TECHNICAL FIELD

This document relates to complexes and compositions for the treatment of proliferative diseases.

BACKGROUND

Many drugs for parenteral use are insoluble in water, and are thus formulated with solubilizing agents, surfactants, solvents, and/or emulsifiers that are irritating, allergenic, or toxic when administered to patients. See, e.g., Briggs et al.,Anesthesis37, 1099 (1982), and Waugh et al.,Am. J. Hosp. Pharmacists,48, 1520 (1991)). Further, many of these drugs, especially those administered intravenously, cause undesirable side effects such as venous irritation, phlebitis, burning and pain on injection, venous thrombosis, extravasation, and other administration related side effects. Additionally, often free drugs present in formulations induce pain or irritation upon administration.

Taxanes play an important role in the treatment of various solid tumors. Cabazitaxel (trade name Jevtana®) is a semi-synthetic taxane derivative. It was developed by Sanofi-Aventis and was approved by the U.S. FDA for the treatment of hormone-refractory prostate cancer on Jun. 17, 2010. Cabazitaxel in combination with prednisone is a treatment option for hormone-refractory prostate cancer following cabazitaxel-based treatment. JEVTANA is supplied as a kit consisting of (a) a JEVTANA injection, which contains 60 mg cabazitaxel in 1.5 mL polysorbate 80; and (b) a diluent, containing approximately 5.7 mL 13% (W/W) ethanol. Prior to administration, the JEVTANA injection must first be mixed with the diluent, which dilutes the amount of Cabazitaxel to 10 mg/mL, and then further diluted with either 0.9% sodium chloride solution or 5% dextrose solution for infusion. See JEVTANA Prescribing Information.

Other taxane compounds include cabazitaxel, which is marketed as Taxotere® and is FDA-approved for breast cancer, non-small cell lung cancer, hormone refractory prostate cancer, gastric adenocarcinoma, and squamous cell carcinoma of head and neck cancer. The clinical intravenous administration of commercially available cabazitaxel (Taxotere®) is formulated in a highly concentrated solution containing 40 mg cabazitaxel and 1040 mg Polysorbate 80 per mL. See TAXOTERE Prescribing Information.

The presence of polysorbate 80 in JEVTANA, as well as TAXOTERE, can result in serious side effects. It has been reported that cabazitaxel administration is associated with the occurrence of unpredictable (acute) hypersensitivity reactions and cumulative fluid retention. See, e.g., Trudeau M E et al.,J Clin Oncol1996; 14:422-8, Piccart M J et al.,J Natl Cancer Inst1995; 87:676-81, Bruno R et al.,J Clin Oncol1998; 16:187-96. These side-effects have been attributed, in part, to the presence of polysorbate 80.

In order to reduce the side effects induced by polysorbate 80, patients may be treated with dexamethasone prior to each dose of JEVTANA. Dexamethasone is a steroid that suppresses the immune response in patients, which can be especially detrimental in cancer patients under chemotherapy, whose immunity may already be compromised due to the destruction of healthy cells by the chemotherapeutic treatment. As a result, these patients can be susceptible to bacterial and fungal infections. Further, despite receiving the dexamethasone pre-medication, patients can report hypersensitivity side effects from the taxane compound treatment. Due to these side effects, patients may stop taxane compound therapy, skip a dose, or continue further therapy at a reduced dose.

Therefore, new formulations of cabazitaxel or other taxane compounds are needed to avoid these side effects, pre-medication requirements, and patient noncompliance issues associated with the currently marketed formulation.

SUMMARY

Provided herein are non-covalently bound complexes comprising cabazitaxel and human serum albumin, e.g., non-covalently bound complexes prepared by a process of contacting (e.g., mixing, e.g., in a solution such as an aqueous solution) cabazitaxel and human serum albumin, wherein the cabazitaxel and the human serum albumin used to prepare the non-covalently bound complexes are in a ratio by weight from about 1:10 to about 1:3000.

In some embodiments, the human serum albumin is a native human serum albumin. In some embodiments, the human serum albumin is a recombinant human serum albumin. In some embodiments, the human serum albumin is a fatty acid free human serum albumin. In some embodiments, the human serum albumin is essentially fatty acid free.

