WO2023159491A1 - 多西他赛组合物和方法 - Google Patents

多西他赛组合物和方法 Download PDF

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WO2023159491A1
WO2023159491A1 PCT/CN2022/078020 CN2022078020W WO2023159491A1 WO 2023159491 A1 WO2023159491 A1 WO 2023159491A1 CN 2022078020 W CN2022078020 W CN 2022078020W WO 2023159491 A1 WO2023159491 A1 WO 2023159491A1
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docetaxel
composition
infusion
cancer
serum albumin
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PCT/CN2022/078020
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English (en)
French (fr)
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孙群
蒋海华
韦小华
刘洁
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珠海贝海生物技术有限公司
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Priority to PCT/CN2022/078020 priority Critical patent/WO2023159491A1/zh
Publication of WO2023159491A1 publication Critical patent/WO2023159491A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to formulations of docetaxel for use in the treatment of cancer.
  • the present invention relates to formulations containing docetaxel and human serum albumin ("HSA"), which are useful in the treatment of patients with breast cancer, non-small cell lung cancer, prostate cancer (such as castration-resistant prostate cancer), gastric cancer (such as adenocarcinoma) or head and neck cancer (such as squamous cell carcinoma of the head and neck).
  • HSA human serum albumin
  • parenteral drugs are insoluble in water and are therefore formulated with irritating, allergenic or toxic solubilizers, surfactants, solvents and/or emulsifiers when administered to the patient. See, eg, Briggs et al., Anesthesis 37, 1099 (1982) and Waugh et al., Am. J. Hosp. Pharmacists, 48, 1520 (1991 )). Furthermore, many of these drugs, especially those administered intravenously, cause adverse side effects such as vein irritation, phlebitis, burning and pain upon injection, venous thrombosis, extravasation, and other administration-related side effects.
  • Taxanes play an important role in the treatment of various solid tumors.
  • docetaxel is about twice as active as paclitaxel in inhibiting microtubule depolymerization, and has a unique ability to alter certain types of microtubules, which is different from most current clinical applications. Spindle poisons are different.
  • docetaxel has very poor water solubility.
  • Commercially available two-pack docetaxel formulation The clinical intravenous administration is formulated as a high-concentration solution containing 40 mg docetaxel and 1040 mg polysorbate 80 per milliliter. This concentrated solution must be carefully diluted with a solvent containing 13% ethanol in saline prior to administration.
  • Preparations include single-bottle preparations or two-bottle preparations (including injections and diluents).
  • the single vial formulation is a solution containing docetaxel in polysorbate 80 and ethanol.
  • the two-pack formulation contains a solution of docetaxel in polysorbate 80 and a vial containing a solvent in aqueous ethanol.
  • both formulations contain high amounts of polysorbate 80, which can cause severe hypersensitivity reactions in some patients and is associated with The most common adverse events associated with the preparation.
  • the formulations of the present invention are not prepared using any toxic surfactants, but they are comparable to commercial Preparations are bioequivalent. Because of this, the formulation allows in clinical use to achieve the same preparations with the same or similar therapeutic effect while avoiding Adverse events associated with polysorbate surfactants in formulations.
  • this formulation allows docetaxel to be administered at a dose of about 75 mg/ m2 for the treatment of various cancers, such as breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer or head and neck cancer.
  • the formulations of the present claims comprise only readily available, relatively inexpensive ingredients, such as human serum albumin, ethanol and citric acid, all of which are approved for pharmaceutical use by regulatory bodies such as FDA or EMA, respectively.
  • Formulations comprising docetaxel, human serum albumin and ethanol are described in WO2021/158632.
