Docetaxel Compositions and Methods

Abstract

The present application provides a pharmaceutical composition comprising docetaxel and human serum albumin, which has the advantage of being free of any polysorbate 80 surfactant and is present in a concentration of 75 mg / m 2 The composition can be used to infuse a patient with docetaxel at a dose of 0.01 to 0.05 wt. The composition can be used to treat cancer, such as breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer or head and neck cancer.

Description

[Technical field]

[0001] The present invention relates to docetaxel formulations for use in the treatment of cancer. In particular, the present invention relates to formulations containing docetaxel and human serum albumin ("HSA") for use in the treatment of patients with breast cancer, non-small cell lung cancer, prostate cancer (e.g., castration-resistant prostate cancer), gastric cancer (e.g., adenocarcinoma), or head and neck cancer (e.g., head and neck squamous cell carcinoma). [Background technology]

[0002] Many parenteral drugs are water insoluble and therefore, when administered to a patient, are formulated with irritating, allergenic, or toxic solubilizers, surfactants, solvents, and / or emulsifiers. See, e.g., Briggs et al., Anesthesis 37, 1099 (1982) and Waugh et al., Am. J. Hosp. Pharmacists, 48, 1520 (1991). Many of these drugs, especially those administered intravenously, also cause adverse side effects, such as venous irritation, phlebitis, burning or pain upon injection, venous thrombosis, extravasation, and other administration-related side effects. Taxanes play an important role in the treatment of various solid tumors. As a second-generation semisynthetic taxane derivative, docetaxel is approximately twice as active as paclitaxel in inhibiting microtubule depolymerization, and unlike most of the spindle poisons currently in clinical use, it has the unique ability to modify a specific class of microtubules. However, docetaxel has very poor water solubility. The commercially available docetaxel 2-vial formulation (Taxotere (登録商標)Clinical intravenous administration of docetaxel is prepared as a high-concentration solution containing 40 mg docetaxel and 1040 mg polysorbate 80 per mL. The high-concentration solution must be carefully diluted with a solvent containing 13% ethanol in saline before administration. Clinical use of docetaxel has been reported to be associated with the occurrence of unpredictable (acute) hypersensitivity reactions and cumulative fluid retention. See, for example, Trudeau ME et al., J Clin Oncol 1996, 14:422-8, Piccart MJ et al., J Natl Cancer Inst 1995, 87:676-81, Bruno R et al., J Clin Oncol 1998, 16:187-96. These side effects are due in part to the presence of polysorbate 80. Polysorbate 80 is a synthetic non-ionic surfactant used as a stabilizer in pharmaceutical formulations. In patients not receiving a prodrug, the reported hypersensitivity reaction rate for docetaxel (Taxotere) with polysorbate 80 is estimated to be 30%. When a prodrug is used, the reported hypersensitivity reaction rate for docetaxel (Taxotere) with polysorbate 80 ranges from 8% to 13%. See Taxotere prescribing information. Fatalities due to allergic reactions to docetaxel containing polysorbate 80 have been reported to still occur after prophylactic therapy has been administered. This increases the importance of developing a docetaxel formulation that does not contain polysorbate 80. Currently, no docetaxel product containing polysorbate 80 has been clinically approved in major pharmaceutical markets (e.g., the United States, the European Union, China, and Japan). There is a dire need to develop a new docetaxel product containing no polysorbate 80 and with better safety in clinical applications. The formulations and methods described in this invention help to meet this need. Summary of the Invention

[0003] Taxotere currently on the market (登録商標)The formulations include 1-vial or 2-vial formulations (including injection and diluent). The 1-vial formulation is a solution containing docetaxel in polysorbate 80 and ethanol. The 2-vial formulation contains one solution having docetaxel in polysorbate 80 and one vial of solvent containing an aqueous solution of ethanol therein.

[0004] Although the one-vial and two-vial forms of Taxotere each have advantages and disadvantages, both formulations contain large amounts of polysorbate 80, which can cause severe hypersensitivity reactions in some patients, and Taxotere (登録商標) Advantageously, the formulations of the present invention are prepared without the use of any toxic surfactants, although they are not associated with the most common adverse events of the formulations. (登録商標) Therefore, the drug product is bioequivalent to Taxotere in clinical use. (登録商標) It is permitted to achieve the same or similar therapeutic effect as the Taxotere (登録商標) The formulation avoids the associated adverse events caused by polysorbate surfactants in the formulation. In particular, the formulation contains docetaxel at approximately 75 mg / m for the treatment of multiple types of cancer, such as breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, or head and neck cancer. 2 Otherwise, the claimed formulations contain only readily available and relatively inexpensive ingredients, such as human serum albumin, ethanol, and citric acid, all of which are approved for pharmaceutical use by regulatory agencies, such as the FDA or EMA, respectively.

[0005] A formulation containing docetaxel, human serum albumin, and ethanol is described in WO2021 / 158632. In one general aspect, the present invention provides a pharmaceutical composition for infusion comprising docetaxel and human serum albumin, wherein the composition is prepared by injecting a first liquid composition comprising docetaxel and ethanol into an infusion bag or bottle containing a second aqueous composition comprising human serum albumin in a parenterally acceptable carrier; wherein the composition does not contain polysorbate 80; The composition is used to treat patients diagnosed with solid tumors selected from breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, and head and neck cancer by infusion administration; The dose of docetaxel infused to the patients in need thereof is approximately 75 mg / m 2 and wherein the composition is prepared within 24 hours prior to infusion into said patient. In some embodiments, the composition is prepared within 4 hours prior to infusion into the patient. In some embodiments, the first liquid composition is a sterile solution. In some embodiments, the second aqueous composition is a sterile solution. In some embodiments, the concentration of docetaxel in the composition is from about 0.05 mg / mL to about 0.5 mg / mL. In some embodiments, the concentration of docetaxel in the composition is from about 0.1 mg / mL to about 0.4 mg / mL. In some embodiments, the concentration of docetaxel in the composition is about 0.20 mg / mL. In some embodiments, the concentration of docetaxel in the composition is about 0.25 mg / mL. In some embodiments, the concentration of docetaxel in the composition is about 0.30 mg / mL. In some embodiments, the concentration of human serum albumin in the composition is about 0.01% to about 20% (w / v). In some embodiments, the concentration of human serum albumin in the composition is about 0.1% to about 10% (w / v). In some embodiments, the concentration of human serum albumin in the composition is about 0.2% to about 5% (w / v). In some embodiments, the concentration of human serum albumin in the composition is about 0.5% to about 2.5% (w / v). In some embodiments, the composition is a clear aqueous infusion solution. In some embodiments, the composition is repeatedly administered to the patient for a new cycle once every three weeks. In some embodiments, the composition comprises a docetaxel dose of 75 mg / m 2 It is administered at . In some embodiments, the composition is administered to treat a patient diagnosed with breast cancer. In some embodiments, the composition is administered to treat a patient diagnosed with locally advanced or metastatic breast cancer. In some embodiments, the composition is administered for adjuvant therapy of breast cancer. In some embodiments, the composition is administered to treat a patient diagnosed with non-small cell lung cancer. In some embodiments, the composition is administered to treat a patient diagnosed with locally advanced or metastatic non-small cell lung cancer. In some embodiments, the composition is administered to treat a patient diagnosed with prostate cancer. In some embodiments, the composition is administered to treat a patient diagnosed with metastatic castration-resistant prostate cancer. In some embodiments, the composition is administered to treat a patient diagnosed with gastric cancer. In some embodiments, the compositions are administered to treat patients diagnosed with advanced gastric adenocarcinoma, including patients with gastroesophageal junction tumors. In some embodiments, the composition is administered to treat a patient suffering from head and neck cancer. In some embodiments, the composition is administered for induction treatment of locally advanced head and neck squamous cell carcinoma.

[0006] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. The methods and materials described herein may be used in this application, and any suitable methods and materials known in the art may also be used. The materials, methods, and examples are merely illustrative and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the definitions contained herein shall control.

[0007] Other features and advantages of the present application will become apparent from the following detailed description and drawings, and from the claims. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 is a diagram of the mean total docetaxel concentration versus time curves following administration of BH009 and Winthrop (an approved generic version of Taxotere) (docetaxel) injection to patients with advanced solid tumors. [Diagram 2] FIG. 1 is a diagram of the mean free docetaxel concentration versus time curves following administration of BH009 and Winthrop (an approved generic of Taxotere) (docetaxel) injection to patients with advanced solid tumors. With reference to FIG. 1 and FIG. 2, "R" represents the reference formulation (Winthrop injection) and "T" represents the test formulation (BH009). Detailed Description of the Invention

[0009] In one general aspect, provided herein is a pharmaceutical formulation comprising docetaxel and human serum albumin. The formulation can generally be administered to a subject in need thereof by a parenteral route. The term "parenteral" refers to a route selected from subcutaneous injection ("SC"), intravenous injection ("IV"), intramuscular injection ("IM"), intradermal injection ("ID"), intraperitoneal injection ("IP"), and the like. In one example, the formulation can be administered to a subject via intravenous infusion, e.g., an infusion bag or bottle, as described herein.

