阅读说明：本技术 包含多西他赛和人血清白蛋白的固体组合物及其制备方法和应用 (Solid composition containing docetaxel and human serum albumin, and preparation method and application thereof ) 是由 孙群 于 2016-05-16 设计创作，主要内容包括：本发明涉及包含多西他赛和人血清白蛋白的固体组合物及其制备方法和应用。该固体组合物中的多西他赛和人血清白蛋白的重量比为1：50至1：1000,其中当固体组合物溶解在水性溶剂中时,该组合物为澄明的水性溶液,并且水性溶液基本上不含除了水以外的溶剂。该固体组合物的制备方法包括(i)获得溶解在极性水混溶性有机溶剂中的多西他赛的有机溶液；(ii)获得人血清白蛋白的第一水性溶液；(iii)将多西他赛的有机溶液与人血清白蛋白的第一水性溶液混合以获得包含包括多西他赛和人血清白蛋白的组合物的第二水性溶液；和(iv)从第二水性溶液中除去有机溶剂和水性溶剂,以获得包含多西他赛和人血清白蛋白的固体组合物。(The invention relates to a solid composition containing docetaxel and human serum albumin, and a preparation method and application thereof. The weight ratio of docetaxel to human serum albumin in the solid composition is 1:50 to 1:1000, wherein when the solid composition is dissolved in an aqueous solvent, the composition is a clear aqueous solution and the aqueous solution is substantially free of solvents other than water. The solid composition is prepared by a process comprising (i) obtaining an organic solution of docetaxel dissolved in a polar water-miscible organic solvent; (ii) obtaining a first aqueous solution of human serum albumin; (iii) mixing an organic solution of docetaxel with a first aqueous solution of human serum albumin to obtain a second aqueous solution comprising a composition comprising docetaxel and human serum albumin; and (iv) removing the organic solvent and the aqueous solvent from the second aqueous solution to obtain a solid composition comprising docetaxel and human serum albumin.)

1. A process for preparing a solid composition comprising docetaxel and human serum albumin, wherein the weight ratio of docetaxel to human serum albumin in the solid composition is 1:50 to 1:1000, wherein when the solid composition is dissolved in an aqueous solvent, the composition is a clear aqueous solution, and wherein the aqueous solution is substantially free of solvents other than water; the method comprises the following steps:

(i) obtaining an organic solution of docetaxel dissolved in a polar water-miscible organic solvent;

(ii) obtaining a first aqueous solution of human serum albumin;

(iii) mixing an organic solution of docetaxel with a first aqueous solution of human serum albumin to obtain a second aqueous solution comprising a composition comprising docetaxel and human serum albumin; and

(iv) removing the organic solvent and the aqueous solvent from the second aqueous solution to obtain a solid composition comprising docetaxel and human serum albumin.

2. The method of claim 1, wherein the solid composition has a weight ratio of docetaxel to human serum albumin of 1:80 to 1: 200.

3. The method of claim 2, wherein the solid composition comprises docetaxel and human serum albumin in a weight ratio of 1:90, 1:100, 1:110, or 1: 120.

4. The method of claim 1, wherein the polar water-miscible organic solvent is an alcohol.

5. The method of claim 4, wherein the polar water-miscible organic solvent is ethanol.

6. The method of claim 1, wherein the second aqueous solution is a clear aqueous solution.

7. The process of claim 1, wherein an organic solution of docetaxel is added to the first aqueous solution to form a second aqueous solution.

8. The method of claim 7, wherein the addition is performed at a temperature of 0 ℃ to 25 ℃.

9. The method of any one of claims 1 to 8, wherein the solvent in the second aqueous solution is removed by lyophilization.

10. A solid composition comprising docetaxel and human serum albumin prepared by the process of any one of claims 1 to 9, wherein the weight ratio of docetaxel to human serum albumin in the solid composition is from 1:50 to 1:1000, wherein the composition is a clear aqueous solution when the solid composition is dissolved in an aqueous solvent, and wherein the aqueous solution is substantially free of solvents other than water.

11. The solid composition of claim 10, wherein the weight ratio of docetaxel to human serum albumin in the composition is from 1:80 to 1: 200.

12. A pharmaceutical composition comprising the solid composition of claim 10 or 11 and a pharmaceutically acceptable carrier.

Technical Field

The present invention relates to complexes and compositions for the treatment of proliferative diseases, more specifically to complexes and compositions comprising docetaxel.

Background

Many drugs for parenteral use are insoluble in water and are therefore formulated with solubilizing agents, surfactants, solvents and/or emulsifiers that are irritating, allergic or toxic when administered to a patient. See, e.g., Briggs et al, Anesthesis 37, 1099(1982) and Waugh et al, am.J.Hosp.Pharmacists, 48, 1520 (1991). In addition, it is possible toMany of these drugs, particularly those administered intravenously, can cause undesirable side effects such as venous irritation, phlebitis, burning and pain upon injection, venous thrombosis, extravasation, and other administration related side effects. In addition, free drug present in the formulation often causes pain or irritation when administered. Taxanes play an important role in the treatment of various solid tumors. As a second generation semi-synthetic taxane derivative, docetaxel is approximately twice as potent in inhibiting microtubule depolymerization as paclitaxel, and has the unique ability to alter certain types of microtubules, unlike most spindle toxins currently in clinical use. However, docetaxel is very poorly water soluble. Commercially available docetaxelClinical intravenous administration was formulated as a high concentration solution containing 40mg docetaxel and 1040mg polysorbate 80 per mL. This concentrated solution must be carefully diluted with a saline solution containing 13% ethanol prior to administration and must be used within 4 hours due to limited stability. These properties limit the administration of docetaxel. Furthermore, docetaxel administration has been reported to be associated with unpredictable (acute) hypersensitivity and the occurrence of cumulative fluid retention. See, e.g., Trudeau ME et al, J clean Oncol 1996; 14:422-8, Picclart MJ et al, J Natl Cancer Inst 1995; 676-81, Bruno R et al, J Clin Oncol 1998; 16:187-96. These side effects are due in part to the presence of polysorbate 80.

Thus, there is a need in the art for stable and non-toxic formulations of docetaxel. The compositions and methods described herein help meet this need.

Disclosure of Invention

Provided herein are various 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 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 from about 0.8:1 to about 1.3: 1. In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.5:1, 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.

In some embodiments, the human serum albumin is native 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.

Further, 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 about 0.1:1 to about 5: 1.

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.

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.

In some embodiments, the human serum albumin is native 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.

Further, 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. 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 0.2:1, 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 human serum albumin is native 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.

In some embodiments, the composition is a solid formulation. For example, solid formulations can be prepared in a uniform manner by lyophilization. One skilled in the art will recognize that other methods may also produce solid formulations, such as rotary evaporation.

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. In some embodiments, the aqueous formulation comprises water and a water miscible organic solvent, including at least one of polyethylene glycol 300, polyethylene glycol 400, ethanol, methanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide. For example, the water-miscible organic solvent may include ethanol. In some embodiments, the aqueous formulation comprises water and ethanol. In some embodiments, the water-miscible organic solvent may be a mixture of water-miscible organic solvents.

In some embodiments, the aqueous formulation may be surfactant free, e.g.A surfactant and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of waterFree of surfactants, e.g.A surfactant and polysorbate 80.

In some embodiments, the aqueous formulation is free of a surfactant selected from the group consisting ofSurfactant and polysorbate 80.

In some embodiments, the aqueous formulation is a clear aqueous solution. For example, the formulation may 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.

Further, provided herein is a pharmaceutical composition comprising a composition as described herein comprising a non-covalently bound complex comprising docetaxel and human serum albumin and a pharmaceutically acceptable carrier.

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

In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from the group consisting of 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 a 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.

Further, 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 the composition is a clear aqueous solution when dissolved in an aqueous solution, and wherein the solubility of the composition in the aqueous solution is at least 10 mg/ml.

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 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: 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.

In some embodiments, the human serum albumin is native 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.

In some embodiments, the composition forms a clear aqueous solution for at least 6 hours when the composition is dissolved in the aqueous solution. In some embodiments, the composition forms a clear aqueous solution for at least 24 hours when the composition is dissolved in the aqueous solution. In some embodiments, the composition forms a clear aqueous solution for at least 3 days when the composition is dissolved in the 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.

In some embodiments, the composition is a solid formulation. For example, solid formulations can be produced in a uniform manner by lyophilization. One skilled in the art will be able to ascertain that other methods may also produce solid formulations, such as rotary evaporation.

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. In some embodiments, the aqueous formulation comprises water and a water miscible organic solvent, including at least one of polyethylene glycol 300, polyethylene glycol 400, ethanol, methanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide. For example, the water-miscible organic solvent may include ethanol. In some embodiments, the aqueous formulation comprises water and ethanol. In some embodiments, the water-miscible organic solvent may be a mixture of water-miscible organic solvents.

In some embodiments, the aqueous formulation may be surfactant free, e.g.A surfactant and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of surfactants, e.g.A surfactant and polysorbate 80.

In some embodiments, the aqueous formulation is free of a surfactant selected from the group consisting ofSurfactant and polysorbate 80.

In some embodiments, the aqueous formulation is a clear aqueous solution. For example, the formulation may 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. 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 one week.

Further, provided herein is a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

Further, provided herein is a method of treating cancer, the method comprising the steps 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.

In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from the group consisting of 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 a 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.

Further, 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 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.

In some embodiments, the human serum albumin is native 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.

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 composition forms a clear aqueous solution for at least 3 hours when the composition is dissolved in the aqueous solution. In some embodiments, the composition forms a clear aqueous solution for at least 6 hours when the composition is dissolved in the aqueous solution. In some embodiments, the composition forms a clear aqueous solution for at least 24 hours when the composition is dissolved in the aqueous solution. In some embodiments, the composition forms a clear aqueous solution for at least 3 days when the composition is dissolved in the aqueous solution. In some embodiments, the aqueous solution is substantially free of solvents other than water.

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 surfactant free, e.g.A surfactant and polysorbate 80. In some embodiments, the aqueous formulation is a clear aqueous solution. In some embodiments, the aqueous formulation is free of a surfactant selected from the group consisting ofSurfactant and polysorbate 80.

Further, provided herein is a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

Further, provided herein is a method of treating cancer comprising the steps 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. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from the group consisting of 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 a 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.

Further, 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 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.