  • the present invention provides a pharmaceutical composition for infusion comprising docetaxel and human serum albumin,
  • composition is obtained by infusing a first liquid composition comprising docetaxel and ethanol into an infusion bag or bottle comprising a second aqueous composition comprising human serum albumin in a parenterally acceptable carrier prepared in
  • composition does not contain polysorbate 80
  • composition is administered by infusion for the treatment of a patient diagnosed with a solid tumor selected from breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer and head and neck cancer,
  • the dose of docetaxel infused into said patient in need thereof is about 75 mg/m 2 .
  • composition is prepared within 24 hours prior to infusion into said patient.
  • the composition is prepared within 4 hours prior to infusion into said patient.
  • the first liquid composition is a sterile solution.
  • the second aqueous composition is a sterile solution.
  • the concentration of docetaxel in the composition is from about 0.05 mg/ml to about 0.5 mg/ml.
  • the concentration of docetaxel in the composition is from about 0.1 mg/ml to about 0.4 mg/ml.
  • the concentration of docetaxel in the composition is about 0.20 mg/ml.
  • the concentration of docetaxel in the composition is about 0.25 mg/ml.
  • the concentration of docetaxel in the composition is about 0.30 mg/ml.
  • the concentration of human serum albumin in the composition is from about 0.01% to about 20% (w/v).
  • the concentration of human serum albumin in the composition is from about 0.1% to about 10% (w/v).
  • the concentration of human serum albumin in the composition is from about 0.2% to about 5% (w/v).
  • the concentration of human serum albumin in the composition is from about 0.5% to about 2.5% (w/v).
  • the composition is a clear aqueous infusion solution.
  • the composition is administered to said patient repeatedly with a new cycle every 3 weeks.
  • the composition is administered at a dose of 75 mg/m 2 of docetaxel.
  • the composition is administered to treat said patient diagnosed with breast cancer.
  • the composition is administered to treat said patient diagnosed with locally advanced or metastatic breast cancer.
  • the composition is administered for adjuvant treatment of breast cancer.
  • the composition is administered to treat said patient diagnosed with non-small cell lung cancer.
  • the composition is administered to treat said patient diagnosed with locally advanced or metastatic non-small cell lung cancer.
  • the composition is administered to treat said patient diagnosed with prostate cancer.
  • the composition is administered to treat said patient diagnosed with metastatic castration-resistant prostate cancer.
  • the composition is administered to treat said patient diagnosed with gastric cancer.
  • the composition is administered for the treatment of patients diagnosed with advanced gastric adenocarcinoma, including patients with gastroesophageal junction tumors.
  • the composition is administered for treating said patient with head and neck cancer.
  • the composition is administered for induction therapy of locally advanced squamous cell carcinoma of the head and neck.
  • Figure 1 is a line graph of the average concentration and time curve of total docetaxel after administration of BH009 and Winthrop (Taxotere authorized generic drug) (docetaxel) injection to patients with advanced solid tumors.
  • Winthrop Tuxotere authorized generic drug
  • Figure 2 is a line graph of the mean concentration and time curve of free docetaxel after administration of BH009 and Winthrop (Taxotere authorized generic drug) (docetaxel) injection to patients with advanced solid tumors.
  • R represents the reference formulation (Winthrop injection)
  • T represents the test formulation (BH009).
  • a pharmaceutical formulation comprising docetaxel and human serum albumin.
  • the formulation can generally be administered parenterally to a subject in need thereof.
  • parenteral means a drug selected from subcutaneous (“SC"), intravenous (“IV”), intramuscular (“IM”), intradermal (“ID”), intraperitoneal (“IP”), etc. way.
  • the formulation may be administered to a subject by intravenous infusion, eg, through an infusion bag or bottle, as described herein.
  • the formulation includes docetaxel, human serum albumin, acid, ethanol, and a liquid carrier (eg, a parenterally acceptable carrier). In some embodiments, the formulation includes docetaxel, human serum albumin, citric acid, ethanol, and a liquid carrier ( eg, a parenterally acceptable carrier). 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.