[0010] In some embodiments, the formulation comprises docetaxel, human serum albumin, acid, ethanol, and a liquid carrier (e.g., a carrier acceptable for parenteral administration). In some embodiments, the formulation comprises docetaxel, human serum albumin, citric acid, ethanol, and a liquid carrier (e.g., a carrier acceptable for parenteral administration). In some embodiments, the formulation is contained in an infusion bag or bottle. In some embodiments, the formulation is prepared in an infusion bag or bottle.

[0011] In some embodiments, the pH value of the formulation is about 4 to about 9.5. In some embodiments, the pH value of the formulation is about 5 to about 9. In some embodiments, the pH value of the formulation is about 6 to about 8. In some embodiments, the pH value of the formulation is about 6.5 to about 7.5. In some embodiments, the pH value of the formulation is about 4 to about 9. In some embodiments, the pH value of the formulation is about 5 to about 8.5. In some embodiments, the pH value of the formulation is about 6 to about 7.5.

[0012] In some embodiments, the formulation is essentially free of any surfactant. In some embodiments, the formulation is essentially free of polysorbate 80. In some embodiments, the formulation contains about 1 ppm or less or about 1 ppb or less of a surfactant (e.g., polysorbate 80). In some embodiments, the formulation is free of polysorbate 80. In some embodiments, the pharmaceutical formulation is free of lipids (e.g., soybean oil). As used herein, the term "docetaxel" refers to the compound having CAS No. 114977-28-5 and the following chemical structure: JPEG2025506788000002.jpg6890, Or its pharmaceutically acceptable salt. Docetaxel is a white to almost white powder. The compound has high lipophilicity and is practically insoluble in water. Docetaxel is a microtubule inhibitor applied to the treatment of breast cancer, non-small cell lung cancer, hormone refractory prostate cancer, gastric adenocarcinoma, and head and neck squamous cell carcinoma. The term "docetaxel" as used herein includes any pharmaceutically acceptable salt of the free base or free acid of the docetaxel compound (e.g., the chemical structure shown above, or any tautomer thereof). In general, a pharmaceutically acceptable salt is a salt that retains the desired biological activity of a given compound and exhibits minimal adverse toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification process of the compound, or can be prepared separately by reacting the purified compound in free acid or free base form with a suitable base or acid, respectively. Such salts may impart greater stability or solubility to a molecule, thus making preparation of formulations within the presently claimed scope more convenient.Suitable examples of pharma- ceutically acceptable acid addition salts of docetaxel include bile acid addition salts, hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, hydrogen sulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicylate, glycolate, lactate, heptane salt, tetrahydrofuran ... Acid salts, phthalates, oxalates, succinates, benzoates, o-acetoxybenzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, mandelates, tannates, formates, stearates, ascorbates, palmitates, oleates, pyruvates, pamoates, malonates, laurates, glutarates, glutamates, propionates, dodecyl sulfates, methanesulfonates (mesylates) , ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate), p-aminophenylsulfonate, p-toluenesulfonate (tosylate), naphthalene-2-sulfonate, ethanedisulfonate, hydrogen disulfide, hydrogen tartrate, gluconate, glucuronate, p-bromophenylsulfonate, carbonate, pyrosulfate, sulfite, bisulfite, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrrophosphate Acid salts include, for example, acid salts, chloride, bromide, iodide, decanoate, caprylate, decanoate, propionate, sebacate, sebacate, butyne-1,4-dioate, hexyne-1,6-dioate, terephthalate, sulfonate, xylenesulfonate, phenylpropionate, phenylbutyrate, beta-hydroxybutyrate, glycolate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and 2,5-dihydroxybenzoate.Suitable examples of pharma- ceutically 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 aluminium and zinc, ammonia, e.g. unsubstituted or hydroxy-substituted mono-, di- or trialkylamines, organic amines, such as dicyclohexylamine, tributylamine, pyridine, N-methyl, N-ethylamine, diethylamine, triethylamine, mono-, bis- or tris-(2-hydroxy-(C1-C6)-alkyl)amines, e.g. N,N-dimethyl-N-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine, N-methyl-D-glucosamine, morpholine, thiomorpholine, piperidine, pyrrolidine, and amino acids, such as arginine and lysine.

[0013] In some embodiments, docetaxel may include 1, 2, or 3 equivalents of hydrate solvate. In some embodiments, docetaxel is a solvate that includes 3 equivalents of water. In some embodiments, docetaxel is docetaxel trihydrate, docetaxel monohydrate, or docetaxel anhydrate. In some embodiments, docetaxel includes 1 equivalent of acetone solvate. In some embodiments, docetaxel may be any of the docetaxel solvates disclosed in, for example, WO2010091650 or US2012007167, the entire disclosures of which are incorporated herein by reference. In some embodiments, docetaxel is crystalline. In some embodiments, docetaxel is any crystalline form disclosed, for example, in WO2012115402, US8410294, US20100197944, US20100099897, US8357811, US20100160653, or US20070142457, the entire disclosures of which are incorporated herein by reference. In some embodiments, docetaxel is non-crystalline. In some embodiments, docetaxel is any amorphous form disclosed, for example, in WO2008102374, the entire disclosures of which are incorporated herein by reference. In some embodiments, the concentration of docetaxel in the formulation is from about 0.05 mg / mL to about 1 mg / mL, from about 0.1 mg / mL to about 0.8 mg / mL, from about 0.05 mg / mL to about 0.75 mg / mL, from about 0.1 mg / mL to about 0.5 mg / mL, from about 0.1 mg / mL to about 0.35 mg / mL, from about 0.15 mg / mL to about 0.4 mg / mL, from about 0.2 mg / mL to about 0.3 mg / mL, from about 0.2 mg / mL to about 0.4 mg / mL, from about 0.2 mg / mL to about 0.35 mg / mL, from about 0.25 mg / mL to about 0.35 mg / mL, or from about 0.5 mg / mL to about 0.75 mg / mL. In some embodiments, the amount (or concentration) of docetaxel in the formulation is about 0.05 mg / mL, about 0.1 mg / mL, about 0.15 mg / mL, about 0.2 mg / mL, about 0.25 mg / mL, about 0.3 mg / mL, about 0.35 mg / mL, about 0.4 mg / mL, about 0.45 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.74 mg / mL, about 0.75 mg / mL, about 0.8 mg / mL, or about 1 mg / mL. In some embodiments, the formulation contains about 10 mg to about 300 mg, about 20 mg to about 200 mg, about 50 mg to about 250 mg, about 60 mg to about 240 mg, about 100 mg to about 200 mg, about 120 mg to about 200 mg, or about 100 mg to about 175 mg of docetaxel. In some embodiments, the formulation comprises about 20 mg, about 40 mg, about 80 mg, about 120 mg, about 150 mg, about 160 mg, about 175 mg, about 200 mg, or about 250 mg of docetaxel. In some embodiments, the formulation comprises about 50 mg / m2, for example, based on the patient's individual body surface area ("BSA"). 2 ~about 150 mg / m 2 In some embodiments, the formulation contains a dose of docetaxel equivalent to about 50 mg / m2, based on, for example, the patient's individual body surface area ("BSA"). 2 , about 60 mg / m 2 , about 75 mg / m 2 , about 90 mg / m 2, about 100 mg / m 2 , or about 120 mg / m 2 For example, if a patient has a body surface area of ​​2.0 and a dose of docetaxel is approximately 75 mg / m 2 wherein the formulation contains about 150 mg of docetaxel.

[0014] As used herein, the term "human serum albumin" refers to natural and recombinant human serum albumin. In some embodiments, the human serum albumin is natural human serum albumin. In some embodiments, the human serum albumin is recombinant human serum albumin. Native human serum albumin and other plasma proteins can be precipitated from human plasma by changing the pH and adding ethanol, which is called the Cohn fractionation process (Cohn EJ et al., J. Am. Chem. Soc. 1946, 68:459-475). By controlling the pH and ethanol content, semi-purified plasma protein fractions can be produced. In the Cohn process, one of the last proteins precipitated is native human serum albumin. After precipitation, a wet paste of crude native human serum albumin is obtained. Subsequent biological processing steps (purification, filtration, pasteurization, etc.) are used to produce a purified, stable form of native 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 component-free, virus-free, and prion-free product that is a substitute for natural human serum albumin, which is structurally identical to both (Bosse D et al., J. Clin. Pharmacol. 2005, 45:57-67). Recombinant human serum albumin is produced by a variety of prokaryotic and eukaryotic hosts (Chen Z et al., Biochimica et Biophysica Acta 2013, 1830:5515-5525).