Also, provided herein is a composition comprising non-covalently bound complexes comprising cabazitaxel and human serum albumin, wherein the cabazitaxel and the human serum albumin in the composition have a ratio by weight from about 1:10 to about 1:3000. In some embodiments, the pH of the composition is neutral (e.g., pH of the composition is from about 5 to about 8, from about 5.5 to about 7.5, or from about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8). In some embodiments, the human serum albumin is essentially fatty acid free.

In some embodiments, the composition is a solid formulation. For example, the solid formulation can be produced in a uniform manner by lyophilization. A skilled artisan would recognize other methods, such as rotary evaporation, that can also produce solid formulations.

In some embodiments, the composition is an aqueous formulation. In some embodiments, the aqueous formulation is substantially free of solvent other than water. In some embodiments, the aqueous formulation is free of solvent other than water. In some embodiments, the aqueous formulation includes water and water-miscible organic solvents including at least one of polyethylene glycol 300, polyethylene glycol 400, ethanol, methanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide. For example, the water-miscible organic solvent can include ethanol. In some embodiments, the aqueous formulation includes water and ethanol. In some embodiments, the water-miscible organic solvent can be a mixture of water-miscible organic solvents.

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

Also, provided herein is a pharmaceutical composition comprising the non-covalently bound complexes or the composition comprising the non-covalently bound complexes of the cabazitaxel and the human serum albumin as described herein, and a pharmaceutically acceptable carrier.

Also, provided herein is a method of treating a cancer, the method comprising the step of administering to a subject in need thereof of a therapeutically effective amount of a pharmaceutical composition comprising non-covalently bound complexes or the composition comprising the cabazitaxel and the 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 a prostate cancer.

In some embodiments, the method of treating a prostate cancer comprises the step of administering to a subject in need thereof of a therapeutically effective amount of a pharmaceutical composition comprising non-covalently bound complexes or the composition comprising the cabazitaxel and the human serum albumin as described herein, prednisone, and a pharmaceutically acceptable carrier.

Also, provided herein is a composition comprising cabazitaxel and human serum albumin, wherein the cabazitaxel and the human serum albumin in the composition have a ratio by weight from about 1:10 to about 1:3000, wherein the composition is a clear aqueous solution when the composition is dissolved in an aqueous solvent, and wherein the composition has a solubility in an aqueous solution of at least 10 mg/mL. In some embodiments, the pH of the composition is neutral (e.g., pH of the composition is from about 5 to about 8, from about 5.5 to about 7.5, or from about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

In some embodiments, the human serum albumin is a native human serum albumin. In some embodiments, the human serum albumin is a recombinant human serum albumin. In some embodiments, the human serum albumin is a fatty acid free human serum albumin. In some embodiments, the human serum albumin is essentially fatty acid free.

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

In some embodiments, the composition is a solid formulation. For example, the solid formulation can be produced in a uniform manner by lyophilization. A skilled artisan would recognize other methods, such as rotary evaporation, that can also produce solid formulations.

In some embodiments, the composition is an aqueous formulation. In some embodiments, the aqueous formulation is substantially free of solvent other than water. In some embodiments, the aqueous formulation is free of solvent other than water.

In some embodiments, the aqueous formulation can be free of a surfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In some embodiments, the aqueous formulation can be substantially free of a surfactant, such as CREMOPHOR® surfactants and Polysorbate 80.

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

Also, provided herein is a pharmaceutical composition comprising the composition comprising the cabazitaxel and the human serum albumin as described herein, and a pharmaceutically acceptable carrier.

Also, provided herein is a method of treating a cancer, the method comprising the step of administering to a subject in need thereof of a therapeutically effective amount of a pharmaceutical composition comprising the composition comprising the cabazitaxel and the 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 a prostate cancer.

In some embodiments, the method of treating a prostate cancer comprises the step of administering to a subject in need thereof of a therapeutically effective amount of a pharmaceutical composition comprising the composition comprising the cabazitaxel and the human serum albumin as described herein, prednisone, and a pharmaceutically acceptable carrier.