In some embodiments, the human serum albumin is native 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.

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, 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 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 surfactant free, e.g.A surfactant and polysorbate 80. In some embodiments, the aqueous formulation is free of a surfactant selected from the group consisting ofSurfactant and polysorbate 80. In some embodiments, the aqueous formulation is a clear aqueous solution.

Further, provided herein is a pharmaceutical composition comprising a composition described herein consisting essentially of docetaxel and human serum albumin, and a pharmaceutically acceptable carrier.

Further, provided herein is a method of treating cancer comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition described herein consisting essentially of docetaxel and human serum albumin and a pharmaceutically acceptable carrier.

In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from the group consisting of 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 a 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.

Further, provided herein is a composition comprising a non-covalently bound complex consisting essentially of 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 2: 1.

Further, provided herein is a composition consisting essentially of docetaxel and human serum albumin in a molar ratio of about 0.1:1 to about 2:1, wherein the composition is a clear aqueous solution when the composition is dissolved in an aqueous solution, wherein the solubility of the composition in the aqueous solution is at least 10 mg/ml.

Further, 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, prepared by a process comprising the steps of:

(i) obtaining an organic solution of docetaxel dissolved in a polar water-miscible organic solvent;

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

(iii) mixing an organic solution of docetaxel and a first aqueous solution of human serum albumin to obtain a second aqueous solution comprising a composition comprising docetaxel and human serum albumin.

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

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

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

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

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

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

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

In some embodiments, the polar water-miscible organic solvent is selected from the group consisting of methanol, ethanol, and mixtures thereof.

In some embodiments, the aqueous solvent is water.

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, the mixing is performed at a temperature of about 0 ℃ to about 25 ℃.

In some embodiments, the mixing is performed at ambient temperature.

In some embodiments, the mixing is performed at a temperature of about 0 ℃ to about 5 ℃.

In some embodiments, the mixing is performed at about 0 ℃.

In some embodiments, the composition further comprises removing the polar water-miscible 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 comprises removing the aqueous solvent from the third aqueous solution to obtain a composition comprising docetaxel and human serum albumin.

In some embodiments, the composition further comprises removing the organic solvent and the aqueous solvent from the second aqueous solution to obtain a composition comprising docetaxel and human serum albumin.

In some embodiments, the removal is performed in a vacuum.

In some embodiments, the removing is performed by lyophilization.

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

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 surfactant.

In some embodiments, the surfactant is selected from the group consisting ofSurfactant 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.

In some embodiments, the present invention provides a pharmaceutical composition comprising a composition prepared by the methods described herein and a pharmaceutically acceptable carrier.

In some embodiments, the present invention provides a method of treating cancer, the method comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein.

In some embodiments, the cancer is a solid tumor.

In some embodiments, the cancer is selected from the group consisting of 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 present invention 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, prepared by a process comprising the steps of:

(i) obtaining an organic solution of docetaxel dissolved in a polar water-miscible organic solvent;

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

(iii) mixing an organic solution of docetaxel and a first aqueous solution of human serum albumin to obtain a second aqueous solution comprising a composition comprising docetaxel and human serum albumin.

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

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

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

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

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

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

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

In some embodiments, the polar water-miscible organic solvent is selected from the group consisting of methanol, ethanol, and mixtures thereof.

In some embodiments, the aqueous solvent is water.

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, the mixing is performed at a temperature of about 0 ℃ to about 25 ℃.

In some embodiments, the mixing is performed at ambient temperature.

In some embodiments, the mixing is performed at a temperature of about 0 ℃ to about 5 ℃.

In some embodiments, the mixing is performed at about 0 ℃.

In some embodiments, the composition further comprises removing the polar water-miscible 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 comprises removing the aqueous solvent from the third aqueous solution to obtain a composition comprising docetaxel and human serum albumin.

In some embodiments, the composition further comprises removing the organic solvent and the aqueous solvent from the second aqueous solution to obtain a composition comprising docetaxel and human serum albumin.

In some embodiments, the removal is performed in a vacuum.

In some embodiments, the removing is performed by lyophilization.

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

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 surfactant.

In some embodiments, the surfactant is selected from the group consisting ofSurfactant 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.

In some embodiments, the present invention provides a pharmaceutical composition comprising a composition prepared by the methods described herein and a pharmaceutically acceptable carrier.

In some embodiments, the present invention provides a method of treating cancer, the method comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein.

In some embodiments, the cancer is a solid tumor.

In some embodiments, the cancer is selected from the group consisting of breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer, ovarian cancer, pancreatic cancer, and kaposi's sarcoma.

Drawings

Fig. 1 is a graph showing the mean blood concentration of docetaxel as a function of time after intravenous injection of a composition comprising docetaxel and human serum albumin at a dose of 680mg/kg in SD rats.

Detailed Description

Provided herein are various 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 present invention 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 about 0.1:1 to about 5: 1.

In some embodiments, the present invention provides a plurality of non-covalently bound complexes comprising docetaxel and human serum albumin, wherein the molar ratio of docetaxel to human serum albumin in the plurality of complexes is about 0.1:1 to about 5: 1.

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.

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 an electrostatic interaction. In some embodiments, the non-covalent interaction between docetaxel and human serum albumin in the complex comprises a hydrophobic interaction. In some embodiments, the non-covalent interaction between docetaxel and human serum albumin in the complex comprises van der waals forces.

The term "human serum albumin" as used in the present invention refers to both natural and recombinant human serum albumin. Native human serum albumin and other plasma proteins can be precipitated from human plasma by varying the pH and adding ethanol, a so-called Cohn fractionation method (Cohn EJ et al, J.Am.chem.Soc.1946; 68: 459-. By controlling the pH and ethanol content, a semi-purified fraction 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 native human serum albumin was obtained. Subsequent biological treatment steps (purification, filtration, pasteurization, etc.) can be used to produce a purified, stabilized form 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 animal, viral and prion-free product, a substitute for natural human serum albumin, and has the same structure as 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, both prokaryotic and eukaryotic (Chen Z et al, Biochimica et Biophysica Acta 2013; 1830: 5515-5525). Fatty acid-free human serum albumin can be prepared by treating human serum albumin with charcoal at low pH. Likewise, treatment of human serum albumin with low pH charcoal can be used to remove fatty acids from human serum albumin (Chen RF, J.biol.chem.167; 242: 173-.

Human Serum Albumin (HSA) is a highly soluble Mr65K globular protein, consisting of 585 amino acids. HSA is the most abundant protein in plasma and accounts for 70-80% of the human plasma colloid osmotic pressure. The amino acid sequence of HSA has a total of 17 disulfide bonds, one free thiol (Cys 34) and one tryptophan (Tip 214). Intravenous injection of HSA solutions is used for the prevention and treatment of hypovolemic shock (see, e.g., Tullis, JAMA, 237, 355-.

Human Serum Albumin (HSA) has multiple hydrophobic binding sites (total of 7 endogenous ligands for medium and long chain fatty acids, HSA) and binds to different combinations of drugs, particularly neutral and negatively charged hydrophobic compounds (Goodman et al, The pharmaceutical Basis of Therapeutics, 9 th edition, McGraw-Hill New York (1996)). Two high affinity binding sites have been proposed in the IIA and IIIA subdomains of HSA, which are highly elongated hydrophobic pockets with charged lysine and arginine residues near the surface that serves as the point of attachment for polar coordination 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 (198203)).

In some embodiments, the human serum albumin is native 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. In some embodiments, the human serum albumin contains no more than 2 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 1 mole of fatty acids bound to 1 mole of human serum albumin.

In some embodiments, the human serum albumin contains no more than 0.5 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.1 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.05 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.01 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.001 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.0005 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.0001 moles of fatty acids bound to 1 mole of human serum albumin.

As used herein, the term "non-covalently bound complex" refers to a complex in which the linkage between the components in the complex is non-covalent (e.g., weak bonds such as hydrogen bonds, electrostatic effects, pi effects, hydrophobic effects, and van der waals forces). Furthermore, Human Serum Albumin (HSA) has multiple hydrophobic binding sites (total of 7 endogenous ligands for medium and long chain fatty acids, HSA) and can bind different combinations of drugs, especially neutral and negatively charged hydrophobic compounds (Goodman et al, The pharmaceutical Basis of Therapeutics, 9 th edition, McGraw-Hill New York (1996)). In addition, after the drug molecule binds to HSA, the drug molecule and HSA form a non-covalently bound drug and protein complex through the binding site of HSA. This concept is generally known to those of ordinary skill in the art to which this invention pertains. One example of a non-covalent binding complex is a non-covalent binding complex of HSA and a fatty acid, wherein the fatty acid binds to HSA through multiple binding sites of HSA. As used herein, the term "stable" refers to non-covalently bound complexes that do not readily dissociate and aggregate into separate moieties, e.g., do not readily dissociate and aggregate over a period of time exceeding 6 hours, 12 hours, 24 hours, or 3 days. For example, a solution comprising a stable non-covalently bound complex will generally appear clear, while a solution comprising a unstable non-covalently bound complex will appear semi-clear or cloudy. Furthermore, one of ordinary skill in the art understands that after a period of time, the stable non-covalently bound complex can separate and aggregate into separate fractions. Thus, a solution comprising a stable non-covalently bound complex may become semi-clear or cloudy after a period of time (e.g., 6 hours, 12 hours, 24 hours, or 3 days).

In vitro studies have shown that docetaxel has a protein binding rate of about 94%, binding predominantly to α 1-acid glycoprotein, albumin and lipoprotein. In three cancer patients, plasma protein binding rate in vitro was found to be approximately 97%. Please refer to docetaxel prescription information.

As used herein, the term "substantially free of fatty acids" refers to proteins (e.g., serum albumin) that contain less than about 0.02 wt.% fatty acids. For example, human serum albumin substantially free of fatty acids may contain less than 0.02 wt.% fatty acids.

As used herein, the term "fatty acid" refers to a non-esterified fatty acid (e.g., linoleic acid, alpha-linoleic acid, gamma-linoleic acid).

As used herein, the term docetaxel is a compound having CAS number 114977-28-5 and the following chemical structure:

docetaxel is a white to almost white powder. It is highly lipophilic and practically insoluble in water.

Furthermore, docetaxel is a microtubule inhibitor against squamous cell carcinoma of breast cancer, non-small cell lung cancer, hormone-independent prostate cancer, gastric adenocarcinoma, and head and neck cancer.