  • the pH of the formulation is from about 4 to about 9.5. In some embodiments, the formulation has a pH of about 5 to about 9. In some embodiments, the formulation has a pH of about 6 to about 8. In some embodiments, the formulation has a pH of about 6.5 to about 7.5. In some embodiments, the formulation has a pH of about 4 to about 9. In some embodiments, the pH of the formulation is from about 5 to about 8.5. In some embodiments, the formulation has a pH of about 6 to about 7.5.
  • the formulation is substantially free of any surfactant. In some embodiments, the formulation is substantially free of polysorbate 80. In some embodiments, the formulation contains no more than about 1 ppm or about 1 ppb of a surfactant (eg, polysorbate 80). In some embodiments, the formulation is free of polysorbate 80. In some embodiments, the pharmaceutical formulation does not contain lipids (eg, soybean oil).
  • docetaxel refers to a compound having CAS No. 114977-28-5 and the following chemical structure:
  • Docetaxel is a white to almost white powder. This compound is highly lipophilic and practically insoluble in water. Docetaxel is a microtubule inhibitor indicated for the treatment of breast cancer, non-small cell lung cancer, hormone-refractory prostate cancer, gastric adenocarcinoma, and squamous cell carcinoma of the head and neck.
  • docetaxel includes any pharmaceutically acceptable salt of the docetaxel compound free base or free acid (eg, the chemical structure depicted above, or any tautomer thereof).
  • pharmaceutically acceptable salts are those that retain the desired biological activity of the indicated compound and exhibit minimal adverse toxicological effects.
  • salts can be prepared in situ during the final isolation and purification of the compound, or separately by reacting the purified compound in its free acid or free base form with an appropriate base or acid, respectively. Such salts may impart greater stability or solubility to the molecule, thereby facilitating preparation of formulations within the scope of the present claims.
  • Suitable examples of pharmaceutically acceptable acid addition salts of docetaxel include bile acid addition salts, hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, bisulfate, sulfamate Phosphates, Acetates, Hydroxyacetates, Phenylacetates, Propionates, Butyrates, Isobutyrates, Valerates, Maleates, Hydroxymaleates, Acrylates , fumarate, malate, tartrate, citrate, salicylate, p-aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate salt, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxy Benzoate, Mandelate, Tanninate, Formate, Stearate, Ascorbate, Palmitate, Oleate, Pyruvate, Pamo
  • Suitable examples of pharmaceutically acceptable base addition salts include hydroxides of alkali metals including sodium, potassium and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia, Organic amines such as unsubstituted or hydroxy-substituted mono-, di- or tri-alkylamines, dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine Amines; mono-, di- or tri-(2-hydroxy-(C1-C6)-alkyl)amines such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tris-(2-hydroxy N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine or lysine.
  • alkali metals including sodium, potassium and
  • docetaxel can include 1, 2, or 3 equivalents of the hydrated solvate.
  • the docetaxel is a solvate comprising three equivalents of water.
  • the docetaxel is docetaxel trihydrate, docetaxel monohydrate, or docetaxel anhydrate.
  • the docetaxel contains one equivalent of acetone solvate.
  • the docetaxel can be any of the solvates of docetaxel disclosed, for example, in WO2010091650 or US2012007167, the disclosures of which are incorporated herein by reference in their entirety.
  • the docetaxel is crystalline.
  • the docetaxel is any of the crystalline forms disclosed in, for example, WO2012115402, US8410294, US20100197944, US20100099897, US8357811, US20100160653, or US20070142457, the disclosures of which are incorporated herein by reference in their entirety.
  • the docetaxel is amorphous.
  • the docetaxel is any one of the amorphous forms disclosed, for example, in WO2008102374, the disclosure of which is incorporated herein by reference in its entirety.
  • 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 ml to about 0.75 mg/ml.
  • 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 0.3mg/ml, about 0.35mg/ml, about 0.4mg/ml, about 0.45mg/ml, about 0.5mg/ml, about 0.6mg/ml, about 0.74mg/ml, about 0.75mg/ml, about 0.8 mg/ml or about 1 mg/ml.
