2-0h, DC-3-0h, DC-4-0h and DC-5-0h. 800μl of acetonitrile was added to 200μl of solution DC-0-0h and DC-5-0h, respectively. The mixture was vortexed for several seconds and then centrifuged at 4,000g for 5 minutes. The supernatant was removed and collected and then injected into HPLC. The same procedure was repeated 2 more times for each of solutions DC-0-0h and DC-5-0h. Based on the HPLC data and the measurement data of Example 19, the docetaxel concentrations of solutions DC-0-0h and DC-5-0h were calculated and shown in Table 1. At 0 hours, the docetaxel concentration after filtration of the clear aqueous solution was about 100.4% of the docetaxel concentration before filtration of the clear aqueous solution.

[0432] Table 1

[0433]

[0434] At 2 hours, 5 ml of clear aqueous solution was taken out from the remaining 44 ml of aqueous solution. Then 1 ml of solution was taken out from the 5 ml of clear aqueous solution and filtered through a 0.22 micron aqueous phase filter to produce solution DC-1-2h, and the remaining 4 ml of solution was filtered through the same 0.22 micron aqueous phase filter, 1 ml each time to produce solutions DC-2-2h, DC-3-2h, DC-4-2h and DC-5-2h. 800 μl of acetonitrile was added to 200 μl of solution DC-5-2h. The mixture was vortexed for several seconds and then centrifuged at 4,000g for 5 minutes. The supernatant was removed and collected and then injected into HPLC. The same procedure was repeated 2 more times for solution DC-5-2h. Based on the HPLC data and measurement data of Example 19, the docetaxel concentration of solution DC-5-2h was calculated and shown in Table 2. At 2 hours, the docetaxel concentration in the clear aqueous solution after filtration was about 100% of the docetaxel concentration in the clear aqueous solution before filtration at 0 hours.

[0435] Table 2

[0436]

[0437] At 4 hours, 5 ml of the clear aqueous solution was taken out from the remaining 39 ml of the aqueous solution. The 5 ml of the clear aqueous solution taken out at 4 hours was subjected to the same experimental protocol as for the 5 ml of the clear aqueous solution taken out at 2 hours. Based on the HPLC data and the measured data of Example 19, the docetaxel concentration of the solution DC-5-4h was calculated and shown in Table 3. At 4 hours, the docetaxel concentration of the clear aqueous solution after filtration was about 99.96% of the docetaxel concentration of the clear aqueous solution before filtration at 0 hours.

[0438] Table 3

[0439]

[0440] At 6 hours, 5 ml of the clear aqueous solution was taken out from the remaining 34 ml of the aqueous solution. The 5 ml of the clear aqueous solution taken out at 6 hours was subjected to the same experimental protocol as for the 5 ml of the clear aqueous solution taken out at 2 hours. Based on the HPLC data and the measured data of Example 19, the docetaxel concentration of the solution DC-5-6h was calculated and shown in Table 4. At 6 hours, the docetaxel concentration of the clear aqueous solution after filtration was about 99.84% of the docetaxel concentration of the clear aqueous solution before filtration at 0 hours.

[0441] Table 4

[0442]

[0443]

[0444] At 8 hours, 5 ml of the clear aqueous solution was taken out from the remaining 29 ml of the aqueous solution. The 5 ml of the clear aqueous solution taken out at 8 hours was subjected to the same experimental protocol as for the 5 ml of the clear aqueous solution taken out at 2 hours. Based on the HPLC data and the measured data of Example 19, the docetaxel concentration of the solution DC-5-8h was calculated and shown in Table 5. At 8 hours, the docetaxel concentration of the clear aqueous solution after filtration was about 99.27% ​​of the docetaxel concentration of the clear aqueous solution before filtration at 0 hours.

[0445] Table 5

[0446]

[0447] At 24 hours, 5 ml of the clear aqueous solution was taken out from the remaining 24 ml of the aqueous solution. The 5 ml of the clear aqueous solution taken out at 24 hours was subjected to the same experimental protocol as for the 5 ml of the clear aqueous solution taken out at 2 hours. Based on the HPLC data and the measured data of Example 19, the docetaxel concentration of the solution DC-5-24h was calculated and shown in Table 6. At 24 hours, the docetaxel concentration of the clear aqueous solution after filtration was about 96.05% of the docetaxel concentration of the clear aqueous solution before filtration at 0 hours.