In some embodiments, the docetaxel may be a pharmaceutically acceptable salt of docetaxel.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the test compound and exhibits minimal undesirable toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds, or separatelyThe purified compound is reacted with a suitable base or acid, in free acid or free base form, respectively. In some embodiments, pharmaceutically acceptable salts may be preferred over the corresponding free base or free acid because such salts impart greater stability or solubility to the molecule, thereby facilitating formulation into 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 the hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, glycolate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, para-aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, embonate, acetate, maleate, fumarate, maleate, acetate, malonate, laurate, glutarate, glutamate, propionate dodecylsulfate, methanesulfonate (methanesulfonate), ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (benzenesulfonate), sulfanilate, p-toluenesulfonate (p-toluenesulfonate), naphthalene-2-sulfonate, ethanedisulfonate, bisulfide, bitartrate, gluconate, glucuronate, p-bromobenzenesulfonate, carbonate, pyrosulfate, sulfite, bisulfite, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, caprate, caprylate, caprate, propiolate, suberate, sebacate, butyne-1, 4-dioate, hexyne-1, 6-dioate, methanesulfonate, p-toluenesulfonate (p-toluenesulfonate), bisulfate, gluconate, glucuronate, monobutyrate, disulfate, bromide, iodide, caprate, caprylate, caprate, propiolate, Terephthalate, sulfonate, xylene sulfonate, phenylpropionate, phenylbutyrate, beta-hydroxybutyrate, ethanolAcid salts, propanesulfonic acid salts, naphthalene-1-sulfonic acid salts, naphthalene-2-sulfonic acid salts and 2, 5-dihydroxybenzoic acid salts. Suitable bases include pharmaceutically acceptable inorganic bases and pharmaceutically acceptable organic bases. Representative pharmaceutically acceptable base addition salts include: hydroxides of alkali metals, including sodium, potassium and lithium; hydroxides of alkaline earth metals, such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines, such as unsubstituted or hydroxy-substituted monoalkylamines, dialkylamines or trialkylamines, dicyclohexylamines; tributylamine; pyridine; n-methylamine, N-ethylamine; diethylamine; triethylamine; mono-, di-or tri (2-OH- (C)₁-C₆) -alkyl) amines, such as N, N-dimethyl-N- (2-hydroxyethyl) amine or tris- (2-hydroxyethyl) amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; a pyrrolidine; and amino acids such as arginine, lysine, and the like.

In some embodiments, the docetaxel may be docetaxel having 1 equivalent, 2 equivalents, or 3 equivalents of a hydrosolvent. In some embodiments, the docetaxel may be docetaxel having 3 equivalents of water solvate. In some embodiments, the docetaxel is docetaxel trihydrate. In some embodiments, the docetaxel is docetaxel monohydrate. In some embodiments, the docetaxel is anhydrous docetaxel.

In some embodiments, the docetaxel may be docetaxel having 1 equivalent of acetone solvate. In some embodiments, the docetaxel may be any of the docetaxel solvates disclosed, for example, in WO2010091650 or US2012007167, the disclosures of which are herein incorporated by reference in their entirety.

In some embodiments, the 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 herein incorporated by reference in their entirety.

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

Further, 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 about 0.1:1 to about 5: 1.

In some embodiments, the present invention 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.

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 from about 0.8:1 to about 1.3: 1. In some embodiments, the molar ratio of docetaxel to human serum albumin is about 0.5:1, 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.

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.

In some embodiments, the human serum albumin is native 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. In some embodiments, the human serum albumin contains no more than 2 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 1 mole of fatty acids bound to 1 mole of human serum albumin.

In some embodiments, the human serum albumin contains no more than 0.5 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.1 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.05 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.01 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.001 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.0005 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.0001 moles of fatty acids bound to 1 mole of human serum albumin.

Further, 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.

In some embodiments, the present invention 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 about 0.1:1 to about 5: 1.

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 0.2:1, 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 human serum albumin is native 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. In some embodiments, the human serum albumin contains no more than 2 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 1 mole of fatty acids bound to 1 mole of human serum albumin.

In some embodiments, the human serum albumin contains no more than 0.5 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.1 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.05 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.01 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.001 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.0005 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.0001 moles of fatty acids bound to 1 mole of human serum albumin.

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, bacteriostats and solutes that render the formulation compatible with the blood of the intended subject, and aqueous and non-aqueous sterile suspensions, which may include suspending agents, solubilizers, thickening agents, stabilizers and preservatives. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition for injection, requiring only the addition of the sterile liquid excipient, for example water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

In some embodiments, the composition is a solid formulation. For example, solid formulations can be produced in a uniform manner by freeze-drying. One skilled in the art will recognize that other methods may also produce solid formulations, such as rotary evaporation.

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. In some embodiments, the aqueous formulation comprises water and a water-miscible organic solvent comprising at least one of polyethylene glycol 300, polyethylene glycol 400, ethanol, methanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide. For example, the water-miscible organic solvent may include ethanol. In some embodiments, the aqueous formulation comprises water and ethanol. In some embodiments, the water-miscible organic solvent may be a mixture of water-miscible organic solvents. As used herein, with "substantially free of solvent" in an aqueous solution, it is meant an aqueous solution containing less than 0.5 wt% of any non-aqueous solvent. In some embodiments, the aqueous solution contains less than 0.1 wt% of any non-aqueous solvent. In some embodiments, the aqueous solution contains less than 0.05 wt% of any non-aqueous solvent.

In some embodiments, the aqueous formulation may be free of surfactants. In some embodiments, the aqueous formulation may be surfactant free, e.g.A surfactant and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of surfactants, e.g.A surfactant and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of surfactant selected from the group consisting ofA surfactant and polysorbate 80.

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% of surfactants and/or less than 0.0005%, less than 0.0003%, or less than 0.0001% of a surfactant.

In some embodiments, the aqueous formulation is a clear aqueous solution. For example, the formulation may 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.

As used herein, the term "clear aqueous solution" refers to a solution comprising docetaxel dissolved in an aqueous solution and human serum albumin that is clear when visually observed and is substantially free of visible particles or precipitates of undissolved docetaxel.

The term "substantially free of undissolved visible particles or precipitates of docetaxel" can be evaluated 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 prior to filtration. The total amount of docetaxel in the aqueous solution prior to filtration includes particles or precipitates of undissolved docetaxel in or with the aqueous solution. The amount of docetaxel in an aqueous solution can be measured by a method using HPLC. The method of measuring the amount of docetaxel in an aqueous solution is illustrated in the experimental examples described herein. Such methods are generally known to those of ordinary skill in the art to which the invention pertains.

When viewed visually, for example, the term "clear aqueous solution" does not include a milky aqueous solution. Further, the term "clear aqueous solution" does not include turbid or hazy aqueous solutions.

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

In some embodiments, after filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration is at least 96% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration is at least 97% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration is 98% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration is at least 99% of the total amount of docetaxel in the aqueous solution before filtration. In some embodiments, after filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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 a clear aqueous solution at a temperature of about 1 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ for at least 3 hours. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ for at least 6 hours. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ for at least 24 hours. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ 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.

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

Further, provided herein is a pharmaceutical composition comprising a composition described herein comprising a non-covalently bound complex comprising docetaxel and human serum albumin, and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition further comprises at least one anti-cancer drug (e.g., any of the anti-cancer drugs described herein).

As used herein, the term "pharmaceutically acceptable carrier" refers to any solution used to solubilize and deliver an agent to a subject. A suitable pharmaceutically acceptable carrier is 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, 20 th edition, a.gennaro, 2003, Lippincon Williams & Wilkins.

Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present application include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (except for 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, colloidal silica, magnesium trisilicate and cellulose-based substances.

In some embodiments, the pharmaceutical composition is free of surfactant, e.g.A surfactant and polysorbate 80.

In some embodiments, the pharmaceutical composition is substantially free of surfactant, e.g.A surfactant and polysorbate 80.

In some embodiments, the pharmaceutical composition is free of a surfactant selected from the group consisting ofSurfactant and polysorbate 80.

Further, provided herein is a method of treating a proliferative disease comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.

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, cattle, sheep, horses, or primates, most preferably humans.

As used herein, the term "proliferative disease" refers to a disease caused by excessive cell proliferation and cellular matrix metabolism. 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).

Further, provided herein is a method of treating cancer, the method comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition described herein comprising a non-covalently bound complex comprising docetaxel and human serum albumin and a pharmaceutically acceptable carrier.

In some embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, urinary system cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, and testicular cancer.

In some embodiments, the cancer is selected from sarcoma, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, non-small cell lung cancer (NSCLC), bronchial carcinoma squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal cancer, esophageal cancer, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, gastric cancer, cancer (carcinoma), lymphoma, leiomyosarcoma, pancreatic cancer, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid-id tumor, vasoactive intestinal peptide tumor, small intestinal cancer, adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, large or colon cancer, myxoma, rhabdomyoma, and non-malignant tumor, Tubular adenoma, villous adenoma, hamartoma, leiomyoma, genitourinary system carcinoma, renal adenocarcinoma, wilm's tumor (nephroblastoma), lymphoma, leukemia, bladder cancer, urinary tract cancer, squamous cell carcinoma, transitional cell carcinoma, prostate cancer, testicular cancer, seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma, liver cancer, hepatohepatocellular carcinoma, cholangioblastoma, hemangiosarcoma, hepatocellular adenoma, hemangioma, bone cancer, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondroma extrachondrogenesis), benign chondrosarcoma, and multiple myeloma, Chondrocytoma, chondroma fibroma, osteoid giant cell tumor, nervous system cancer, cranial cancer, osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, meningitis cerebroma, meningioma, glioma disease, brain cancer, astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal cord cancer, neurofibroma, meningioma, glioma, sarcoma, gynecological cancer, uterine cancer, endometrial cancer, cervical precancerous lesion of the cervix, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, undifferentiated carcinoma, granulocytic tumor cell tumor, Sertoli Leydig cell tumor, dysgerminoma, malignant teratoma, vulval cancer, malignant teratoma, neuroblastoma, hemangioma, glioblastoma, xanthoma, teratoma, neuroblastoma, ependymoma, neuroblastoma, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, vaginal carcinoma, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tube carcinoma, hematological cancer, Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), Acute Lymphocytic Leukemia (ALL), chronic lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, hodgkin lymphoma, non-hodgkin lymphoma (malignant lymphoma), waldenstrom's macroglobulinemia, skin cancer, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, cutaneous fibroma, keloid tumor, psoriasis, adrenal cancer, and neuroblastoma.