[0015] Human serum albumin (HSA) has a relative molecular weight (M r HSA is a highly soluble globular protein with a pH of 65 K and consists of 585 amino acids. HSA is the most abundant protein in plasma, accounting for 70-80% of the colloid osmotic pressure of human plasma. The amino acid sequence of HSA contains a total of 17 disulfide bridges, one free sulfhydryl group (Cys34), and a single tryptophan (Trp214). Intravenous use of HSA solutions has been indicated for the prevention and treatment of hypovolemic shock (see, e.g., Tullis, JAMA, 237, 355-360, 460-463, (1977) and Houser et al., Surgery, Gynecology and Obstetrics, 150, 811-816 (1980)), and in combination with blood exchange therapy for neonatal hyperbilirubinemia (see, e.g., Finlayson, Seminars in Thrombosis and Hemostasis, 6, 85-120, (1980)). The human serum albumin herein may be a human serum albumin solution.Suitable human serum albumin solutions include, but are not limited to, commercially available human serum albumin solutions for infusion.Commercially available serum albumin solutions for infusion include pharma- ceutically acceptable stabilizers, such as sodium N-acetyltryptophan, sodium octanoate, sodium chloride, sodium bicarbonate, sodium hydroxide or acetic acid, or mixtures thereof.In some embodiments, the human serum albumin solution can be prepared by diluting commercially available human serum albumin solutions for infusion with a carrier acceptable for parenteral administration. Alternatively, human serum albumin can be prepared by mixing human serum albumin powder dissolved in water with other pharma- ceutically acceptable stabilizers included in commercially available albumin products. In some embodiments, the human serum albumin is a commercially available human serum albumin solution for infusion. In some embodiments, the human serum albumin solution is a commercially available human serum albumin solution for infusion. In some embodiments, the human serum albumin solution comprises a commercially available human serum albumin solution for infusion. In some embodiments, a commercially available human serum albumin solution for infusion is used as a source of human serum albumin. In some embodiments, the human serum albumin solution for infusion is a 5% human serum albumin solution (w / v). In some embodiments, the human serum albumin solution for infusion is a 20% human serum albumin solution (w / v). In some embodiments, the human serum albumin solution for infusion is a 25% human serum albumin solution (w / v). In some embodiments, the human serum albumin solution for infusion is an aqueous solution prepared by diluting a commercially available human serum albumin for infusion.

[0016] In some embodiments, the concentration of human serum albumin in the formulation is about 0.1% to about 20% (w / v), about 0.05% to about 10% (w / v), about 0.05% to about 5% (w / v), about 0.05% to about 3% (w / v), about 0.02% to about 3% (w / v), about 0.2% to about 10% (w / v), about 0.5% to about 15% (w / v), about 0.5% to about 5% (w / v), about 1% to about 10% (w / v), or about 1% to about 3% (w / v). In some embodiments, the concentration of human serum albumin in the formulation is about 0.05% (w / v), about 0.1% (w / v), about 0.25% (w / v), about 0.5% (w / v), about 1% (w / v), about 2% (w / v), about 3% (w / v), about 5% (w / v), about 10% (w / v), about 15% (w / v), or about 20% (w / v). In some embodiments, the formulation contains about 1 g to about 50 g, about 2 g to about 40 g, about 1 g to about 10 g, about 2 g to about 20 g, about 1 g to about 5 g, or about 5 g to about 10 g of human serum albumin. In some embodiments, the weight ratio of human serum albumin to docetaxel in the formulation is about 20:1 to about 200:1, or about 20:1 to about 100:1. In some embodiments, the weight ratio of human serum albumin to docetaxel is about 20:1, about 30:1, about 40:1, about 50:1, about 75:1, about 90:1, about 95:1, about 100:1, or about 150:1. In some embodiments, the amount of liquid carrier (e.g., a carrier acceptable for parenteral administration) in the formulation is about 10 mL to about 2 L, about 50 mL to about 1 L, about 100 mL to about 1 L, about 250 mL to about 1 L, about 100 mL to about 500 mL, or about 250 mL to about 500 mL. Suitable examples of liquid carriers include water (e.g., sterile water), saline (e.g., a 0.9 wt.% NaCl aqueous solution), or a glucose solution (e.g., a 5 wt.% glucose solution).

[0017] In some embodiments, the formulation is a clear (e.g., transparent) infusion solution and is not a nanoparticle suspension. In some embodiments, the formulation is a clear solution. In some embodiments, the clear infusion solution remains clear and precipitate-free for at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, or at least 8 hours. In some embodiments, when the clear solution is kept at about 15-30° C., the clear infusion solution remains clear and precipitate-free for at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, or at least 6 hours. In some embodiments, when the clear solution is kept at about 18-25° C., the clear infusion solution remains clear and precipitate-free for at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, or at least 6 hours. In some embodiments, the clear solution remains clear and precipitate-free for at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, or at least 24 hours when the clear solution is kept at about 2-8° C. In some embodiments, the clear infusion solution remains clear and precipitate-free for at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, or at least 8 hours when the clear solution is kept at ambient temperature. In some embodiments, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70% of the docetaxel in the formulation (clear infusion solution) is free (unbound) docetaxel. Free (unbound) docetaxel refers to the portion of docetaxel in the infusion composition (solution) that is not bound (e.g., non-covalently bound) to human serum albumin. In one embodiment, the amount of free (unbound) docetaxel in the parenterally administered infusion composition (solution) is measured by 30 KDa membrane ultrafiltration. The parenterally administered infusion composition (solution) has approximately the same characteristics in dynamic light scattering (DLS) as compared to the corresponding human serum albumin salt solution in DLS. In some embodiments, 1 mL of the formulation (e.g., an infusion composition used for parenteral administration) contains no more than 50 particles greater than 10 μm in size, no more than 100 particles greater than 10 μm in size, no more than 150 particles greater than 10 μm in size, or no more than 200 particles greater than 10 μm in size. In some embodiments, 1 mL of the formulation (e.g., an infusion composition used for parenteral administration) contains no more than 5 particles greater than 25 μm in size, no more than 10 particles greater than 25 μm in size, no more than 5 particles greater than 15 μm in size, or no more than 20 particles greater than 25 μm in size. In some embodiments, the formulation includes an organic acid. Examples of organic acids include citric acid, acetic acid, formic acid, aspartic acid, glutamic acid, ascorbic acid, benzoic acid, tartaric acid, lactic acid, maleic acid, and succinic acid, or pharma- ceutically acceptable salts thereof. In some embodiments, the formulation includes citric acid. In some embodiments, the formulation includes about 0.001 mg / mL to about 2 mg / mL citric acid, about 0.005 mg / mL to about 1 mg / mL citric acid, or about 0.01 mg / mL to about 0.5 mg / mL citric acid. Without being bound to any particular theory, it is believed that the addition of an organic acid (e.g., citric acid) to the formulation is used to create or maintain the appropriate pH required for the formulation (e.g., infusion solution). In some embodiments, the pH value of the infusion composition used for parenteral administration is about 4 to about 9.5, about 5 to about 9, about 6 to about 8, about 6.5 to about 7.4, about 4 to about 9, about 5 to about 8.5, or about 6 to about 7.5.

[0018] In some embodiments, the formulation includes an organic solvent or a combination of organic solvents. In some embodiments, the organic solvent is an alcohol. Suitable examples of alcohol include ethanol, propylene glycol, polyethylene glycol 300, and the like. In some embodiments, the organic solvent is ethanol. In some embodiments, the amount of ethanol in an infusion composition used for parenteral administration of docetaxel does not exceed about 10% (v / v), about 5% (v / v), about 2% (v / v), about 1.75% (v / v), about 1.5% (v / v), or about 1.4% (v / v). In some embodiments, the formulation (e.g., an infusion composition used for the parenteral administration) is prepared from a first liquid composition and a second aqueous composition, as further described herein. In some embodiments, the formulation is prepared less than 24 hours, less than 12 hours, less than 8 hours, less than 6 hours, less than 4 hours, or less than 1 hour before infusion to a cancer patient. The first liquid composition is injected into an infusion bag or bottle containing the second aqueous composition, and then the first liquid composition and the second aqueous composition are mixed uniformly to obtain a clear infusion solution without precipitate in a carrier acceptable for parenteral administration, comprising human serum albumin, docetaxel, citric acid, and ethanol. In some embodiments, the present invention provides a method for treating a pulmonary circulation comprising administering to a patient a therapeutically effective amount of about 75 mg / m 2 and human serum albumin, wherein the composition does not include polysorbate 80. In some embodiments, the invention provides a pharmaceutical composition for infusion comprising docetaxel at a dose of about 50 mg to about 200 mg and human serum albumin, wherein the composition does not include polysorbate 80. In some embodiments, the composition is prepared within 24 hours prior to infusion into the patient. In some embodiments, the invention provides a pharmaceutical composition prepared from a first liquid composition and a second aqueous composition, as further described.