  • the formulation comprises from about 10 mg to about 300 mg, from about 20 mg to about 200 mg, from about 50 mg to about 250 mg, from about 60 mg to about 240 mg, from about 100 mg to about 200 mg, from about 120 mg to about 200 mg Or from about 100 mg to about 175 mg of docetaxel.
  • 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.
  • the formulation comprises an administered dose of docetaxel equivalent to from about 50 mg/m 2 to about 150 mg/m 2 , eg, based on the individual patient's body surface area (“BSA”).
  • the formulation comprises, eg, based on the patient's individual body surface area ("BSA"), equivalent to about 50 mg/m 2 , about 60 mg/m 2 , about 75 mg/m 2 , about 90 mg/m 2 , about Docetaxel at a dose of 100 mg/m 2 or about 120 mg/m 2 .
  • BSA body surface area
  • the formulation contains about 150 mg of docetaxel.
  • human serum albumin refers to native and recombinant human serum albumin.
  • the human serum albumin is native human serum albumin.
  • 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, a process known as Cohn fractionation (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 to precipitate is native human serum albumin. After precipitation, a wet paste of crude native human serum albumin was obtained.
  • Recombinant human serum albumin is a highly purified animal component-free, virus-free, and prion-free product that serves as a substitute for native human serum albumin, which are structurally identical (Bosse D et al., J. Clin. Pharmacol. 2005;45:57-67). Recombinant human serum albumin is produced by various prokaryotic and eukaryotic hosts (Chen Z et al., Biochimica et Biophysica Acta 2013; 1830:5515-5525).
  • HSA Human serum albumin
  • M r relative molecular weight
  • Intravenous administration of HSA solutions has been shown to be useful in 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 combined with exchange transfusion therapy for neonatal hyperbilirubinemia (see eg Finlayson, Seminars in Thrombosis and Hemostasis, 6, 85-120, (1980)).
  • the human serum albumin herein may also 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.
  • the commercially available serum albumin solution for infusion includes pharmaceutically acceptable stabilizers such as sodium N-acetyl tryptophan, sodium caprylate, sodium chloride, sodium bicarbonate, sodium hydroxide, acetic acid, etc. or mixtures thereof.
  • a human serum albumin solution can be prepared by diluting a commercially available human serum albumin solution for infusion with a parenterally acceptable carrier.
  • human serum albumin can be prepared by mixing human serum albumin powder dissolved in water with other pharmaceutically acceptable stabilizers contained in commercially available albumin products.
  • 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 the 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 is an aqueous solution prepared by diluting commercially available human serum albumin for infusion.
  • the concentration of human serum albumin in the formulation is from about 0.1% to about 20% (w/v), from about 0.05% to about 10% (w/v), from about 0.05% to about 5% (w/v), from about 0.05% to about 3% (w/v), from about 0.02% to about 3% (w/v), from about 0.2% to about 10% (w/v), From about 0.5% to about 15% (w/v), from about 0.5% to about 5% (w/v), from about 1% to about 10% (w/v), or from about 1% to about 3% (w/v).
  • 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).
  • the formulation comprises from about 1 g to about 50 g, from about 2 g to about 40 g, from about 1 g to about 10 g, from about 2 g to about 20 g, from about 1 g to about 5 g, or from about 5 g to about 10 g of human serum albumin.
  • the weight ratio of human serum albumin to docetaxel in the formulation is from about 20:1 to about 200:1 or from 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.
  • the amount of liquid carrier (eg, a parenterally acceptable carrier) in the formulation is from about 10 mL to about 2 L, from about 50 mL to about 1 L, from about 100 mL to about 1 L, from about 250 mL to About 1 L, from about 100 mL to about 500 mL, or from about 250 mL to about 500 mL.