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. Such an outcome may be a reduction, alleviation, delay, reduction in resolution of an expected or observed side effect, toxicity, disorder, or adverse condition, alleviation of a sign or symptom or medically beneficial effect on the underlying pathophysiology or pathogenesis, or any other desired alteration of a biological system. In cancer treatment, outcomes typically include reduction, remission, limitation, and/or delay in deleterious physiological manifestations, tumor growth or metastasis.

In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from the group consisting of 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 a 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.

In some embodiments, a method of treating cancer (e.g., any of the cancers described herein) comprises the steps of: administering to a subject in need thereof a therapeutically effective amount of a composition described herein comprising a non-covalently bound complex comprising docetaxel and human serum albumin, and a therapeutically effective amount of at least one inhibitor of the following kinases for treating cancer: PIM, Akt1, Akt2, Akt3, TGF- β R, PKA, PKG, PKC, CaM kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGF α R, PDGF β R, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, FLT-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Ftk, Btk, Fagrk, SYK, ABK, ABF-JAK, and ABL.

In some embodiments, a method of treating cancer (e.g., any of the cancers described herein) comprises the steps of: administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition described herein and a therapeutically effective amount of at least one anti-cancer drug, the composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin. Examples of anticancer drugs include abiraterone, abiraterone acetate, abarelix, aldesleukin, alemtuzumab, alitame, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bavacizumab, bevacizumab, bexarotene, bleomycin, bortezomib, intravenous busulfan, oral busulfan, carpestosterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, dinil interleukin, dinil-toxin linker, dexrazoxane, docetaxel, doxorubicin, tasandrone propionate, eculain, enzalutamide, arazzein, altretamine, alemtuzumab, adalimumab, bab, bazedoary, bazedo, Epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, temozolomide, demethoxydaunorubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditol ditosylate, lenalidomide, letrozole, leucovorin, leuprorelin acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nanapalone, nelarabine, nonisotol, oxaliplatin, paclitaxel, pamirubine, disodium pamidronate, panitumumab, etoposide, valnemadelomustine, gefitinib, valbutin, doxepirubicin, flutamarine, fludar, Pemetrexed, pegylated filgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, labyrine, rituximab, ruxolitinib, sorafenib, streptozotocin, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoid, uramustine, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronic acid.

In some embodiments, a composition described herein comprising a non-covalently bound complex comprising docetaxel and human serum albumin and an anti-cancer drug are administered simultaneously.

In some embodiments, a composition comprising a non-covalently bound complex comprising docetaxel and human serum albumin and an anti-cancer drug as described herein are administered sequentially.

The compositions comprising a non-covalently bound complex comprising docetaxel and human serum albumin described herein can be administered to an individual (e.g., human) by various routes, such as parenterally, including intravenously, intraarterially, intraperitoneally, intrapulmonary, orally, inhalatively, intravesicularly, intramuscularly, intratracheally, subcutaneously, intraocularly, intrathecally, or transdermally. For example, the compositions may be administered by inhalation to treat respiratory diseases. The composition can be used for treating respiratory diseases such as pulmonary fibrosis, obliterative bronchitis, lung cancer, bronchoalveolar carcinoma, etc. In some embodiments, the nanoparticle composition is administered intravenously.

The methods described herein can be performed alone or in combination with another therapy, such as surgery, radiation therapy, chemotherapy, immunotherapy, gene therapy, and the like. In addition, persons at greater risk of developing a proliferative disease may be treated to inhibit or and/or delay disease progression.

As will be appreciated by those of ordinary skill in the art, a suitable dose of docetaxel will approximate the dose of docetaxel when administered alone or in combination with other chemotherapeutic agents that has been used in clinical therapy. Depending on the condition being treated, variations in dosage may occur. As recognized by those skilled in the art, the appropriate effective dosage will also vary depending upon the severity of the disease, the route of administration, the sex, age and general health of the subject, excipient usage, the possibility of co-use with other therapeutic methods, e.g., the use of other drugs, and the judgment of the treating physician. For example, guidance for selection of an effective dose can be determined with reference to prescription information for docetaxel.

Further, provided herein is a composition comprising docetaxel and human serum albumin, wherein the docetaxel and human serum albumin in the composition have a molar ratio of about 0.1:1 to about 5:1, wherein the composition forms a clear aqueous solution when the composition is dissolved in the aqueous solution, and wherein the solubility of the composition in the aqueous solution is at least 10 mg/ml.

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

In some embodiments, the solubility of the composition in aqueous solution is about 10mg/ml, about 20mg/ml, about 30mg/ml, about 40mg/ml, about 50mg/ml, 60mg/ml, about 70mg/ml, about 80mg/ml, about 90mg/ml, about 100mg/ml, about 150mg/ml, or about 200 mg/ml. As used herein, the term "aqueous solution" refers to a solution in which at least one solvent is water, and the weight percentage of water in the solvent mixture is at least 50%, at least 60%, at least 70%, or at least 90%. In some embodiments, the aqueous solution is a solution with water as the only solvent. 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.

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 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.

In some embodiments, the human serum albumin is native 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. In some embodiments, the human serum albumin contains no more than 2 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 1 mole of fatty acids bound to 1 mole of human serum albumin.

In some embodiments, the human serum albumin contains no more than 0.5 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.1 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.05 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.01 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.001 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.0005 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.0001 moles of fatty acids bound to 1 mole of human serum albumin.

In some embodiments, the docetaxel may be a pharmaceutically acceptable salt of docetaxel. In some embodiments, the docetaxel may be docetaxel having 3 equivalents of water solvate. In some embodiments, docetaxel can be in any of the crystalline forms, amorphous forms, solvates, and hydrates as described herein.

In some embodiments, the composition forms a clear aqueous solution for at least 6 hours when the composition is dissolved in the aqueous solution. In some embodiments, the composition forms a clear aqueous solution for at least 24 hours when the composition is dissolved in the aqueous solution. In some embodiments, the composition forms a clear aqueous solution for at least 3 days when the composition is dissolved in the 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.

In some embodiments, the composition is a solid formulation. For example, solid formulations can be produced in a uniform manner by freeze-drying. Those skilled in the art will recognize that other methods may also produce solid formulations, such as rotary evaporation.

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. In some embodiments, the aqueous formulation comprises water and a water-miscible organic solvent comprising at least one of polyethylene glycol 300, polyethylene glycol 400, ethanol, methanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide. For example, the water-miscible organic solvent may include ethanol. In some embodiments, the aqueous formulation comprises water and ethanol. In some embodiments, the water-miscible organic solvent may be a mixture of water-miscible organic solvents.

In some embodiments, the aqueous formulation may be surfactant free, e.g.A surfactant and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of surfactants, e.g.A surfactant and polysorbate 80.

In some embodiments, the aqueous formulation may be substantially free of surfactants selected from the group consisting ofSurfactant and polysorbate 80.

In some embodiments, the aqueous formulation is a clear aqueous solution. For example, the formulation may 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.

In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ for at least 3 hours. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ for at least 6 hours. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ for at least 24 hours. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ 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.

Further, provided herein is a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition is free of surfactant, e.g.A surfactant and polysorbate 80.

In some embodiments, the pharmaceutical composition is substantially free of surfactant, e.g.A surfactant and polysorbate 80.

Further, provided herein is a method of treating a proliferative disease comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition described herein comprising docetaxel and human serum albumin and a pharmaceutically acceptable carrier.

Further, provided herein is a method of treating cancer, the method comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition described herein comprising docetaxel and human serum albumin and a pharmaceutically acceptable carrier.

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

In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from the group consisting of 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 a 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.

In some embodiments, a method of treating cancer (e.g., any of the cancers described herein) comprises the steps 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 described herein for the treatment of cancer.

In some embodiments, a method of treating cancer (e.g., any of the cancers described herein) comprises the steps 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 as described herein.

In some embodiments, a composition comprising docetaxel and human serum albumin described herein and an anti-cancer drug are administered simultaneously.

In some embodiments, a composition comprising docetaxel and human serum albumin described herein and an anti-cancer drug are administered sequentially. The compositions described herein, which comprise docetaxel and human serum albumin, can be administered to an individual (e.g., human) by a variety of routes, such as parenterally, including intravenously, intraarterially, intraperitoneally, intrapulmonary, orally, inhaled, intravesicularly, intramuscularly, intratracheally, subcutaneously, intraocularly, intrathecally, or transdermally. For example, the compositions may be administered by inhalation to treat respiratory diseases. The composition can be used for treating respiratory diseases such as pulmonary fibrosis, obliterative bronchitis, lung cancer, bronchoalveolar carcinoma, etc. In some embodiments, the nanoparticle composition is administered intravenously.

The methods described herein can be performed alone or in combination with another therapy, such as surgery, radiation therapy, chemotherapy, immunotherapy, gene therapy, and the like. In addition, persons at greater risk of developing a proliferative disease may be treated to inhibit or otherwise and/or delay disease progression.

As will be appreciated by those of ordinary skill in the art, a suitable dose of docetaxel will approximate the dose of docetaxel when administered alone or in combination with other chemotherapeutic agents that has been used in clinical therapy. Depending on the condition being treated, variations in dosage may occur. As recognized by those skilled in the art, effective dosages suitable will also vary depending upon the severity of the disease, the route of administration, the sex, age and general health of the subject, excipient usage, the possibility of co-use with other therapeutic methods, e.g., the use of other drugs, and the judgment of the treating physician. For example, guidance for selection of an effective dose can be determined with reference to prescription information for docetaxel.

Further, 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 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 human serum albumin in the composition is from 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.

In some embodiments, the human serum albumin is native 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. In some embodiments, the human serum albumin contains no more than 2 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 1 mole of fatty acids bound to 1 mole of human serum albumin.

In some embodiments, the human serum albumin contains no more than 0.5 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.1 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.05 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.01 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.001 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.0005 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.0001 moles of fatty acids bound to 1 mole of human serum albumin.