[0019] Method for preparing pharmaceutical formulations In some embodiments, the present invention provides a method for preparing a formulation (e.g., a pharmaceutical composition for infusion) comprising docetaxel and human serum albumin, the method comprising mixing two compositions: (a) a first liquid composition comprising docetaxel and ethanol; and (b) a second aqueous composition comprising human serum albumin and a carrier acceptable for parenteral administration. In some embodiments, neither the first liquid composition nor the second aqueous composition comprises polysorbate 80, a surfactant, or a lipid (e.g., soybean oil). In some embodiments, the two compositions are mixed less than about 24 hours, less than about 8 hours, less than about 4 hours, or less than about 1 hour before infusion or administration to a patient. In some embodiments, the mixing of the two compositions is completed in an infusion bag or bottle. For example, when the second aqueous composition is contained in an infusion bag or bottle, the first liquid composition is injected into the infusion bag or bottle containing the second aqueous composition. In some embodiments, the first liquid composition is injected using a syringe into an infusion bag or bottle containing the second aqueous composition. In some embodiments, the first liquid composition comprises docetaxel and ethanol. In some embodiments, the first liquid composition comprises docetaxel, ethanol, and other organic solvents (e.g., propylene glycol, polyethylene glycol 300, etc.). In some embodiments, the first liquid composition further comprises an acid (e.g., citric acid). Preferably, the organic acid is selected from the group consisting of citric acid, acetic acid, formic acid, ascorbic acid, benzoic acid, tartaric acid, lactic acid, maleic acid, succinic acid, or pharma- ceutically acceptable salts thereof. In some embodiments, the first liquid composition is an ethanol solution containing docetaxel. In some embodiments, the weight ratio of docetaxel to citric acid in the first liquid composition is about 5000:1 to about 1:1, about 2000:1 to about 1:1, about 1000:1 to about 1:1, about 500:1 to about 1:1, about 5000:1 to about 5:1, about 2000:1 to about 5:1, about 1000:1 to about 5:1, about 500:1 to about 5:1, about 5000:1 to about 10:1, about 2000:1 to about 10:1, about 1000:1 to about 10:1, about 500:1 to about 10:1, about 2000:1 to about 100:1, about 1000:1 to about 100:1, about 500:1 to about 100:1, or about 500:1 to about 200:1. In some embodiments, the weight ratio of docetaxel to citric acid in the first liquid composition is about 1000:1, about 500:1, about 200:1, or about 100:1. In some embodiments, the concentration of citric acid in the first liquid composition is about 0.005 mg / mL to about 10 mg / mL, about 0.01 mg / mL to about 2 mg / mL, about 0.01 mg / mL to about 1 mg / mL, about 0.02 mg / mL to about 0.5 mg / mL, or about 0.02 mg / mL to about 0.2 mg / mL. In some embodiments, the first liquid composition is prepared by dissolving docetaxel (and / or citric acid) in alcohol (e.g., ethanol and / or propylene glycol).In some embodiments, the concentration of docetaxel in alcohol (e.g., ethanol and / or propylene glycol) is about 1 mg / mL to about 200 mg / mL, about 5 mg / mL to about 100 mg / mL, about 5 mg / mL to about 40 mg / mL, about 10 mg / mL to about 50 mg / mL, about 10 mg / mL to about 20 mg / mL, or about 10 mg / mL to about 30 mg / mL. In some embodiments, the concentration of docetaxel in alcohol (e.g., ethanol and / or propylene glycol) is about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, or about 30 mg / mL. In some embodiments, the amount of docetaxel in the first liquid composition is about 10 mg to about 300 mg, or about 20 mg to about 200 mg. In some embodiments, the amount of docetaxel in the first liquid composition is about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, or about 160 mg. In some embodiments, the amount of ethanol in the first liquid composition is about 0.5 mL to about 50 mL, about 1 mL to about 20 mL, about 1 mL to about 10 mL, or about 3 mL to about 6 mL.

[0020] Generally, the first liquid composition is an injectable composition (e.g., prepared or adjusted for injection into an infusion bag or bottle containing an aqueous composition containing human serum albumin). In some embodiments, the first liquid composition is an injectable pharmaceutical formulation. The concentration of docetaxel in the injectable pharmaceutical composition (pharmaceutical formulation) may be about 5 mg / mL to about 40 mg / mL, or about 10 mg / mL to about 20 mg / mL. In some embodiments, the concentration of docetaxel in the injectable pharmaceutical composition (pharmaceutical formulation) is about 10 mg / mL, about 15 mg / mL, or about 20 mg / mL. In some embodiments, the pH of the injectable pharmaceutical composition (first liquid composition) is about 3 to about 9, about 3 to 8, about 3 to 7, about 3 to 6.5, about 3.5 to 6.5, about 3.5 to 6, about 3.5 to about 5.5, or about 4 to about 5. In one embodiment, to measure the pH value of the injectable pharmaceutical formulation, the injectable pharmaceutical formulation is mixed with saline in a 1:1 ratio (v / v) to obtain an aqueous solution, and then the pH value of the aqueous solution is measured. In some embodiments, the injectable pharmaceutical composition (pharmaceutical formulation) comprising the first liquid composition comprises about 20 mg, about 40 mg, about 80 mg, about 120 mg, or about 160 mg of docetaxel, citric acid, and ethanol, in which the concentration of docetaxel in the injectable pharmaceutical formulation is about 5 mg / mL to about 40 mg / mL (e.g., about 20 mg / mL or about 10 mg / mL), and the pH of the composition is about 3 to about 6.5, or about 3.5 to about 5.5. In some embodiments, the second aqueous composition is prepared by adding a human serum albumin solution to a parenterally acceptable carrier. For example, the second aqueous composition is prepared by adding a suitable amount of human serum albumin solution to an infusion bag or bottle containing an appropriate amount of a parenterally acceptable carrier (e.g., saline solution or glucose solution). In some embodiments, the second aqueous composition is prepared by adding 20%, 25%, or 5% commercially available human serum albumin solution (w / v) for infusion to saline solution or glucose solution. In some embodiments, the concentration of human serum albumin in the second aqueous composition is about 0.1% to about 20% (w / v), about 0.5% to about 10% (w / v), about 0.5% to about 15% (w / v), about 0.5% to about 5% (w / v), about 1% to about 10% (w / v), or about 1% to about 3% (w / v). In some embodiments, the second aqueous composition comprises about 1 g to about 50 g of human serum albumin, about 1 g to about 20 g, about 2 g to about 10 g, or about 2 g to about 20 g of human serum albumin. In some embodiments, the volume of the second aqueous composition is about 100 mL to about 1 L. In some embodiments, the volume of the second aqueous composition is about 250 mL to about 1 L. In some embodiments, the volume of the second aqueous composition is about 250 mL to about 500 mL.

[0021] Generally, the injection of the first liquid composition into the infusion bag or bottle containing the second aqueous composition is rapid. In some embodiments, the injection time is 60 seconds or less, 30 seconds or less, 15 seconds or less, 10 seconds or less, 5 seconds or less, or 3 seconds or less. Generally, the injection process of the first liquid composition into the infusion bag or bottle containing the second aqueous composition does not require any artificial shaking or stirring (e.g., intentional stirring). After the injection of the first liquid composition into the infusion bag or bottle is completed, the first liquid composition and the second aqueous composition are mixed uniformly (e.g., by gently turning the bag containing the composition by hand) to obtain a clear infusion solution without precipitation. In some embodiments, the infusion bag or bottle containing the second aqueous composition remains stationary during the injection process. In some embodiments, the first liquid composition is injected below the liquid surface of the second aqueous composition during the injection process. In some embodiments, after the injection is completed, the infusion bag or bottle is repeatedly gently turned upside down to mix the first liquid composition and the second aqueous composition uniformly. A clear infusion solution without precipitation can be obtained by simply turning the infusion bag or bottle upside down (e.g., about 5 to 30 times). The mixing time may be, for example, about 5 seconds to about 10 minutes, about 5 seconds to about 3 minutes, about 5 seconds to about 2 minutes, or about 0.1 minutes to about 1 minute. After the first liquid composition is injected into the infusion bag or bottle containing the second aqueous composition and then the first liquid composition and the second aqueous composition are uniformly mixed, a clear infusion solution without precipitation in a carrier acceptable for parenteral administration comprising human serum albumin, docetaxel, ethanol, and citric acid is obtained. In some embodiments, the injection process does not require any artificial stirring (e.g., stirring) to mix the compositions. In some embodiments, the injection of the first liquid composition into the infusion bag or bottle containing the second aqueous composition is completed at a temperature of about 15° C. to about 30° C., about 15° C. to about 25° C., or about 20° C. to about 25° C. In some embodiments, the injection of the first liquid composition into the infusion bag or bottle containing the second aqueous composition is completed at ambient temperature.