  • suitable examples of liquid carriers include water (eg sterile water), physiological saline (eg 0.9 wt.% NaCl aqueous solution) or glucose solution (eg 5 wt.% glucose solution).
  • the formulation is a clear (eg, transparent) infusion solution rather than a nanoparticle suspension. In some embodiments, the formulation is a clear solution. In some embodiments, the clear infusion solution remains clear without precipitation 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, the clear infusion solution remains clear without precipitation for at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, or at least 6 hours when the clear solution remains at about 15-30°C.
  • the clear infusion solution remains clear without precipitation for at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, or at least 6 hours when the clear solution remains at about 18-25. In some embodiments, the clear solution remains clear and free of precipitation 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 remains at about 2-8. In some embodiments, the clear infusion solution remains clear without precipitation 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 maintained at ambient temperature.
  • 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 that portion of the docetaxel in the infusion composition (solution) that is not bound (eg, non-covalently bound) to human serum albumin.
  • the amount of free (unbound) docetaxel in a parenterally administered infusion composition (solution) is measured by ultrafiltration through a 30 kDa membrane.
  • this parenterally administered infusion composition As measured by dynamic light scattering (DLS), this parenterally administered infusion composition (solution) has almost the same characteristics in DLS compared to the corresponding human serum albumin saline solution.
  • 1 mL of the formulation eg, an infusion composition for parenteral administration
  • 1 ml of the formulation (eg, an infusion composition for parenteral administration) includes no more than 5 particles with a size greater than 25 ⁇ m, no more than 10 particles with a size greater than 25 ⁇ m, no more than 5 particles with a size Particles larger than 15 ⁇ m or not more than 20 particles with a size larger than 25 ⁇ m.
  • the formulation includes an organic acid.
  • 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 pharmaceutically acceptable salts thereof.
  • the formulation comprises citric acid.
  • the formulation comprises from about 0.001 mg/ml to about 2 mg/ml citric acid, from about 0.005 mg/ml to about 1 mg/ml citric acid, or from about 0.01 mg/ml to about 0.5 mg/ml ml of citric acid.
  • the addition of an organic acid (eg, citric acid) to the formulation serves to create or maintain the desired pH of the formulation (eg, infusion solution).
  • the infusion composition for parenteral administration has a pH of from about 4 to about 9.5, from about 5 to about 9, from about 6 to about 8, from about 6.5 to about 7.4, From about 4 to about 9, from about 5 to about 8.5, or from about 6 to about 7.5.
  • the formulation comprises an organic solvent or a combination of organic solvents.
  • the organic solvent is alcohol. Suitable examples of alcohols include ethanol, propylene glycol, polyethylene glycol 300, and the like.
  • the organic solvent is ethanol.
  • the amount of ethanol in the infusion composition for parenteral administration of docetaxel is no more than 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).
  • the formulation (eg, the infusion composition for 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 into the cancer patient. After injecting the first liquid composition into the infusion bag or bottle containing the second aqueous composition, and then uniformly mixing the first liquid composition and the second aqueous composition, the parenteral administration acceptable carrier is obtained. A clear, precipitate-free infusion solution containing human serum albumin, docetaxel, citric acid, and ethanol.
  • the invention provides a pharmaceutical composition for infusion comprising docetaxel and human serum albumin at a dose of about 75 mg/m 2 , wherein the composition is free of polysorbate 80. In some embodiments, the invention provides a pharmaceutical composition for infusion comprising docetaxel and human serum albumin at a dose of about 50 mg to about 200 mg, wherein the composition does not contain polysorbate 80. In some embodiments, the composition is prepared within 24 hours prior to infusion into said patient. In some embodiments, the present invention provides a pharmaceutical composition prepared from a first liquid composition and a second aqueous composition, as further described.