In some embodiments, the docetaxel may be a pharmaceutically acceptable salt of docetaxel. In some embodiments, the docetaxel may be docetaxel having 3 equivalents of water solvate. In some embodiments, docetaxel can be in any of the crystalline forms, amorphous forms, solvates, and hydrates as described herein.

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, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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 filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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 filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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 filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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.

In some embodiments, the composition is an aqueous solution, wherein after filtering the aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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 filtering the aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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 filtering the aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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, 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 is free of solvents other than water.

In some embodiments, the composition is a solid formulation. For example, solid formulations can be produced in a homogeneous manner by freeze-drying. One skilled in the art will recognize other methods of producing solid formulations, such as rotary evaporation, are also possible.

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. In some embodiments, the aqueous formulation comprises water and a water-miscible organic solvent comprising at least one of polyethylene glycol 300, polyethylene glycol 400, ethanol, methanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide. For example, the water-miscible organic solvent may include ethanol. In some embodiments, the aqueous formulation comprises water and ethanol. In some embodiments, the water-miscible organic solvent may be a mixture of water-miscible organic solvents.

In some embodiments, the aqueous formulation may be surfactant free, e.g.A surfactant and polysorbate 80. In some embodiments, the aqueous formulation may be substantially free of surfactants, e.g.A surfactant and polysorbate 80.

In some embodiments, the aqueous formulation may be substantially free of surfactants selected from the group consisting ofSurfactant and polysorbate 80.

In some embodiments, the aqueous formulation is a clear aqueous solution. For example, the formulation may 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.

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 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ 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 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ 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 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ for at least 24 hours. In some embodiments, the aqueous formulation is a clear aqueous solution for at least 3 days. In some embodiments, the aqueous formulation is a clear aqueous solution at a temperature of about 1 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ 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.

Further, provided herein is a pharmaceutical composition comprising a composition comprising docetaxel and human serum albumin as described herein and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition is free of surfactant, e.g.A surfactant and polysorbate 80.

In some embodiments, the pharmaceutical composition is substantially free of surfactant, e.g.A surfactant and polysorbate 80. Further, provided herein is a method of treating a proliferative disease comprising the steps of: administering to a subject in need thereof a pharmaceutical composition comprising a composition described herein comprising docetaxel and human serum albumin and a pharmaceutically acceptable carrier.

Further, provided herein is a method of treating cancer (e.g., any one of the cancers described herein), the method comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a composition described herein comprising docetaxel and human serum albumin and a pharmaceutically acceptable carrier.

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

In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from the group consisting of 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 a 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.

In some embodiments, a method of treating cancer (e.g., any of the cancers described herein) comprises the steps 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 described herein for the treatment of cancer.

In some embodiments, a method of treating cancer (e.g., any of the cancers described herein) comprises the steps 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 as described herein.

In some embodiments, a composition comprising docetaxel and human serum albumin described herein and an anti-cancer drug are administered simultaneously.

In some embodiments, a composition comprising docetaxel and human serum albumin described herein and an anti-cancer drug are administered sequentially. The compositions described herein, which comprise docetaxel and human serum albumin, can be administered to an individual (e.g., human) by a variety of routes, such as parenterally, including intravenously, intraarterially, intraperitoneally, intrapulmonary, orally, inhaled, intravesicularly, intramuscularly, intratracheally, subcutaneously, intraocularly, intrathecally, or transdermally. For example, the compositions may be administered by inhalation to treat respiratory diseases. The composition can be used for treating respiratory diseases such as pulmonary fibrosis, obliterative bronchitis, lung cancer, bronchoalveolar carcinoma, etc. In some embodiments, the composition is administered intravenously.

The methods described herein can be performed alone or in combination with another therapy, such as surgery, radiation therapy, chemotherapy, immunotherapy, gene therapy, and the like. In addition, persons at greater risk of developing a proliferative disease may receive treatment that inhibits or and/or delays the progression of the disease.

As will be appreciated by those of ordinary skill in the art, a suitable dose of docetaxel will approximate the dose of docetaxel when administered alone or in combination with other chemotherapeutic agents that have been used in clinical therapy. Depending on the condition being treated, variations in dosage may occur. As recognized by those skilled in the art, the appropriate effective dosage will also vary depending upon the severity of the disease, the route of administration, the age, sex, and general health of the subject, excipient usage, the possibility of co-use with other therapeutic methods, e.g., the use of other drugs, and the judgment of the treating physician. For example, guidance for selection of an effective dose can be determined with reference to prescription information for docetaxel.

Further, provided herein are compositions 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 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 human serum albumin in the composition is from 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.

In some embodiments, the human serum albumin is native 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. In some embodiments, the human serum albumin contains no more than 2 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 1 mole of fatty acids bound to 1 mole of human serum albumin.

In some embodiments, the human serum albumin contains no more than 0.5 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.1 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.05 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.01 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.001 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.0005 moles of fatty acids bound to 1 mole of human serum albumin. In some embodiments, the human serum albumin contains no more than 0.0001 moles of fatty acids bound to 1 mole of human serum albumin.

In some embodiments, the docetaxel may be a pharmaceutically acceptable salt of docetaxel. In some embodiments, the docetaxel may be docetaxel having 3 equivalents of water solvate. In some embodiments, docetaxel can be in any of the crystalline forms, amorphous forms, solvates, and hydrates as described herein.

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, when the composition is dissolved in an aqueous solution, the composition is a clear aqueous solution, wherein after filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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 filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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 filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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 filtering the clear aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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.

In some embodiments, the composition is an aqueous solution, wherein after filtering the aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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 filtering the aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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 filtering the aqueous solution through a 0.22 micron filter, the amount of docetaxel in the aqueous solution after filtration 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, 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 is free of solvents other than water.

In some embodiments, the composition is a solid formulation. For example, solid formulations can be produced in a uniform manner by freeze-drying. One skilled in the art will recognize that other methods, such as rotary evaporation, may also produce solid formulations.

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. In some embodiments, the aqueous formulation comprises water and a water-miscible organic solvent comprising at least one of polyethylene glycol 300, polyethylene glycol 400, ethanol, methanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide. For example, the water-miscible organic solvent may include ethanol. In some embodiments, the aqueous formulation comprises water and ethanol. In some embodiments, the water-miscible organic solvent may be a mixture of water-miscible organic solvents.

In some embodiments, the aqueous formulation may be surfactant free, e.g.A surfactant and polysorbate 80.In some embodiments, the aqueous formulation may be substantially free of surfactants, e.g.A surfactant and polysorbate 80.

In some embodiments, the aqueous formulation may be substantially free of surfactants selected from the group consisting ofSurfactant and polysorbate 80.

In some embodiments, the aqueous formulation is a clear aqueous solution. For example, the formulation may 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.

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 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ 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 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ 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 dissolved in an aqueous solution, the aqueous formulation is a clear aqueous solution at a temperature of about 1 ℃ to about 35 ℃, about 1 ℃ to about 10 ℃, about 10 ℃ to about 20 ℃, about 20 ℃ to about 35 ℃, or about 1 ℃, about 5 ℃, about 10 ℃, about 15 ℃, about 20 ℃, about 25 ℃, about 30 ℃, or about 35 ℃ 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.

Further, provided herein is a pharmaceutical composition comprising a composition as described herein consisting essentially of docetaxel and human serum albumin, and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition is free of surfactant, e.g.A surfactant and polysorbate 80.

In some embodiments, the pharmaceutical composition is substantially free of surfactant, e.g.A surfactant and polysorbate 80.

Further, provided herein is a method of treating a proliferative disease comprising the steps of: administering to a subject in need thereof a pharmaceutical composition comprising a composition described herein consisting essentially of docetaxel and human serum albumin and a pharmaceutically acceptable carrier.

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

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

In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from the group consisting of 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 a 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.

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

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

In some embodiments, a composition described herein consisting essentially of docetaxel and human serum albumin and an anti-cancer drug are administered simultaneously.

In some embodiments, the compositions described herein consisting essentially of docetaxel and human serum albumin and the anti-cancer drug are administered sequentially.

The compositions described herein consisting essentially of docetaxel and human serum albumin can be administered to an individual (e.g., human) by a variety of routes, such as parenterally, including intravenously, intraarterially, intraperitoneally, intrapulmonary, orally, inhaled, intravesicularly, intramuscularly, intratracheally, subcutaneously, intraocularly, intrathecally, or transdermally. For example, the compositions may be administered by inhalation to treat respiratory diseases. The composition can be used for treating respiratory diseases such as pulmonary fibrosis, obliterative bronchitis, lung cancer, bronchoalveolar carcinoma, etc. In some embodiments, the composition is administered intravenously.

The methods described herein can be performed alone or in combination with another therapy, such as surgery, radiation therapy, chemotherapy, immunotherapy, gene therapy, and the like. In addition, persons at greater risk of developing a proliferative disease may be treated to inhibit or and/or delay disease progression.

As will be appreciated by those of ordinary skill in the art, a suitable dose of docetaxel will approximate the amount of docetaxel when administered alone or in combination with other chemotherapeutic agents that has been used in clinical therapy. Depending on the condition being treated, variations in dosage may occur. As recognized by those skilled in the art, the appropriate effective dosage will also vary depending upon the severity of the disease, the route of administration, the age, sex and general health of the subject, the use of excipients, the possibility of co-use with other therapeutic methods, e.g., the use of other drugs, and the judgment of the treating physician. For example, guidance for selection of an effective dose can be determined with reference to prescription information for docetaxel.

Further, provided herein is a composition comprising a non-covalently bound complex consisting essentially of docetaxel and human serum albumin, wherein the docetaxel and human serum albumin in the composition have a molar ratio of about 0.1:1 to about 2: 1.

Further, provided herein is a composition comprising a non-covalently bound complex consisting essentially of 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 2: 1.

Further, provided herein is a composition consisting essentially of docetaxel and human serum albumin in a molar ratio of about 0.1:1 to about 2:1, wherein the composition is a clear aqueous solution when the composition is dissolved in the aqueous solution, wherein the solubility of the composition in the aqueous solution is at least 10 mg/ml.

Further, provided herein is a composition consisting essentially of 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 2:1, wherein the composition forms a clear aqueous solution when the composition is dissolved in an aqueous solution, the solubility of the composition in the aqueous solution being at least 10 mg/ml.