[0022] In some embodiments, the present invention provides a method for preparing a clear (e.g., precipitate-free) docetaxel infusion composition for parenteral administration as described herein. One embodiment of the preparation method is as follows: 1) preparing a first liquid composition by dissolving docetaxel and an acid (e.g., citric acid) in ethanol or a mixed solvent containing ethanol (e.g., a mixed solvent of ethanol and PEG300, or ethanol and PEG400); 2) adding a human serum albumin solution (e.g., commercially available and clinically used 20%, 25%, or 5% human serum albumin solutions for infusion (w / v)) to an infusion bag or bottle containing a parenterally acceptable carrier (e.g., a saline solution or a glucose solution), thereby preparing a second aqueous composition; 3) injecting the first liquid composition into an infusion bag or bottle containing a second aqueous composition, the infusion bag or bottle typically not requiring manual mixing or agitation during the injection process; 4) After the injection of the first liquid composition into the infusion bag or bottle is completed, the first liquid composition and the second aqueous composition are mixed uniformly (e.g., by gently turning the infusion bag or bottle containing the compositions upside down by hand) to obtain a clear infusion solution without precipitation. One embodiment of the method is as follows, for example, the method includes: 1) preparing a first liquid composition by dissolving docetaxel and an acid (e.g., citric acid) in ethanol or a mixed solvent containing ethanol (e.g., a mixed solvent of ethanol and PEG300, or ethanol and PEG400) (e.g., the method includes obtaining a first liquid composition comprising a solution of docetaxel and an acid in ethanol or a mixed solvent containing ethanol); 2) adding a human serum albumin solution (e.g., a clinically used 20%, 25% or 5% human serum albumin solution for infusion (w / v)) to an infusion bag or bottle containing a parenterally acceptable carrier (e.g., a saline solution or a glucose solution) to prepare a second aqueous composition (e.g., the method includes obtaining an infusion bag or bottle containing a second aqueous composition containing a solution of HSA and a parenterally acceptable carrier); 3) the first liquid composition is injected into an infusion bag or bottle containing a second aqueous composition, and the injection process does not typically require any artificial mixing or agitation of the infusion bag or bottle (e.g., the method includes injecting the first liquid composition into an infusion bag or bottle containing a second aqueous composition, and the compositions are not artificially mixed and / or the infusion bag or bottle is not agitated (e.g., by holding the infusion bag or bottle stationary); and 4) After the injection of the first liquid composition into the infusion bag or bottle is complete, the first liquid composition and the second aqueous composition are mixed uniformly (e.g., by gently turning the infusion bag or bottle containing the compositions by hand) to obtain a clear infusion solution without precipitates. The first and second steps in the preparation can be completed simultaneously or in different orders. Once mixing is complete, the resulting formulation can be administered at the required dosage level, e.g., about 50 mg / m2 based on the individual patient's body surface area ("BSA"). 2 ~about 150 mg / m 2 In some embodiments, the formulation can be administered to a cancer patient at a dose of about 50 mg / m 2 , about 60 mg / m 2 , about 75 mg / m 2 , about 90 mg / m 2 , about 100 mg / m 2 , or about 120 mg / m 2 The docetaxel may be administered at a dose of 100 mg / kg / day.

[0023] How to Treat Cancer The present invention further provides a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of any of the compositions or formulations described herein. In some embodiments, the method comprises parenterally administering to a subject in need thereof a therapeutically effective amount of a liquid infusion formulation of the present invention. In some embodiments, the formulation is administered in an amount of about 50 mg / m2 based on the patient's BSA (body surface area). 2 , about 60 mg / m 2 , about 75 mg / m 2 , about 90 mg / m 2 , about 100 mg / m 2 , or about 120 mg / m 2 The method may comprise or may be configured to administer to the patient a dose of docetaxel.

[0024] As used herein, the term "body surface area" or "BSA" refers to the measured or calculated surface area of ​​the human body. Such measurements are commonly used as an indicator of metabolic rate instead of body weight. The table below shows the body surface area for typical heights and weights. Calculated using the DuBois & DuBois formula: (body weight (kg)) 0.425 ×(Height(cm)) 0.725 × 0.007184. Weight is the horizontal axis, first according to pounds, then according to kilograms. Height is the vertical axis, first according to inches, then according to centimeters. The result is body surface area according to square meters. Typical BSA is provided in the table below. JPEG2025506788000003.jpg126164

[0025] In one embodiment, the average BSA of cancer patients is about 1.73 m 2 It is. In some embodiments, when the formulations described herein are infused into a patient, the infusion bag or bottle contains a desired dose of docetaxel depending on the patient's body surface area, e.g., about 75 mg / m, after a predetermined amount of the first liquid composition is injected. 2In some embodiments, multiple infusion bags or bottles are used to prepare the desired infusion formulation containing the dose of docetaxel required for a single infusion to a patient. In one example, about 2 ml of BSA is used. 2 For a cancer patient with a cancer of 0.5-1.0 mg / kg, the dose of docetaxel in the infusion bag is about 150 mg. In some embodiments, the infusion time is about 1 hour to about 2 hours. In some embodiments, the infusion time is about 1 hour. The liquid infusion flow rate can be determined and / or adjusted depending on the desired infusion time (e.g., 1 hour). In other embodiments, one infusion bag or multiple infusion bags (e.g., two infusion bags) can contain the amount of docetaxel required for one infusion dose. In this case, the desired dose, e.g., about 75 mg / m 2The dose can be administered to the patient by adjusting the infusion rate (drip rate) within a desired infusion time (e.g., 1 hour). In some embodiments, the concentration of docetaxel in the infusion bag is about 0.1 mg / mL to about 0.5 mg / mL. In some embodiments, the concentration of docetaxel in the infusion bag is about 0.15 mg / mL to about 0.4 mg / mL. In some embodiments, the concentration of docetaxel in the infusion bag is about 0.2 mg / mL, about 0.25 mg / mL, about 0.30 mg / mL, or about 0.35 mg / mL. The volume of the infusion solution can be determined based on the concentration of docetaxel in the infusion bag. For example, if the required dose is 120 mg of docetaxel per infusion (treatment) and the concentration of docetaxel in the infusion bag is 0.25 mg / mL, the total volume of the infusion solution in the infusion bag reaches 480 mL. Based on the volume of the infusion solution and the size of the infusion bag, the amount of infusion solution required for one infusion of a patient may be contained in one infusion bag or in multiple infusion bags (e.g., two infusion bags). For example, one infusion bag may contain about 450 mL of infusion solution containing about 90 mg of docetaxel at a docetaxel concentration of about 0.20 mg / mL. In another example, two infusion bags may contain a total of about 600 mL of infusion solution containing about 150 mg of docetaxel at a docetaxel concentration of about 0.25 mg / mL.

[0026] In some embodiments, "cancer" refers to sarcoma, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, non-small cell lung cancer (NSCLC), bronchial squamous cell carcinoma, small cell undifferentiated carcinoma, large cell undifferentiated carcinoma, adenocarcinoma, alveolar bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal cancer, esophageal cancer, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, gastric cancer, carcinoma, lymphoma, leiomyosarcoma, pancreatic cancer, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma, small intestine cancer, adenocarcinoma, lymphoma, carcinoma id tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, colorectal or colon cancer, tubular adenoma, villous adenoma, hamartoma, leiomyoma, genitourinary tract cancer, renal adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia, bladder cancer, urethral cancer, squamous cell carcinoma, transitional cell carcinoma, prostate cancer, testicular cancer, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, bone cancer, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma malignant giant cell tumor of bone, chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid giant cell tumor of bone, nervous system cancer, skull cancer, osteoma, hemangioma, granuloma, xanthomas, Paget's disease of bone, meningioma cancer, glioma, brain cancer, astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, neurinoma, retinoblastoma, congenital tumor, spinal cancer, neurofibroma, meningioma, glioma, sarcoma, gynecological cancer, uterine cancer, endometrial cancer, cervical cancer, cervical tumor, precancerous cervical dysplasia, ovarian cancer, Ovarian tumor, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumor, ovarian Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma, vulvar cancer, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, vaginal cancer, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tube cancer, blood cancer, blood cancer, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma),Waldenstrom's macroglobulinemia, skin cancer, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, hydatidiform dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, adrenal carcinoma, and neuroblastoma.