[0448] Table 6

[0449]

[0450] At 48 hours, 5 ml of the clear aqueous solution was taken out from the remaining 19 ml of the aqueous solution. The 5 ml of the clear aqueous solution taken out at 24 hours was subjected to the same experimental protocol as for the 5 ml of the clear aqueous solution taken out at 2 hours. Based on the HPLC data and the measured data of Example 19, the docetaxel concentration of the solution DC-5-48h was calculated and shown in Table 7. At 48 hours, the docetaxel concentration of the clear aqueous solution after filtration was about 89.10% of the docetaxel concentration of the clear aqueous solution before filtration at 0 hours.

[0451] Table 7

[0452]

[0453]

[0454] At 72 hours, 5 ml of the clear aqueous solution was taken from the remaining 14 ml of the aqueous solution. The 5 ml of the clear aqueous solution taken at 24 hours was subjected to the same experimental protocol as for the 5 ml of the clear aqueous solution taken at 2 hours. Based on the HPLC data and the measured data of Example 19, the docetaxel concentration of the solution DC-5-72h was calculated and shown in Table 8. At 72 hours, the docetaxel concentration of the clear aqueous solution after filtration was about 75.57% of the docetaxel concentration of the clear aqueous solution before filtration at 0 hours.

[0455] Table 8

[0456]

[0457] Example 21: Pharmacokinetic study of a composition comprising docetaxel and human serum albumin (HSA).

[0458] A group of 3 Sprague Dawley mice were used in the pharmacokinetic study. ("SD") male rats. The route of administration studied was intravenous (IV). The dose for the PK study of a composition comprising docetaxel and HSA (the weight ratio of docetaxel to HSA in the composition being about 1:85) was 680 mg / kg. The 11 time points studied were 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 hr after administration. All blood samples were collected from the carotid cannula. The blood samples were transferred to EDTA-K2 anticoagulant tubes and immediately placed on ice. During the half hour collection, the blood samples were processed into plasma by centrifugation at 3000g at about 4°C. The plasma samples will be stored in polypropylene tubes, quickly frozen with dry ice and kept at -70±10°C until LC / MS / MS analysis.

[0459] The LC-MS / MS method was performed on docetaxel in male SD rat plasma. Table 9 shows the PK parameters of the PK study. Figure 1 Shown are mean plasma concentration-time data for docetaxel following intravenous (IV) administration of 680 mg / kg of a composition comprising docetaxel and HSA to SD rats.

[0460] Table 9

[0461] CL(mL / min / kg) Vdss(L / kg) <![CDATA[T 1 / 2 (hr)]]> <![CDATA[AUC 0-最后 (ng.h / mL)]]> 140 112 15.8 600

[0462] Example 22: Compositions comprising docetaxel and human serum albumin (HSA)

[0463] The weight ratio of docetaxel to HSA was prepared to be about 1:100.

[0464] Docetaxel (100 mg) was dissolved in methanol (42.9 ml) in a glass vial to produce a clear solution. Powdered HSA (10 g) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm of fatty acids) was dissolved in 100 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The resulting clear aqueous solution was lyophilized overnight to produce a white solid.

[0465] A 100 mg sample of lyophilized solid was reconstituted by adding 2 mL of water to produce a clear solution.

[0466] Example 23: Compositions comprising docetaxel and human serum albumin (HSA)

[0467] The weight ratio of docetaxel to HSA was prepared to be about 1:180.

[0468] Docetaxel (10 mg) was dissolved in methanol (15.4 ml) in a glass vial to produce a clear solution. HSA solution (1800 mg, 9 ml) (20% human serum albumin solution for infusion (product name: AlbuRx), from CSL Behring) was added to 27 ml of water in a round-bottom flask to produce an HSA solution (36 ml). The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The clear aqueous solution obtained was lyophilized overnight to produce a white solid.

[0469] A 100 mg sample of lyophilized solid was reconstituted by adding 2 mL of water to produce a clear solution.

[0470] Example 24: Compositions comprising docetaxel and human serum albumin (HSA)

[0471] The weight ratio of docetaxel to HSA was prepared to be about 1:100.

[0472] Docetaxel (10 mg) was dissolved in methanol (8.6 ml) in a glass vial to produce a clear solution. Powdered HSA (1000 mg) (natural fatty acid-free human serum albumin purchased from Golden West Biologicals, Inc., CAT#: HA1020) was dissolved in 20 ml of water in a round-bottom flask. The methanol solution of docetaxel was slowly added dropwise to the HSA solution flask at 0°C with rapid stirring. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous phase filter. The resulting clear aqueous solution was lyophilized overnight to produce a white solid.

[0473] A 100 mg sample of lyophilized solid was reconstituted by adding 2 mL of water to produce a clear solution.