Preparation method

Furthermore, provided herein are several methods of preparing compositions as described herein, which are compositions comprising a non-covalently bound complex (the non-covalently bound complex comprising docetaxel and human serum albumin), compositions comprising docetaxel and human serum albumin, or compositions consisting essentially of docetaxel and human serum albumin.

In some embodiments, the present invention provides methods of making 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.

In some embodiments, the present invention 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.

In some embodiments, the present invention 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 the composition forms a clear aqueous solution when dissolved in the aqueous solution, and wherein the solubility of the composition in the aqueous solution is at least 10 mg/ml.

In some embodiments, the present invention provides a method of 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.

In some embodiments, the present invention 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.

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

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

Non-limiting preferred methods are as follows.

Formation of organic solution

In some embodiments, docetaxel is dissolved in a polar organic solvent (e.g., an alcohol such as methanol, ethanol, isopropanol, and/or n-butanol; THF, CH₃CN; DMF or mixtures thereof) to form an organic solution.

As used herein, the term "organic solution" refers to a mixture wherein at least one solvent is a non-aqueous solvent and the weight% of 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.

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.

The polar organic solvent is miscible with 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.

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

Formation of the first aqueous solution

In some embodiments, a quantity of human serum albumin is dissolved in a quantity of water to form a first aqueous solution.

In some embodiments, the amount of aqueous solvent to prepare the first aqueous solution is about 1mL to about 1000L, about 2mL to about 100L, about 3mL to about 10L, about 4mL to about 1L, about 5mL to about 200mL, about 6mL to about 100mL, about 10mL to about 90mL, about 4mL to about 20mL, or about 10mL to about 20 mL. In some embodiments, the amount of water used to prepare the first aqueous solution is about 4mL, about 4.5mL, about 5mL, about 6mL, about 10mL, about 16mL, about 17mL, about 90mL, or about 100 mL.

In some embodiments, the amount of HSA that is prepared for the first aqueous solution is from about 100mg to about 500kg, from about 150mg to about 100kg, from about 200mg to about 10kg, from about 300mg to about 500g, from about 200mg to about 100g, or from about 200mg to about 10 g. In some embodiments, the amount of HSA that is prepared for the first aqueous solution is about 100mg, about 200mg, about 300mg, about 600mg, about 700mg, about 800mg, about 850mg, about 900mg, about 4500mg, or about 5000 mg.

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

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 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.

In some embodiments, the preparation of the organic solution and the preparation of the first aqueous solution are performed simultaneously.

In some embodiments, the preparation of the organic solution and the preparation of the first aqueous solution are performed sequentially. In some embodiments, the preparation of the organic solution is performed prior to the preparation of the first aqueous solution. In some embodiments, the preparation of the first aqueous solution is performed prior to the preparation of the organic solution.

Formation of the second aqueous solution

In some embodiments, an organic solution of docetaxel is mixed with a 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.

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.

In some embodiments, an organic solution is added to the first aqueous solution to form a second aqueous solution. In some embodiments, the organic solution is added dropwise to the first aqueous solution to form a second aqueous solution. In some embodiments, the first aqueous solution is added to the organic solution to form a second aqueous solution. In some embodiments, the mixing is performed by vibration. In some embodiments, the mixing is performed with stirring. In some embodiments, the mixing is performed under shaking.

In some embodiments, the addition is performed at a temperature of about 0 ℃ to about 35 ℃. In some embodiments, the addition is performed at a temperature of about 0 ℃ to about 25 ℃. In some embodiments, the addition is performed at a temperature of about 0 ℃ to about 10 ℃. In some embodiments, the addition is performed at a temperature of about 0 ℃ to about 5 ℃. In some embodiments, the addition is performed at a temperature of about 0 ℃. In some embodiments, the addition is performed at a temperature of about 5 ℃. In some embodiments, the addition is performed at a temperature of about 10 ℃.

In some embodiments, the addition time is in the range of about 0.1 minutes to about 24 hours. In some embodiments, the addition time is in the range of about 1 minute to about 2 hours. In some embodiments, the addition time is in the range of about 1 minute to about 1 hour. In some embodiments, the addition time is in the range of about 5 minutes to about 30 minutes.

Removal of organic solvents

In some embodiments, the polar organic solvent is removed from the second aqueous solution after completion of mixing the organic solution with the first aqueous solution to form the second aqueous solution.

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.

In some embodiments, removal of the polar organic solvent produces a clear aqueous solution. In some embodiments, the 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, the water is removed from the aqueous solution by lyophilization.

In some embodiments, the solvent comprising water and organic solvent is simultaneously removed from the second aqueous solution to provide the 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 prior to removing the solvent.

Removing water from the second aqueous solution

In some embodiments, when the organic solvent is removed from the second aqueous solution, the water may be removed from the second aqueous solution to provide a solid.

In some embodiments, the second aqueous solution is filtered prior to removing the water. For example, the second aqueous solution may be filtered with a 0.22 micron filter prior to removal of the water.

As used herein, the term "micrometer" refers to a unit of measurement of one thousandth of a millimeter.

In some embodiments, the water is removed under vacuum. In some embodiments, water is removed using rotary evaporation. In some embodiments, the water is removed by lyophilization.

Reconstitution of solids

In some embodiments, a solid comprising docetaxel and human serum albumin is mixed with an aqueous solution. In some embodiments, the aqueous solution is a saline solution. In some embodiments, the aqueous solution is a 5% aqueous glucose solution. In some embodiments, the mixing is adding an aqueous solution to the solid. In some embodiments, the mixing is adding a solid to the aqueous solution. In some embodiments, the mixing reconstitutes the solid. In some embodiments, the mixing produces a clear aqueous solution.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present invention 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 not intended to be limiting. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Compositions prepared by the process

In some embodiments, the present invention 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, prepared by a process comprising the steps of:

(i) obtaining an organic solution of docetaxel dissolved in a polar water-miscible organic solvent;

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

(iii) mixing an organic solution of docetaxel with a first aqueous solution of human serum albumin to obtain a second aqueous solution comprising a composition comprising docetaxel and human serum albumin.

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 2:1, about 0.5:1 to about 2:1, about 0.75:1 to about 1.5:1, about 0.8:1 to about 1.4:1, 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, 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.

In some embodiments, the present invention 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, prepared by a process comprising the steps of:

(i) obtaining an organic solution of docetaxel dissolved in a polar water-miscible organic solvent;

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

(iii) mixing an organic solution of docetaxel with a first aqueous solution of human serum albumin to obtain a second aqueous solution comprising a composition comprising docetaxel and human serum albumin.

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.

In some embodiments, the docetaxel may be a pharmaceutically acceptable salt of docetaxel. In some embodiments, the docetaxel may be docetaxel having 3 equivalents of water solvate. In some embodiments, docetaxel can be in any of the crystalline forms, amorphous forms, solvates, and hydrates as described herein.

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

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

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

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

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

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

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

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

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

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

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

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

In some embodiments, the polar water-miscible organic solvent is selected from the group consisting of methanol, ethanol, and mixtures thereof.

In some embodiments, the polar water-miscible organic solvent is methanol.

In some embodiments, the aqueous solvent is water.

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, the addition is performed in a dropwise manner. In some embodiments, the addition is performed over a period of several minutes to several hours. In some embodiments, the addition is performed over a period of 2 minutes to 24 hours. In some embodiments, the addition is performed over a period of 2 minutes to 12 hours, 2 minutes to 6 hours, 3 minutes to 3 hours, 2 minutes to 1 hour, 2 minutes to 30 minutes, or 2 minutes to 25 minutes.

In some embodiments, the mixing is performed at a temperature of about 0 ℃ to about 25 ℃. In some embodiments, mixing is performed at ambient temperature (e.g., about 25 ℃). In some embodiments, the mixing is performed at a temperature of about 0 ℃ to about 5 ℃. In some embodiments, the mixing is performed at about 0 ℃.

In some embodiments, the volume ratio of the amount of aqueous solvent to the amount of organic solvent in the second aqueous solution is in the range of about 1:1 to about 1000: 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 in the range of about 1.5:1 to about 100: 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 in the range of about 1.5:1 to about 20: 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 in the range of about 1.5:1 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 in the range of about 2:1 to about 10: 1. In some embodiments, the amount of water is in a volumetric ratio, e.g., relative to the amount of organic solvent in the second aqueous solution, of 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.

In some embodiments, the composition further comprises removing the polar water-miscible 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 comprises removing the aqueous solvent from the third aqueous solution to obtain a composition comprising docetaxel and human serum albumin.

In some embodiments, the composition further comprises removing the organic solvent (e.g., methanol) and the aqueous solvent (e.g., water) from the second aqueous solution to obtain a composition comprising docetaxel and human serum albumin.

In some embodiments, the removal is performed in vacuum (e.g., using a rotary evaporator). In some embodiments, the removing is performed by lyophilization.

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

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 surfactant. In some embodiments, the surfactant is selected from the group consisting ofSurfactant 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.

In some embodiments, the present invention provides a pharmaceutical composition comprising a composition prepared by the methods described herein and a pharmaceutically acceptable carrier.

In some embodiments, the present invention provides a method of treating cancer, the method comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein.

In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from the group consisting of breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer, ovarian cancer, pancreatic cancer, and kaposi's sarcoma.

Examples

Materials and methods

HPLC analysis: the HPLC system used herein is a SHIMADZU LC-10AT vp series system consisting of a SHIMADZU LC-10AT vp pump, a manual injector, a SHIMADZU CTO-10AS vp column incubator, a SHIMADZU SPD-10A wavelength detector, and a SHIMADZU LC solution workstation. A Waters XTERRA RP10 column (4.6 mm. times.150 mm, 5 μm) was used as analytical HPLC column. The column oven temperature was 30 ℃. The mobile phase consisted of methanol and water (70:30, v/v) and was pumped at a flow rate of 1 ml/min. The effluent was detected using a UV detector at a wavelength of 233 nm. The sample injection amount was 20. mu.l.

Example 1: a composition comprising docetaxel and Human Serum Albumin (HSA).

The molar ratio of docetaxel to HSA prepared was about 1: 1.

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

A sample of 50mg of the lyophilized solid was reconstituted by adding 1mL of water to give a clear solution. The clear aqueous solution remained clear after 24 hours without any solid precipitation.

A sample of 50mg of the lyophilized solid was reconstituted by adding 1mL of 2% aqueous ethanol (2% ethanol in water) to give a clear solution. After 24 hours, the 2% aqueous ethanol solution remained clear without any solid precipitation.