[0027] In some embodiments, the cancer is a solid tumor cancer. Some examples of solid tumors include breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, and melanoma. In some embodiments, the cancer is selected from breast cancer, non-small cell lung cancer, prostate cancer (e.g., castration-resistant prostate cancer), gastric cancer (e.g., adenocarcinoma), and head and neck cancer (e.g., head and neck squamous cell carcinoma). In some embodiments, the methods of treating cancer of the present invention include the combined administration of docetaxel and other anti-cancer therapeutic agents. Suitable examples of other anti-cancer therapeutic agents include doxorubicin, cyclophosphamide, cisplatin, prednisone, and fluorouracil, or combinations thereof. These other anti-cancer therapeutic agents can be administered sequentially (before or after) or simultaneously with the docetaxel formulations described in the present claims. In some embodiments, the other anti-cancer therapeutic agents are administered at a dose of about 50 mg / m2, according to the exact diagnosis of the patient and the recommendations of the treating physician. 2 ~about 750 mg / m 2 can be administered at a dose of

[0028] In some embodiments, the present invention provides a method of treating cancer (e.g., breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer) in a subject, the method comprising: i) mixing a first liquid composition described herein with a second aqueous composition described herein to obtain an infusion formulation comprising docetaxel; and ii) The desired docetaxel dose (e.g., about 50 mg / m, based on the patient's BSA) 2 , about 60 mg / m 2 , about 75 mg / m 2 , about 90 mg / m 2 , about 100 mg / m 2 , or about 120 mg / m 2docetaxel dose) to a subject in need thereof by infusion of the formulation obtained in step (i). In some embodiments, the present invention provides a method of treating cancer (e.g., breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer) in a subject, the method comprising: i) mixing a first liquid composition described herein with a second aqueous composition described herein to obtain a desired docetaxel dose (e.g., about 50 mg / m based on the patient's BSA); 2 , about 60 mg / m 2 , about 75 mg / m 2 , about 90 mg / m 2 , about 100 mg / m 2 , or about 120 mg / m 2 (a) a docetaxel dose of 0.01g / mL; and ii) administering the formulation obtained in step (i) by infusion to a subject in need thereof at the desired docetaxel dose. In some embodiments, the desired docetaxel dose (e.g., about 50 mg / m based on the patient's BSA) 2 , about 60 mg / m 2 , about 75 mg / m 2 , about 90 mg / m 2 , about 100 mg / m 2 , or about 120 mg / m 2 docetaxel dose) can be prepared in multiple infusion bags or bottles (eg, in two infusion bags or bottles).

[0029] Reagent Kit Also provided herein is a reagent kit for preparing the infusion formulation described herein, comprising a first container containing a composition comprising docetaxel and a second container containing a composition comprising human serum albumin. In some embodiments, the reagent kit comprises a first container containing a liquid composition comprising docetaxel and a second container containing a liquid composition comprising human serum albumin. In some embodiments, the reagent kit comprises a first container containing a liquid composition comprising docetaxel and ethanol and a second container containing a liquid composition comprising human serum albumin. In some embodiments, the reagent kit comprises a first container containing a liquid composition comprising docetaxel, citric acid, and ethanol and a second container containing a liquid composition comprising human serum albumin. In some embodiments, the reagent kit comprises a first container containing a liquid composition comprising docetaxel, citric acid, and ethanol and a second container containing a liquid composition comprising human serum albumin. In some embodiments, the reagent kit comprises a first container containing a liquid composition comprising docetaxel, citric acid, and absolute ethanol and a second container containing a liquid composition comprising human serum albumin. In some embodiments, the reagent kit includes a first container containing a liquid composition including docetaxel, citric acid, and ethanol, and a second container containing a human serum albumin solution (e.g., 20%, 25%, or 5% (w / v)). In some embodiments, the liquid compositions in the first container and the second container are both sterile solutions.

[0030] In some embodiments, the ethanol contained in the first container is absolute ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel and ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel, an acid, and ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel, an organic acid, and ethanol. In some embodiments, the first container contains a liquid composition comprising docetaxel, ethanol, and another organic solvent (e.g., an alcohol such as propylene glycol or polyethylene glycol 300). In some embodiments, the first container contains a liquid composition comprising docetaxel, citric acid, and ethanol. In some embodiments, the first container contains an ethanol solution comprising docetaxel. In some embodiments, the first container contains an ethanol solution comprising docetaxel and citric acid. In some embodiments, the concentration of citric acid in the first container is about 0.005 mg / mL to about 10 mg / mL. In some embodiments, the concentration of citric acid in the first container is about 0.01 mg / mL to about 2 mg / mL. In some embodiments, the concentration of citric acid in the first container is about 0.01 mg / mL to about 1 mg / mL. In some embodiments, the concentration of citric acid in the first container is about 0.02 mg / mL to about 0.5 mg / mL. In some embodiments, the concentration of citric acid in the first container is about 0.02 mg / mL to about 0.2 mg / mL. In some embodiments, the amount of docetaxel contained in the first container is about 10 mg to about 300 mg of docetaxel. In some embodiments, the amount of docetaxel contained in the first container is about 20 mg to about 200 mg of docetaxel. In some embodiments, the amount of docetaxel contained in the first container is about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, or about 160 mg of docetaxel. In some embodiments, the amount of ethanol contained in the first container is about 0.5 mL to about 50 mL of ethanol. In some embodiments, the amount of ethanol contained in the first container is about 1 mL to about 20 mL of ethanol. In some embodiments, the amount of ethanol contained in the first container is about 1 mL to about 10 mL of ethanol. In some embodiments, the amount of ethanol contained in the first container is about 1 mL to about 5 mL of ethanol. In some embodiments, the amount of ethanol contained in the first container is about 5 mL to about 10 mL of ethanol. In some embodiments, the concentration of docetaxel in the first container is about 5 mg / mL to about 100 mg / mL. In some embodiments, the concentration of docetaxel in the first container is about 10 mg / mL to about 40 mg / mL. In some embodiments, the concentration of docetaxel in the first container is about 20 mg / mL. In some embodiments, the first container contains an injectable pharmaceutical formulation product of the first liquid composition described herein. In some embodiments, the first container contains an injectable pharmaceutical formulation product of the first liquid composition described herein in an amount of about 0.5 mL to about 30 mL. In some embodiments, the first container contains an injectable pharmaceutical formulation product of the first liquid composition described herein in an amount of about 1 mL to about 20 mL. In some embodiments, the first container contains an injectable pharmaceutical formulation product of the first liquid composition described herein in an amount of about 1 mL to about 10 mL. In some embodiments, the first container contains an injectable pharmaceutical formulation product of the first liquid composition described herein in an amount of about 1 mL, about 2 mL, about 4 mL, about 6 mL, and about 8 mL. In some embodiments, the first container contains about 80 mg of docetaxel. In some embodiments, the first container contains about 80 mg of docetaxel and about 4 mL of ethanol. In some embodiments, the second container contains a liquid composition comprising human serum albumin. In some embodiments, the second container contains a human serum albumin solution. In some embodiments, the second container contains a human serum albumin solution, in which the concentration of human serum albumin in the solution is about 1% to about 25% (w / v). In some embodiments, the second container contains a human serum albumin solution, in which the concentration of human serum albumin in the solution is about 5% to about 25% (w / v). In some embodiments, the second container contains a human serum albumin solution for infusion. In some embodiments, the second container contains a 20% human serum albumin solution (w / v) for infusion. In some embodiments, the second container contains a 25% human serum albumin solution (w / v) for infusion. In some embodiments, the second container contains a 5% human serum albumin solution (w / v) for infusion. In some embodiments, the second container contains a liquid composition comprising about 1 g to about 50 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 1 g to about 30 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 1 g to about 20 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 1 g to about 10 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 2 g to about 6 g of human serum albumin. In some embodiments, the second container contains a liquid composition comprising about 2 g, about 4 g, about 6 g, about 8 g, about 10 g, about 12 g, or about 16 g of human serum albumin. In some embodiments, the first container contains about 80 mg of docetaxel. In some embodiments, the first container contains about 4 mL of ethanol. In some embodiments, the first container contains about 80 mg of docetaxel and about 4 mL of ethanol.

[0031] In some embodiments, the reagent kit includes a first container containing about 80 mg of docetaxel and a second container containing about 2 g to about 10 g of human serum albumin. In some embodiments, the reagent kit includes a first container containing about 80 mg of docetaxel and a second container containing about 10 g of human serum albumin. In some embodiments, a desired amount of the first liquid composition is removed from one or more first containers using a syringe and injected into an infusion bag or bottle containing a corresponding amount of the second aqueous composition to prepare an infusion formulation as described herein.

[0032] In some embodiments, the present invention provides a method for preparing a docetaxel composition for infusion for the treatment of cancer in a subject (e.g., breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer). One embodiment of the preparation method is as follows: 1) using a syringe to extract a required amount of human serum albumin solution (e.g., commercially available and clinically used 20%, 25%, or 5% human serum albumin solution for infusion (w / v)) from one or more second containers, and injecting it into an infusion bag or bottle containing a corresponding required amount of a carrier acceptable for parenteral administration (e.g., saline solution or glucose solution), and after uniform mixing, obtain one second aqueous composition; 2) withdrawing a first liquid composition containing the desired dose of docetaxel from one or more first containers using a syringe; 3) injecting the first liquid composition extracted from the syringe of 2) above into an infusion bag or bottle containing the second aqueous composition of 1) above; 4) After the injection of the first liquid composition into the infusion bag or bottle is completed, the first liquid composition and the second aqueous composition are mixed uniformly (e.g., by gently turning the infusion bag or bottle containing the compositions upside down by hand) to obtain a clear infusion solution without precipitation.