[0474] Example 25: Measuring the pH of a clear aqueous solution of a composition comprising docetaxel and human serum albumin (HSA)

[0475] 250 mg of the lyophilized solid of the composition comprising docetaxel and HSA (weight ratio of about 1:100) from Example 22 was dissolved in 10 ml of water to produce a clear aqueous solution. The clear aqueous solution was kept at about 25° C. and the pH was measured. The pH of the clear aqueous solution was 6.72 (3 measurements: 6.71, 6.72 and 6.72).

[0476] 500 mg of the lyophilized solid of the composition comprising docetaxel and HSA (weight ratio of about 1:100) from Example 22 was dissolved in 10 ml of water to produce a clear aqueous solution. The clear aqueous solution was kept at about 25° C. and the pH was measured. The pH of the clear aqueous solution was 6.73 (3 measurements: 6.73, 6.74 and 6.73).

[0477] 750 mg of the lyophilized solid of the composition comprising docetaxel and HSA (weight ratio of about 1:100) from Example 22 was dissolved in 10 ml of water to produce a clear aqueous solution. The clear aqueous solution was kept at about 25° C. and the pH was measured. The pH of the clear aqueous solution was 6.75 (3 measurements: 6.75, 6.75 and 6.76).

[0478] 250 mg of the lyophilized solid of the composition comprising docetaxel and HSA (weight ratio of about 1:100) from Example 22 was dissolved in 10 ml of 0.9% saline solution (which has a pH of about 5.41) to produce a clear aqueous solution. The clear aqueous solution was kept at about 25°C and the pH was measured. The pH of the clear aqueous solution was 6.74 (3 measurements: 6.73, 6.74 and 6.74).

[0479] 500 mg of the lyophilized solid of the composition comprising docetaxel and HSA (weight ratio of about 1:100) from Example 22 was dissolved in 10 ml of 0.9% saline solution (which has a pH of about 5.41) to produce a clear aqueous solution. The clear aqueous solution was kept at about 25° C. and the pH was measured. The pH of the clear aqueous solution was 6.75 (3 measurements: 6.74, 6.75 and 6.76).

[0480] 750 mg of the lyophilized solid of the composition comprising docetaxel and HSA (weight ratio of about 1:100) from Example 22 was dissolved in 10 ml of 0.9% saline solution (which has a pH of about 5.41) to produce a clear aqueous solution. The clear aqueous solution was kept at about 25° C. and the pH was measured. The pH of the clear aqueous solution was 6.78 (3 measurements: 6.77, 6.79 and 6.78).

[0481] 250 mg of the lyophilized solid of the composition comprising docetaxel and HSA (weight ratio of about 1:100) from Example 22 was dissolved in 10 ml of a 5% glucose solution (having a pH of about 4.40) to produce a clear aqueous solution. The clear aqueous solution was kept at about 25° C. and the pH was measured. The pH of the clear aqueous solution was 6.67 (3 measurements: 6.67, 6.66 and 6.67).

[0482] 500 mg of the lyophilized solid of the composition comprising docetaxel and HSA (weight ratio of about 1:100) from Example 22 was dissolved in 10 ml of a 5% glucose solution (having a pH of about 4.40) to produce a clear aqueous solution. The clear aqueous solution was kept at about 25° C. and the pH was measured. The pH of the clear aqueous solution was 6.75 (3 measurements: 6.73, 6.75 and 6.76).

[0483] 750 mg of the lyophilized solid of the composition comprising docetaxel and HSA (weight ratio of about 1:100) from Example 22 was dissolved in 10 ml of a 5% glucose solution (having a pH of about 4.40) to produce a clear aqueous solution. The clear aqueous solution was kept at about 25° C. and the pH was measured. The pH of the clear aqueous solution was 6.76 (3 measurements: 6.75, 6.76 and 6.76).

[0484] Example 26: Measuring the pH of a clear aqueous solution of a composition comprising docetaxel and human serum albumin (HSA)

[0485] 500 mg of the lyophilized solid of the composition comprising docetaxel and HSA (weight ratio of about 1:180) from Example 23 was dissolved in 10 ml of water to produce a clear aqueous solution. The clear aqueous solution was kept at about 25° C. and the pH value was measured. The pH value of the clear aqueous solution was 7.10 (3 measurements: 7.09, 7.10 and 7.11).

[0486] Example 27: Measuring the pH of a clear aqueous solution of a composition comprising docetaxel and human serum albumin (HSA)

[0487] 250 mg of the lyophilized solid of the composition comprising docetaxel and HSA (weight ratio of about 1:100) from Example 24 was dissolved in 10 ml of water to produce a clear aqueous solution. The clear aqueous solution was kept at about 25° C. and the pH was measured. The pH of the clear aqueous solution was 6.85 (3 measurements: 6.86, 6.84 and 6.85).