Example 2: compositions comprising docetaxel and Human Serum Albumin (HSA)

The molar ratio of docetaxel to HSA prepared was about 1.3: 1.

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

A sample of 50mg of the lyophilized solid was reconstituted by adding 1mL of water to give a clear solution. The clear aqueous solution remained clear after 24 hours at room temperature without any solid precipitate.

Example 3: compositions comprising docetaxel and Human Serum Albumin (HSA)

The molar ratio of docetaxel to HSA prepared was about 1.5: 1.

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

A sample of 50mg of the lyophilized solid was reconstituted by adding 1mL of water to give a slightly turbid solution.

Example 4: compositions comprising docetaxel and Human Serum Albumin (HSA)

The molar ratio of docetaxel to HSA prepared was about 1.2: 1.

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

A sample of 50mg of the lyophilized solid was reconstituted by adding 1mL of water to give a clear solution. After 6 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 24 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 3 days at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation.

A sample of 70mg of the lyophilized solid was reconstituted by adding 1mL of water to give a clear solution. After 6 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 24 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 3 days at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation.

A sample of 50mg of the lyophilized solid was reconstituted by adding 1mL of water to give a clear solution. After 6 hours at 4 ℃, the clear aqueous solution remained clear with no docetaxel precipitation. After 24 hours at 4 ℃, the clear aqueous solution remained clear with no docetaxel precipitation. After 3 days at 4 ℃, the clear aqueous solution remained clear with no docetaxel precipitation.

A sample of approximately 50mg of the lyophilized solid was reconstituted by the addition of 1mL of saline to give a clear solution. After 6 hours at room temperature, the clear saline solution remained clear with no docetaxel precipitation. After 24 hours at room temperature, the clear saline solution remained clear with no docetaxel precipitation. After 3 days at room temperature, the clear saline solution remained clean with no docetaxel precipitation.

Example 5: compositions comprising docetaxel and Human Serum Albumin (HSA)

The molar ratio of docetaxel to HSA prepared was about 1.2: 1.

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

A sample of 50mg of the lyophilized solid was reconstituted by adding 1mL of water to give a clear solution. After 6 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 24 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 3 days at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation.

Example 6: compositions comprising docetaxel and Human Serum Albumin (HSA)

The molar ratio of docetaxel to HSA prepared was about 0.5: 1.

Docetaxel (2mg) was dissolved in methanol (1ml) in a glass vial to give a clear solution. Powdered HSA (329mg) (natural fatty acid free human serum albumin from SeraCare Life Sciences, commercial code: HS-455-80, which contains fatty acids <0.2mg/gm) was dissolved in 6ml of water in a round bottom flask. A methanol solution of docetaxel was slowly added dropwise to a flask of HSA solution with rapid stirring. The addition takes about 2-3 minutes to complete. After the addition was complete, a clear solution was obtained. The methanol was removed under vacuum until the volume of the solution was about 5ml, yielding a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid. A sample of 50mg of the lyophilized solid was reconstituted by adding 1mL of water to give a clear solution. After 6 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 24 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 3 days at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation.

Example 7: composition comprising docetaxel and human serum albumin (recombinant human serum albumin)

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

Docetaxel (10mg) was dissolved in methanol (7ml) in a glass vial to give a clear solution. Powdered recombinant human serum albumin (823mg) (fatty acid free recombinant human serum albumin (tested free of fatty acids), purchased from Wuhan healthcare Biotechnology corp., www.oryzogen.com) was dissolved in 16ml of water in a round bottom flask. A solution of docetaxel in methanol was slowly dropped into a flask of recombinant human serum albumin solution with rapid stirring. After the addition was complete, a clear solution was obtained. The methanol was removed under vacuum until the volume of the solution was about 14ml, resulting in a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid.

A sample of 50mg of the lyophilized solid was reconstituted by adding 1mL of water to give a clear solution. After 6 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 24 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 3 days at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation.

Example 8: compositions comprising docetaxel and Human Serum Albumin (HSA)

The weight ratio of docetaxel to HSA prepared was about 1: 85.

Docetaxel (10mg) was dissolved in methanol (7ml) in a glass vial to give a clear solution. Powdered HSA (850mg) (natural fatty acid free human serum albumin from SeraCare Life Sciences, product number: HS-455-80, which contains fatty acids <0.2mg/gm) was dissolved as a powder in 17ml water in a round bottom flask. With rapid stirring at 0 ℃, a methanol solution of docetaxel was slowly added dropwise to a flask of HSA solution. After the addition was complete, a clear solution was obtained. The methanol in the solution was then removed in vacuo to give a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid.

A sample of 100mg of the lyophilized solid was reconstituted by the addition of 2mL of water to give a clear solution. After 6 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 24 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation.

Example 9: compositions comprising docetaxel and Human Serum Albumin (HSA)

The weight ratio of docetaxel to HSA prepared was about 1: 90.

Docetaxel (50mg) was dissolved in methanol (30ml) in a glass vial to give a clear solution. Powdered HSA (4500mg) (natural fatty acid free human serum albumin from SeraCare Life Sciences, product code: HS-455-80 with fatty acids <0.2mg/gm) was dissolved in 90ml water in a round bottom flask. With rapid stirring at 0 ℃, a methanol solution of docetaxel was slowly added dropwise to a flask of HSA solution. After the addition was complete, a clear solution was obtained. To this solution was added 8.5ml of methanol. The methanol in the solution was then removed in vacuo to give a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid.

A sample of 100mg of the lyophilized solid was reconstituted by the addition of 2mL of water to give a clear solution. After 6 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 24 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation.

Example 10: compositions comprising docetaxel and Human Serum Albumin (HSA)

The weight ratio of docetaxel to HSA prepared was about 1: 100.

Docetaxel (50mg) was dissolved in methanol (30ml) in a glass vial to give a clear solution. Powdered HSA (5000mg) (natural fatty acid free human serum albumin from SeraCare Life Sciences, commercial code: HS-455-80, which contains fatty acids <0.2mg/gm) was dissolved in 100ml of water in a round bottom flask. With rapid stirring at 0 ℃, a methanol solution of docetaxel was slowly added dropwise to a flask of HSA solution. After the addition was complete, a clear solution was obtained. To the solution was added 13ml of methanol. The methanol in the solution was then removed in vacuo to give a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid.

A sample of 100mg of the lyophilized solid was reconstituted by the addition of 2mL of water to give a clear solution. After 6 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 24 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation.

Example 11: compositions comprising docetaxel and Human Serum Albumin (HSA)

The weight ratio of docetaxel to HSA prepared was about 1: 100.

Docetaxel (5mg) was dissolved in methanol (4.3ml) in a glass vial to give a clear solution. Powdered HSA (500mg) (native fatty acid-free human serum albumin, CAT #: HA1020, available from Golden West Biologicals, Inc) was dissolved in 10ml of water in a round bottom flask. With rapid stirring at 0 ℃, a methanol solution of docetaxel was slowly added dropwise to a flask of HSA solution. After the addition was complete, a clear solution was obtained. The methanol in the solution was then removed in vacuo to give a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid.

A sample of 100mg of the lyophilized solid was reconstituted by the addition of 2mL of water to give a clear solution. After 3 hours at room temperature, the clear aqueous solution remained clear with no docetaxel. After 6 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation. After 24 hours at room temperature, the clear aqueous solution remained clear with no docetaxel precipitation.

Example 12: compositions comprising docetaxel and Human Serum Albumin (HSA)

The weight ratio of docetaxel to HSA prepared was about 1: 200.

Docetaxel (1mg) was dissolved in methanol (1.7ml) in a glass vial to give a clear solution. Powdered HSA (200mg) (native human serum albumin, CAT #: HA1000, available from Golden West Biologicals, Inc.) was dissolved in 4ml water in a round bottom flask. With rapid stirring at 0 ℃, a methanol solution of docetaxel was slowly added dropwise to a flask of HSA solution. After the addition was complete, a clear solution was obtained. The methanol in the solution was then removed in vacuo to give a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid.

A sample of 100mg of the lyophilized solid was reconstituted by adding 2mL of water to give a clear solution without docetaxel precipitation.

Example 13: compositions comprising docetaxel and Human Serum Albumin (HSA)

The weight ratio of docetaxel to HSA prepared was about 1: 150.

Docetaxel (1mg) was dissolved in methanol (1ml) in a glass vial to give a clear solution. Powdered HSA (150mg) (native human serum albumin, CAT #: HA1000, available from Golden West Biologicals, Inc.) was dissolved in 3ml water in a round bottom flask. With rapid stirring at 0 ℃, a methanol solution of docetaxel was slowly added dropwise to a flask of HSA solution. After the addition was complete, a clear solution was obtained. The methanol in the solution was then removed in vacuo to give a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid.

A sample of 100mg of the lyophilized solid was reconstituted by adding 2mL of water to give a clear solution without docetaxel precipitation.

Example 14: compositions comprising docetaxel and Human Serum Albumin (HSA)

The weight ratio of docetaxel to HSA prepared was about 1: 150.

Docetaxel (2mg) was dissolved in methanol (2.5ml) in a glass vial to give a clear solution. A solution of HSA (300mg, 1.5ml) (20% human serum albumin solution for infusion from CSL Behring (trade name: Alburx)) was added to 4.5ml of water in a round-bottomed flask to give a HSA solution (6 ml). With rapid stirring at 0 ℃, a methanol solution of docetaxel was slowly added dropwise to a flask of HSA solution. After the addition was complete, a clear solution was obtained. The methanol in the solution was then removed in vacuo to give a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid.

A sample of 100mg of the lyophilized solid was reconstituted by the addition of 2mL of water to give a clear solution.

Example 15: compositions comprising docetaxel and Human Serum Albumin (HSA)

The weight ratio of docetaxel to HSA prepared was about 1: 160.

Docetaxel (2mg) was dissolved in methanol (2.7ml) in a glass vial to give a clear solution. A solution of HSA (320mg, 1.6ml) (20% human serum albumin solution for infusion from CSL Behring (product name: Alburx)) was added to 4.8ml of water in a round-bottomed flask to give a HSA solution (6.4 ml). With rapid stirring at 0 ℃, a methanol solution of docetaxel was slowly added dropwise to a flask of HSA solution. After the addition was complete, a clear solution was obtained. The methanol in the solution was then removed in vacuo to give a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid.