[0033] The first and second steps in the preparation can be completed simultaneously or in different orders. Thus, the infusion formulation containing the required docetaxel dose for infusion obtained in the fourth step can be infused into a subject in need thereof. For example, about 50 mg / m2 based on the body surface area ("BSA") of the patient individual. 2 ~about 150 mg / m 2 In some embodiments, the formulation is administered to a cancer patient at a dose of about 50 mg / m 2 , about 60 mg / m 2 , about 75 mg / m 2 , about 90 mg / m 2 , about 100 mg / m 2 , or about 120 mg / m 2 In some embodiments, the formulation can be administered at a docetaxel dose of about 75 mg / m 2 The docetaxel may be administered at a dose of 100 mg / kg / day. In some embodiments, the reagent kit further comprises instructions for preparing the infusion formulations (compositions) described herein.

[0034] Working Example Materials and Methods Winthrop (docetaxel injection), Taxotere (登録商標) Authorized generic drugs (reference preparations) of: Winthrop (docetaxel) injection is a solution containing 20 mg / mL docetaxel in ethanol and polysorbate 80 and is purchased from Winthrop US, a subsidiary of Sanofi-Aventis US. (登録商標) It is an approved generic drug of Winthrop (Docetaxel) Injection. One vial of Winthrop (Docetaxel) Injection contains 20 mg of Docetaxel (anhydrous), 540 mg of Polysorbate 80, and 395 mg of a solution in absolute ethanol (50% v / v), with the pH value adjusted with citric acid. In this clinical study, each patient was administered 0.3 mg / mL and 75 mg / m 2The final infusion solution of the reference formulation was infused with docetaxel at a dose of 2 m 2 Taking a patient with idiopathic pulmonary syndrome (IPS), the preparation method of the reference formulation infusion solution (formulation) is as follows: BSA is about 2 m 2 For a cancer patient with pulmonary embolism, the dose of docetaxel in the infusion bag was approximately 150 mg. To prepare a final infusion solution with a docetaxel concentration of 0.3 mg / mL, 7.5 mL of Winthrop (docetaxel) injection (20 mg docetaxel / mL) and 492.5 mL of 0.9% sodium chloride injection were used in the preparation. Using only a 21 gauge needle, 7.5 mL of Winthrop (Docetaxel) Injection (20 mg docetaxel / mL) was extracted under sterile conditions with a calibrated syringe and injected by single injection (one injection) into an infusion bag or bottle containing 492.5 mL of 0.9% sodium chloride solution to produce a final concentration of 0.3 mg / mL docetaxel infusion solution. The infusion solution was thoroughly mixed by gentle manual swirling. The docetaxel infusion solution should be administered intravenously as a 1-hour infusion at ambient room temperature (below 25°C) and under light exposure conditions.

[0035] BH009 (test formulation): BH009 was developed as a polysorbate 80-free docetaxel injection formulation product. BH009 was prepared as an injectable sterile product (a solution of 20 mg / mL docetaxel in ethanol). The BH009 drug reagent kit contains one vial containing 80 mg (docetaxel) / 4 mL of BH009 drug (docetaxel injection) and one vial containing 10 g of commercially available 20% human albumin solution for infusion (50 mL). Each 4 mL of BH009 drug (docetaxel injection) contains 80 mg docetaxel (anhydrous) and 3156 mg absolute ethanol, pH adjusted with citric acid. In this clinical study, each patient was administered 0.25 mg / mL and 75 mg / mL docetaxel. 2The infusion solution containing the test formulation was infused at a dose of docetaxel of 1:7.5:71.5 (v / v) in the preparation of the infusion solution of the test formulation. 2 Taking a patient as an example, the preparation method of the infusion solution (preparation) of the test preparation is as follows: BSA is about 2 m 2 For cancer patients with pulmonary tuberculosis, the dose of docetaxel in the infusion bag was about 150 mg. To prepare an infusion solution of the test formulation with a docetaxel concentration of 0.25 mg / mL, 7.5 mL of BH009 (20 mg docetaxel / mL), 56.25 mL of 20% human albumin solution for infusion, and 536.25 mL of 0.9% sodium chloride injection were used in the preparation. Using a syringe, 56.25 mL of the 20% human albumin solution for infusion was injected into an infusion bag or bottle containing 536.25 mL of 0.9% sodium chloride solution. The infusion bag or bottle was then gently inverted manually upside down approximately 10 times to thoroughly mix the resulting albumin-saline solution. Using only a 21-gauge needle, a calibrated syringe was used to extract 7.5 mL of BH009 drug solution (20 mg docetaxel / mL) under sterile conditions and injected into the infusion bag or bottle containing the mixed albumin-saline solution by a single injection (one rapid injection) to obtain an infusion solution with a final docetaxel concentration of 0.25 mg / mL. Immediately after the single injection was completed, the infusion bag or bottle was gently turned upside down by hand approximately 20 times (total mixing time was approximately 1 minute) to thoroughly and homogenously mix the infusion solution. The resulting infusion solution was a clear solution. · BH009 infusion solution (test product) should be administered intravenously as a 1-hour infusion at ambient room temperature (<25°C) and under light exposure conditions. The patients' unbound docetaxel drug concentrations and total docetaxel drug concentrations in plasma were quantitatively measured using two independent validated analytical methods, respectively, the details of which are described below.

[0036] A validated liquid chromatography-mass spectrometry (LC-ESI-MS / MS) method for measuring total docetaxel in human K3EDTA-anticoagulated plasma: A liquid chromatography-tandem mass spectrometry (LC-MS / MS) method was developed to assess total docetaxel in human plasma using liquid-liquid extraction technology. The method was used in conjunction with triple quadrupole mass spectrometry to monitor docetaxel in electrospray positive ion mode, of which docetaxel-d9 was used as the internal standard (IS). Docetaxel was extracted with an extraction solvent and then separated on a chromatographic column (model number Gemini 5 μm C18 150×4.6 mm) using a mobile phase buffer (aqueous solution containing acetic acid 0.1% v / v):methanol, 30:70 v / v, under isocratic conditions at a flow rate of 1.000 mL / min. Quantitative analysis of docetaxel and docetaxel-d9 was performed using multiple reaction monitoring mode (MRM). The method is suitable for measuring total docetaxel in K3EDTA human plasma within the linear range of 10.000 ng / mL (LLOQ) to 6000.000 ng / mL (ULOQ) using 0.200 mL of human plasma. The method has been verified for analytical reliability for a 10-fold diluted sample (reaching 27000.000 ng / mL).

[0037] Validated liquid chromatography-mass spectrometry (LC-ESI-MS / MS) method for measuring free docetaxel in human K3EDTA-anticoagulated plasma: A liquid chromatography-tandem mass spectrometry (LC-MS / MS) method was developed to assess free docetaxel in human plasma using liquid-liquid extraction technology. The method utilized triple quadrupole mass spectrometry in combination to monitor docetaxel in electrospray positive ion mode, of which docetaxel-d9 was used as an internal standard (IS). To directly measure the concentration of unbound docetaxel, plasma samples were filtered using a Centrifree® ultrafiltration device (1.0 mL, 30 KDa centrifugal filter). Docetaxel was extracted with an extraction solvent and then separated on a chromatographic column (model Gemini 5 μm C18 150×4.6 mm) using a mobile phase buffer (aqueous solution containing acetic acid 0.1% v / v):methanol, 30:70 v / v, under isocratic conditions at a flow rate of 1.000 mL / min. Quantitative analysis of docetaxel and docetaxel-d9 was performed using multiple reaction monitoring mode (MRM). The method is suitable for measuring free docetaxel in K3EDTA human plasma within the linear range of 10.000 ng / mL (LLOQ) to 600.000 ng / mL (ULOQ) using 0.200 mL of human plasma. The method was verified for analytical reliability for a 10-fold diluted sample (reaching 8000.000 ng / mL).