  • the present invention provides a method of preparing a formulation (such as a pharmaceutical composition for infusion) comprising docetaxel and human serum albumin, the method comprising mixing the following two compositions, (a) a first liquid composition comprising docetaxel and ethanol; and (b) a second aqueous composition comprising human serum albumin and a parenterally acceptable carrier.
  • neither the first liquid composition nor the second aqueous composition comprises polysorbate 80, surfactants, or lipids (eg, soybean oil).
  • the two compositions are mixed less than about 24 hours, about 8 hours, about 4 hours, or about 1 hour prior to infusion or administration to the patient.
  • mixing of the two compositions is done in an infusion bag or bottle.
  • the first liquid composition is injected into the infusion bag or bottle containing the second aqueous composition.
  • a syringe is used to inject the first liquid composition into an infusion bag or bottle containing the second aqueous composition.
  • the first liquid composition comprises docetaxel and ethanol. In some embodiments, the first liquid composition comprises docetaxel, ethanol, and other organic solvents (eg, propylene glycol, polyethylene glycol 300, etc.). In some embodiments, the first liquid composition further comprises an acid (eg, 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 pharmaceutically acceptable salts thereof. In some embodiments, the first liquid composition is an ethanolic solution containing docetaxel.
  • an acid eg, citric acid
  • 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 pharmaceutically acceptable salts thereof.
  • the first liquid composition is an ethanolic solution containing docetaxel.
  • the weight ratio of docetaxel to citric acid in the first liquid composition is from about 5000:1 to about 1:1, from about 2000:1 to about 1:1, from about 1000:1 to about 1:1, from about 500:1 to about 1:1, from about 5000:1 to about 5:1, from about 2000:1 to about 5:1, from about 1000:1 to about 5:1, From about 500:1 to about 5:1, from about 5000:1 to about 10:1, from about 2000:1 to about 10:1, from about 1000:1 to about 10:1, from about 500:1 to About 10:1, from about 2000:1 to about 100:1, from about 1000:1 to about 100:1, from about 500:1 to about 100:1, or from about 500:1 to about 200:1.
  • 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.
  • the concentration of citric acid in the first liquid composition is from about 0.005 mg/ml to about 10 mg/ml, from about 0.01 mg/ml to about 2 mg/ml, from about 0.01 mg/ml to about 1 mg /ml, from about 0.02mg/ml to about 0.5mg/ml, from about 0.02mg/ml to about 0.2mg/ml.
  • the first liquid composition is prepared by dissolving docetaxel (and/or citric acid) in alcohol (eg, ethanol and/or propylene glycol).
  • the concentration of docetaxel in alcohol is from about 1 mg/ml to about 200 mg/ml, from about 5 mg/ml to about 100 mg/ml, from about 5 mg/ml to about 40 mg/ml, from about 10 mg/ml to about 50 mg/ml, from about 10 mg/ml to about 20 mg/ml, from about 10 mg/ml to about 30 mg/ml.
  • the concentration of docetaxel in the alcohol is about 10 mg/ml, about 15 mg/ml, about 20 mg/ml, or about 30 mg/ml.
  • the amount of docetaxel in the first liquid composition is from about 10 mg to about 300 mg or from 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 from about 0.5 ml to about 50 ml, from about 1 ml to about 20 ml, from about 1 ml to about 10 ml, or from about 3 ml to about 6 ml.
  • the first liquid composition is an injectable composition (eg, prepared or adapted for injection into an infusion bag or bottle comprising an aqueous composition comprising human serum albumin).
  • the first liquid composition is an injectable pharmaceutical formulation.
  • the concentration of docetaxel in the injectable pharmaceutical composition (pharmaceutical formulation) may be from about 5 mg/ml to about 40 mg/ml or from 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.
  • the pH of the injectable pharmaceutical composition is from about 3 to about 9, from about 3 to 8, from about 3 to 7, from about 3 to 6.5, from about 3.5 to 6.5, from about 3.5 to 6, from about 3.5 to about 5.5 or from about 4 to about 5.