A sample of 100mg of the lyophilized solid was reconstituted by the addition of 2mL of water to give a clear solution.

Example 16: compositions comprising docetaxel and Human Serum Albumin (HSA)

The weight ratio of docetaxel to HSA prepared was about 1: 170.

Docetaxel (2mg) was dissolved in methanol (2.9ml) in a glass vial to give a clear solution. A solution of HSA (340mg, 1.7ml) (20% human serum albumin solution for infusion from CSL Behring (product name: Alburx)) was added to 5.1ml of water in a round-bottomed flask to give a HSA solution (6.8 ml). With rapid stirring at 0 ℃, a methanol solution of docetaxel was slowly added dropwise to a flask of HSA solution. After the addition was complete, a clear solution was obtained. The methanol in the solution was then removed in vacuo to give a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid

A sample of 100mg of the lyophilized solid was reconstituted by the addition of 2mL of water to give a clear solution.

Example 17: compositions comprising docetaxel and Human Serum Albumin (HSA)

The weight ratio of docetaxel to HSA prepared was about 1: 180.

Docetaxel (2mg) was dissolved in methanol (3.1ml) in a glass vial to give a clear solution. A solution of HSA (360mg, 1.8ml) (20% human serum albumin solution for infusion from CSL Behring (product name: Alburx)) was added to 5.4ml of water in a round bottom flask to give a HSA solution (7.2 ml). With rapid stirring at 0 ℃, a methanol solution of docetaxel was slowly added dropwise to a flask of HSA solution. After the addition was complete, a clear solution was obtained. The methanol in the solution was then removed in vacuo to give a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid.

A sample of 100mg of the lyophilized solid was reconstituted by the addition of 2mL of water to give a clear solution.

Example 18: compositions comprising docetaxel and Human Serum Albumin (HSA)

The weight ratio of docetaxel to HSA prepared was about 1: 200.

Docetaxel (2mg) was dissolved in methanol (3.4ml) in a glass vial to give a clear solution. A solution of HSA (400mg, 2ml) (20% human serum albumin solution for infusion from CSL Behring (product name: Alburx)) was added to 6ml of water in a round-bottomed flask to give a HSA solution (8 ml). With rapid stirring at 0 ℃, a methanol solution of docetaxel was slowly added dropwise to a flask of HSA solution. After the addition was complete, a clear solution was obtained. The methanol in the solution was then removed in vacuo to give a clear solution. The clear aqueous solution was filtered through a 0.22 micron aqueous filter. The resulting clear aqueous solution was lyophilized overnight to give a white solid.

A sample of 100mg of the lyophilized solid was reconstituted by the addition of 2mL of water to give a clear solution.

Example 19: the correlation between HPLC peak area and docetaxel concentration was measured.

Methanol solutions of 7 different concentrations of docetaxel were prepared at concentrations of 0.025mg/ml, 0.05mg/ml, 0.075mg/ml, 0.1mg/ml, 0.15mg/ml, 0.2mg/ml and 0.25 mg/ml. 7 docetaxel methanol solutions were analyzed in HPLC. The peak area of docetaxel was correlated to concentration using linear regression. The linear regression data are shown below.

Y (peak area) 61390+2.571E 7X (concentration), R0.9999, P < 0.0001.

Example 20: the concentration of docetaxel in the clear aqueous solution was measured before and 0 hour after the filtration, and 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 hours and 72 hours after the filtration.

2.5g of the lyophilized solid of the composition comprising docetaxel and HSA from example 10 (weight ratio about 1:100) were dissolved in 50ml of water to give a clear aqueous solution maintained at about 20 ℃. Immediately after dissolving the lyophilized solid in water, 6ml of clear aqueous solution was taken from 50ml of solution. Then 1ml of the solution was taken out of 6ml of the clear aqueous solution to obtain a solution DC-0-0h, and the remaining 5ml of the solution was filtered with the same 0.22 μm aqueous phase filter for 1ml each time to obtain solutions DC-1-0h, DC-2-0h, DC-3-0h, DC-4-0h and DC-5-0 h. To 200. mu.l of the solution DC-0-0h and DC-5-0h was added 800. mu.l of acetonitrile, respectively. The mixture was vortexed for several seconds and then centrifuged at 4,000g for 5 minutes. The supernatant was removed and collected, then injected into HPLC. The same procedure was repeated 2 times for each solution DC-0-0h and DC-5-0 h. Based on the HPLC data and the measurement data of example 19, the docetaxel concentrations of the DC-0 to 0h and DC-5 to 0h solutions were calculated and shown in Table 1. At 0 hours, the docetaxel concentration of the filtered clear aqueous solution was about 100.4% of the docetaxel concentration of the filtered clear aqueous solution.

TABLE 1

5ml of clear aqueous solution was taken from the remaining 44ml of aqueous solution over 2 hours. Then 1ml of the solution was taken from 5ml of the clear aqueous solution and filtered through a 0.22 micron aqueous phase filter to give a solution DC-1-2h, and the remaining 4ml of the solution was filtered through the same 0.22 micron aqueous phase for 1ml each time to give solutions DC-2-2h, DC-3-2h, DC-4-2h and DC-5-2 h. To 200. mu.l of the DC-5-2h solution was added 800. mu.l of acetonitrile. 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 onto HPLC. The same procedure was repeated 2 times for solution DC-5-2 h. The docetaxel concentrations of the solutions DC-5-2h have been calculated according to the HPLC data and assay data of example 19 and are shown in table 2. At 2 hours, the docetaxel concentration of the filtered clear aqueous solution was about 100% of the docetaxel concentration of the clear aqueous solution at 0 hour before filtration.

TABLE 2

5ml of clear aqueous solution was taken from the remaining 39ml of aqueous solution over 4 hours. The experiment was performed on 5ml of clear aqueous solution taken out at 4 hours, using the same protocol as for 5ml of clear aqueous solution taken out at 2 hours. The docetaxel concentrations of the solutions DC-5-4h have been calculated according to the HPLC data and assay data of example 19 and are shown in table 3. At 4 hours, the docetaxel concentration of the filtered clear aqueous solution was about 99.96% of the docetaxel concentration of the clear aqueous solution at 0 hour before filtration.

TABLE 3

5ml of clear aqueous solution were taken from the remaining 34ml of aqueous solution over 6 hours. The experiment was carried out on 5ml of clear aqueous solution taken out over 6 hours, using the same protocol as for 5ml of clear aqueous solution taken out over 2 hours. The docetaxel concentrations of the solutions DC-5-6h have been calculated according to the HPLC data and assay data of example 19 and are shown in table 4. At 6 hours, the docetaxel concentration of the filtered clear aqueous solution was about 99.84% of the docetaxel concentration of the clear aqueous solution at 0 hour before filtration.

TABLE 4

5ml of clear aqueous solution was taken from the remaining 29ml of aqueous solution over 8 hours. The experiment was performed on 5ml of clear aqueous solution taken out at 8 hours, using the same protocol as for 5ml of clear aqueous solution taken out at 2 hours. Based on the HPLC data and assay data of example 19, the docetaxel concentrations for solutions DC-5-8h have been calculated and are shown in table 5. At 8 hours, the docetaxel concentration of the filtered clear aqueous solution was about 99.27% of the docetaxel concentration of the clear aqueous solution at 0 hours before filtration.

TABLE 5

At 24 hours, 5ml of clear aqueous solution was taken from the remaining 24ml of aqueous solution. The experiment was performed on 5ml of clear aqueous solution taken out at 24 hours, using the same protocol as for 5ml of clear aqueous solution taken out at 2 hours. Based on the HPLC data and assay data of example 19, the docetaxel concentrations of the solutions DC-5-24h have been calculated and are shown in table 6. At 24 hours, the docetaxel concentration of the filtered clear aqueous solution was about 96.05% of the docetaxel concentration of the clear aqueous solution at 0 hours before filtration.

TABLE 6

At 48 hours, 5ml of clear aqueous solution was removed from the remaining 19ml of aqueous solution. The experiment was performed on 5ml of clear aqueous solution taken out at 24 hours, using the same protocol as for 5ml of clear aqueous solution taken out at 2 hours. Based on the HPLC data and assay data of example 19, docetaxel concentrations for solutions DC-5-48h have been calculated and are shown in table 7. At 48 hours, the docetaxel concentration of the filtered clear aqueous solution was about 89.10% of the docetaxel concentration of the clear aqueous solution at 0 hours before filtration.

TABLE 7

5ml of clear aqueous solution was taken from the remaining 14ml of aqueous solution at 72 hours. The experiment was performed on 5ml of clear aqueous solution taken out at 24 hours, using the same protocol as for 5ml of clear aqueous solution taken out at 2 hours. The docetaxel concentrations of the solutions DC-5 to 72h have been calculated according to the HPLC data and assay data of example 19 and are shown in table 8. At 72 hours, the docetaxel concentration of the filtered clear aqueous solution was about 75.57% of the docetaxel concentration of the clear aqueous solution at 0 hours before filtration.

TABLE 8

Example 21: pharmacokinetic studies of compositions comprising docetaxel and Human Serum Albumin (HSA).

One group of 3 pieces("SD") male rats were used for pharmacokinetic studies. The route of administration studied was intravenous. The dose for the PK study of the composition comprising docetaxel and HSA (weight ratio of docetaxel to HSA in the composition 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 hours post-dose. All blood samples were collected from the carotid cannula. Blood samples were transferred to EDTA-K2 anticoagulated blood vessels and immediately placed on ice. Blood samples will be centrifuged at 3000g at about 4 ℃ for half an hour of collection for plasma treatment. Plasma samples will be stored in polypropylene tubes, snap frozen on dry ice, and maintained at-70 ± 10 ℃ until LC/MS analysis.

LC-MS/MS method was used for docetaxel in plasma of male SD rats. Table 9 shows PK parameters for the PK study. Figure 1 shows mean plasma concentration-time data for docetaxel in SD rats after intravenous injection of 680mg/kg of a composition comprising docetaxel and HSA.

TABLE 9

CL(mL/min/kg)	Vdss(L/kg)	T1/2(hr)	AUC0-Final(ng.h/mL)
				140	112	15.8	600

Other embodiments

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, benefits and modifications are within the scope of the following claims.