[0038] Example 1 Patients received either the test product BH009 or the reference product Taxotere (登録商標) (Docetaxel) Injection or Taxotere (登録商標) We conducted a multicenter, open-label, randomized, balanced, two-treatment, two-cycle, two-sequence, crossover, single-dose bioequivalence study of 100 mg of nivolumab administered orally in patients treated with an approved generic equivalent of nivolumab. Patient selection criteria Inclusion criteria: Age ≥ 18 years, regardless of gender. 75 mg / m 2 Patients with histologically or cytologically confirmed solid tumors who are scheduled to receive docetaxel monotherapy at a dose of 75 mg / m 2 Previously received docetaxel monotherapy at a dose of(登録商標) or Taxotere already approved for marketing (登録商標) Patients with solid tumors who have been treated with ≥ 2 treatment courses at the same dose according to the actual treatment plan (limited to generic drugs of ≥ 1000 mg / mm3). Patients with ECOG physical status score of 0 or 1 and expected survival time of ≥ 3 months. Patients with sufficient hematopoietic, renal and hepatic function (bone marrow function: ANC ≥ 1500 / mm3). 3 , platelet count ≥100,000 / mm 3 , hemoglobin >9.0 g / dL. Liver function: ALT / AST ≤1.5×ULN, alkaline phosphatase ≤2.5×ULN, total bilirubin ≤ULN. Renal function: serum creatinine ≤1.5×ULN). Prothrombin time, international normalized ratio, or activated partial thromboplastin time <1.5×ULN. The use of full doses of anticoagulants was permitted. Patients had recovered from adverse events related to previous anticancer treatment to grade 0-1 (according to CTCAE 5.04 criteria), except for alopecia and endocrine disorders controlled by hormone replacement therapy. Exclusion criteria: allergic or specific reactions to docetaxel and its excipients and / or related substances (including polysorbate 80, paclitaxel, alcohol, dexamethasone, and antiemetics (granisetron or ondansetron)); or patients with severe cardiovascular disease, active infection (e.g., pulmonary tuberculosis, sepsis, or opportunistic infection), severe pleural effusion, and / or peripheral neuropathy grade ≥2; patients with hepatitis B surface antigen and hepatitis C (HCV) virus antibody positivity, HIV infection, brain metastasis, or patients with neurological symptoms due to brain metastasis; pregnant or lactating women, etc.

[0039] research design The clinical study included 46 patients. Cycle I (Day 1): On Day 1 of chemotherapy initiation, patients received docetaxel 75 mg / m 2 (test or reference formulation) was infused intravenously. Cycle II (Day 22): On Day 1 of the initiation of the second chemotherapy cycle, patients received another docetaxel formulation 75 mg / m 2(Test or Reference product) were administered cross-over. To reduce the incidence and severity of fluid retention and the severity of allergic reactions, all patients should receive corticosteroids such as dexamethasone orally for 3 days at 16 mg / day (e.g., 8 mg / dose twice daily) one day before docetaxel administration. In cycle 2, all patients should receive prophylactic granisetron (antiemetic) 2 mg IV or ondansetron (antiemetic) 4-8 mg IV before infusion of the study drug (approximately 30 minutes before administration). Investigators may decide for themselves whether to allow prophylactic antiallergic treatment and G-CSF. Prophylactic treatment and dosage before cycle 2 should be the same. Six mL of venous blood was collected for pharmacokinetic analysis at 0 h before intravenous infusion, 0.500 h, 0.667 h, 0.833 h, 1.000 h after infusion (immediately after infusion completion), and 0.083, 0.167, 0.333, 0.500, 1.000, 2.000, 3.000, 6.000, 8.000, 12.000, 24.000, and 48.000 h after infusion completion. Total and free docetaxel plasma concentrations were analyzed using two independently validated analytical methods. The following variables were calculated using the obtained concentration-time curves of free and total docetaxel: Primary variable: C max , AUC 0-t and AUC 0-∞ , secondary variable: T max , t 1 / 2 , K el , V d , CL and AUC _%Extrap_obs . For free docetaxel and total docetaxel, the pharmacokinetic parameters C max , AUC 0-t and AUC 0-∞ Based on the statistical results of the 90% confidence interval of the geometric least squares mean ratio (test product (T) / reference product (R)), a conclusion was drawn as to whether the test product was bioequivalent to the reference product. The acceptable range of bioequivalence was C max , AUC 0-t and AUC 0-∞The 90% confidence interval for the geometric least squares mean ratio (T / R) is 80.00% to 125.00%.

[0040] Research results During the study, a total of 52 patients were screened, of which 46 patients were randomly selected, and all randomly selected patients (N=46) were included in the safety analysis set population (see Table 1). A total of 5 patients withdrew from the clinical study, and 41 patients completed the full 2 ​​cycles of the study. Total docetaxel and free docetaxel plasma drug concentration analysis was performed on samples collected from 46 subjects. Based on the requirements of statistical analysis, pharmacokinetic analysis data (N=41) included subjects who completed all studies according to the study protocol. Pharmacokinetic parameters of total docetaxel and free docetaxel are shown in Tables 2 and 3. Of the 41 patients, one patient had a blood concentration of C max Because the proportion of patients with docetaxel in the total group exceeded 5% and met the exclusion criteria specified in the statistical analysis, the patient's data was excluded from the bioequivalence analysis data, and finally, the data of a total of 40 patients were included in the BE analysis group. The bioequivalence analysis results of total docetaxel and free docetaxel are shown in Tables 4 and 5. The study results were based on the efficacy and safety of the test drug BH009 and the reference drug Winthrop (docetaxel) injection (Taxotere (登録商標) The study demonstrated that the AUC of total docetaxel was bioequivalent to the approved generic version of docetaxel in patients with advanced solid tumors. 0-t , AUC 0-∞ and C max The 90% confidence intervals for were 91.89% to 107.18%, 91.10% to 106.04%, and 92.18% to 108.00%, respectively, and the AUC 0-t , AUC 0-∞ and C max The 90% confidence intervals for were 89.98% to 103.15%, 90.24% to 102.75%, and 85.22% to 101.70%, respectively. AUCs for total and free docetaxel 0-t , AUC0-∞ and C max The 90% confidence intervals for all were within the bioequivalence (BE) range (80%-125%). Safety analysis data showed that the test formulation BH009 was well tolerated in the human body, and the incidence of hematological toxicity in the test formulation group (BH009) was significantly lower than that in the reference formulation group (Winthrop (docetaxel) injection) (see Table 6). In the study, the most common grade 3 / 4 toxicities were neutropenia, anemia, lymphopenia, and leukopenia, and grade 3 / 4 hematological toxicity in the test formulation group was significantly reduced compared to the reference formulation group (R / T: 15.9% vs. 2.3%), especially leukopenia and neutropenia (R / T: 6.8% vs. 0.0%, 4.6% vs. 0.0%). The incidence of febrile neutropenia in the study was 0.0%. The mean plasma drug concentration-time curves of total docetaxel and free docetaxel in patients with advanced solid tumors for BH009 and Winthrop (docetaxel) injection are shown in Figures 1 and 2, respectively. Patient demographics, pharmacokinetic parameters, BE results for the major pharmacokinetic parameters of total and free docetaxel, and safety statistics are summarized below. JPEG2025506788000004.jpg102161JPEG2025506788000005.jpg37161JPEG2025506788000006.jpg38161 JPEG2025506788000007.jpg68161JPEG2025506788000008.jpg68161JPEG2025506788000009.jpg212161

[0041] Other embodiments While the present application has been described with reference to its detailed description, it should be understood that the foregoing description is intended to illustrate, but not to limit, the scope of the present application, which is defined by the appended claims. Other aspects, advantages, and improvements are within the scope of the following claims.

Claims

1. A pharmaceutical composition for infusion comprising docetaxel and human serum albumin, wherein the composition is prepared by injecting a first liquid composition comprising docetaxel and ethanol into an infusion bag or bottle containing a second aqueous composition comprising human serum albumin in a parenterally acceptable carrier; wherein the composition does not contain polysorbate 80; The composition is used to treat patients diagnosed with solid tumors selected from breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, and head and neck cancer by infusion administration; The dose of docetaxel infused to said patient in need thereof is about 75 mg / m 2 and wherein the composition is prepared within 24 hours prior to infusion into the patient; Pharmaceutical compositions.

2. 10. The pharmaceutical composition of claim 1, wherein the composition is prepared within 4 hours prior to infusion into the patient.

3. 2. The pharmaceutical composition of claim 1, wherein the concentration of docetaxel in the composition is from about 0.05 mg / mL to about 0.5 mg / mL.

4. 2. The pharmaceutical composition of claim 1, wherein the concentration of human serum albumin in the composition is from about 0.01% to about 20% (w / v).

5. 10. The pharmaceutical composition of claim 1, wherein the composition is a clear aqueous infusion solution.

6. 10. The pharmaceutical composition of claim 1, wherein the composition is repeatedly administered to the patient in a new cycle once every three weeks.

7. The composition contains docetaxel at a dose of 75 mg / m 2 The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is administered

8. The pharmaceutical composition of claim 1 , wherein the composition is administered to treat a patient diagnosed with prostate cancer.

9. The pharmaceutical composition of claim 1 , wherein the composition is administered to treat the patient diagnosed with breast cancer.

10. The pharmaceutical composition of claim 1, wherein the composition is administered to treat a patient diagnosed with non-small cell lung cancer.

11. The pharmaceutical composition of claim 1 , wherein the composition is administered to treat the patient diagnosed with gastric cancer.

12. The pharmaceutical composition of claim 1 , wherein the composition is administered to treat the patient diagnosed with head and neck cancer.

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