[0488] Example 28: Compositions comprising paclitaxel and human serum albumin (HSA)

[0489] The weight ratio of paclitaxel to HSA was prepared to be about 1:240.

[0490] Will Paclitaxel(2 mg) was dissolved in methanol (4.3 ml) in a glass vial to produce a clear solution. Powdered HSA (480 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm fatty acids) was dissolved in 10 ml of water in a round-bottom flask. Slowly dropwise add 1% HCl to the HSA solution flask at 0°C with rapid stirring. Paclitaxel After the addition was complete, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The resulting clear aqueous solution was lyophilized overnight to produce a white solid.

[0491] A 100 mg sample of lyophilized solid was reconstituted by adding 2 mL of water to produce a clear solution.

[0492] Example 29: Compositions comprising paclitaxel and human serum albumin (HSA)

[0493] The weight ratio of paclitaxel to HSA was prepared to be about 1:200.

[0494] Will Paclitaxel (3 mg) was dissolved in methanol (5.1 ml) in a glass vial to produce a clear solution. Powdered HSA (600 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm fatty acids) was dissolved in 12 ml of water in a round-bottom flask. Slowly add dropwise to the HSA solution flask at 0°C with rapid stirring. Paclitaxel After the addition was complete, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The resulting clear aqueous solution was lyophilized overnight to produce a white solid. A 100 mg freeze-dried solid sample was reconstituted by adding 2 mL of water to produce a turbid solution.

[0495] Example 30: Compositions comprising paclitaxel and human serum albumin (HSA)

[0496] The weight ratio of paclitaxel to HSA was prepared to be about 1:160.

[0497] Will Paclitaxel (3 mg) was dissolved in methanol (4.3 ml) in a glass vial to produce a clear solution. Powdered HSA (480 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm fatty acids) was dissolved in 10 ml of water in a round-bottom flask. Slowly add dropwise to the HSA solution flask at 0°C with rapid stirring. PaclitaxelThe methanol solution of 100mg was added. After the addition was completed, a clear solution was obtained. The methanol in the solution was then removed under vacuum to produce a clear solution. The clear aqueous solution obtained was lyophilized overnight to produce a white solid. 100mg of the lyophilized solid sample was reconstituted to produce a turbid solution by adding 2mL of water. The solution remained turbid and formed a white precipitate in approximately 2 hours.

[0498] Example 31: Compositions comprising paclitaxel and human serum albumin (HSA)

[0499] The weight ratio of paclitaxel to HSA was prepared to be about 1:120.

[0500] Will Paclitaxel (3 mg) was dissolved in methanol (3 ml) in a glass vial to produce a clear solution. Powdered HSA (360 mg) (natural fatty acid-free human serum albumin purchased from SeraCare Life Sciences, product code: HS-455-80, which contains <0.2 mg / gm fatty acids) was dissolved in 7 ml of water in a round-bottom flask. Slowly add dropwise to the HSA solution flask at 0°C with rapid stirring. Paclitaxel After the addition was complete, a clear solution was obtained. After the methanol in the solution was removed under vacuum, a turbid solution was obtained.

[0501] Other Implementations

[0502] It should be understood that although the invention has been described in conjunction with specific embodiments, the above description is intended to illustrate but not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.

Claims

1. A composition comprising docetaxel and human serum albumin, wherein the weight ratio of the docetaxel to the human serum albumin in the composition is about 1:50 to about 1:1000, and wherein the pH of the composition is about 5 to about 8; the composition is an aqueous preparation, and the aqueous preparation is a clear aqueous solution; the preparation method of the composition comprises the following steps: (i) obtaining an organic solution containing docetaxel dissolved in a polar water-soluble organic solvent; (ii) obtaining a first aqueous solution of human serum albumin; as well as (iii) mixing the organic solution of docetaxel with the first aqueous solution of human serum albumin to obtain a second aqueous solution comprising a composition including docetaxel and human serum albumin.

2. The composition of claim 1, wherein the weight ratio of the docetaxel to the human serum albumin in the composition is about 1:60 to about 1:

300.

3. The composition of claim 1, wherein the polar water-soluble organic solvent in the composition is ethanol.

4. The composition of claim 1, wherein the mixing comprises adding an organic solution to the first aqueous solution.

5. The composition of any one of claims 1 to 4, wherein the aqueous formulation is a clear aqueous solution for at least 3 hours.

6. A pharmaceutical composition comprising the composition according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

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