Also, provided herein is a composition consisting essentially of cabazitaxel and human serum albumin, wherein the cabazitaxel and the human serum albumin in the composition have a ratio by weight from about 1:10 to about 1:3000. In some embodiments, the pH of the composition is neutral (e.g., pH of the composition is from about 5 to about 8, from about 5.5 to about 7.5, or from about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

In some embodiments, the human serum albumin is a native human serum albumin. In some embodiments, the human serum albumin is a recombinant human serum albumin. In some embodiments, the human serum albumin is a fatty acid free human serum albumin. In some embodiments, the human serum albumin is essentially fatty acid free.

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

In some embodiments, the composition is a clear aqueous solution for at least 6 hours when the composition is dissolved in an aqueous solvent. In some embodiments, the composition is a clear aqueous solution for at least 24 hours when the composition is dissolved in an aqueous solvent. In some embodiments, the composition is a clear aqueous solution for at least 3 days when the composition is dissolved in an aqueous solvent. In some embodiments, the aqueous solution is substantially free of solvent 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 solvent other than water. In some embodiments, the aqueous formulation is free of a surfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In some embodiments, the aqueous formulation is a clear aqueous solution.

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

Also, provided herein is a method of treating cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the composition consisting essentially of the cabazitaxel and the 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 a prostate cancer.

In some embodiments, the method of treating a prostate cancer comprises the step of administering to a subject in need thereof of a therapeutically effective amount of a pharmaceutical composition comprising the composition consisting essentially of the cabazitaxel and the human serum albumin as described herein, prednisone, and a pharmaceutically acceptable carrier.

Also, provided herein is a composition comprising cabazitaxel and human serum albumin, wherein the cabazitaxel and the human serum albumin in the composition have a ratio by weight from about 1:100 to about 1:3000. In some embodiments, the pH of the composition is neutral (e.g., pH of the composition is from about 5 to about 8, from about 5.5 to about 7.5, or from about 6 to about 7, or the pH of the composition is about 5, about 5.5, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 8).

In some embodiments, the human serum albumin is a native human serum albumin. In some embodiments, the human serum albumin is a recombinant human serum albumin. In some embodiments, the human serum albumin is essentially fatty acid free.

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

In some embodiments, the composition is a clear aqueous solution for at least 3 hours when the composition is dissolved in an aqueous solvent. In some embodiments, the composition is a clear aqueous solution for at least 6 hours when the composition is dissolved in an aqueous solvent. In some embodiments, the composition is a clear aqueous solution for at least 24 hours when the composition is dissolved in an aqueous solvent. In some embodiments, the composition is a clear aqueous solution for at least 3 days when the composition is dissolved in an aqueous solvent. In some embodiments, the aqueous solution is substantially free of solvent 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 solvent other than water. In some embodiments, the aqueous formulation is free of a surfactant, such as CREMOPHOR® surfactants and Polysorbate 80. In some embodiments, the aqueous formulation is a clear aqueous solution.

Also, provided herein is a pharmaceutical composition comprising the composition comprising the cabazitaxel and the human serum albumin as described herein, and a pharmaceutically acceptable carrier.

Also, provided herein is a method of treating cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the composition comprising the cabazitaxel and the 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 a prostate cancer.

In some embodiments, the method of treating a prostate cancer comprises the step of administering to a subject in need thereof of a therapeutically effective amount of a pharmaceutical composition comprising the composition comprising the cabazitaxel and the human serum albumin as described herein, prednisone, and a pharmaceutically acceptable carrier.

Also, provided herein is a composition consisting essentially of human serum albumin and non-covalently bound complexes of cabazitaxel and human serum albumin, wherein the cabazitaxel and the human serum albumin in the composition have a ratio by weight from about 1:10 to about 1:3000.

Also, provided herein is a composition comprising non-covalently bound complexes consisting essentially of cabazitaxel and human serum albumin, wherein the cabazitaxel and the human serum albumin in the composition have a ratio by weight from about 1:10 to about 1:3000.