  • the injectable pharmaceutical formulation in order to measure the pH of the injectable pharmaceutical formulation, is mixed with physiological saline at a ratio of 1:1 (v/v) to obtain an aqueous solution, and then the pH of the aqueous solution is tested.
  • concentration of docetaxel in the injectable pharmaceutical formulation is from about 5 mg/ml to about 40 mg/ml (for example about 20 mg/ml or about 10 mg/ml)
  • the pH of the composition is from about 3 to about 6.5 or from about 3.5 to about 5.5.
  • the second aqueous composition is prepared by adding a solution of human serum albumin to a parenterally acceptable carrier.
  • the second aqueous composition is prepared by adding an appropriate amount of human serum albumin solution to an infusion bag or bottle containing an appropriate amount of a parenterally acceptable carrier such as saline solution or glucose solution.
  • the second aqueous composition is prepared by adding 20%, 25%, or 5% commercially available human serum albumin for infusion solution (w/v) to saline solution or glucose solution.
  • the concentration of human serum albumin in the second aqueous composition is from about 0.1% to about 20% (w/v), from about 0.5% to about 10% (w/v), from about 0.5% % to about 15% (w/v), from about 0.5% to about 5% (w/v), from about 1% to about 10% (w/v), or from about 1% to about 3% (w/ v).
  • the second aqueous composition comprises from about 1 g to about 50 g of human serum albumin, from about 1 g to about 20 g, from about 2 g to about 10 g, or from about 2 g to about 20 g of human serum albumin.
  • the volume of the second aqueous composition is from about 100 ml to about 1 L. In some embodiments, the volume of the second aqueous composition is from about 250 ml to about 1 L. In some embodiments, the volume of the second aqueous composition is from about 250 ml to about 500 ml.
  • the injection of the first liquid composition is rapid in an infusion bag or bottle containing the second aqueous composition.
  • the injection time is not longer than 60 seconds, not longer than 30 seconds, not longer than 15 seconds, not longer than 10 seconds, not longer than 5 seconds, or not longer than 3 seconds.
  • no artificial shaking or agitation eg, intentional stirring
  • mixing the first liquid composition and the second aqueous composition well eg, gently invert the bag containing the composition by hand
  • the infusion bag or bottle containing the second aqueous composition remains stationary during the injection.
  • the first liquid composition is injected below the liquid surface of the second aqueous composition during injection.
  • the infusion bag or bottle is gently inverted repeatedly to uniformly mix the first liquid composition and the second aqueous composition.
  • a clear, precipitate-free infusion solution can be obtained by simply inverting the infusion bag or bottle gently (eg, about 5-30 times).
  • the mixing time can be, for example, from about 5 seconds to about 10 minutes, from about 5 seconds to about 3 minutes, from about 5 seconds to about 2 minutes, or from about 0.1 minute to about 1 minute.
  • injecting the first liquid composition into an infusion bag or bottle containing the second aqueous composition and then mix the first liquid composition and the second aqueous composition uniformly to obtain the parenterally acceptable carrier
  • no human agitation eg, stirring
  • injecting the first liquid composition into the infusion bag or bottle containing the second aqueous composition is accomplished at ambient temperature.
  • the present invention provides a process for the preparation of a clear (eg, precipitation-free) infusion composition for parenteral administration of docetaxel as described herein.
  • An embodiment of the preparation method is as follows:
  • human serum albumin solution such as commercially available and clinically used 20%, 25% or 5% human serum albumin solution for infusion (w/v)
  • parenteral administration-acceptable carrier such as physiological saline solution or glucose solution
  • An embodiment of the method is as follows, for example the method includes:
  • a first liquid composition (such as the method comprising obtaining a first liquid composition of a solution of docetaxel and acid in ethanol or a mixed solvent comprising ethanol);
  • a second aqueous composition e.g., the method comprises obtaining an infusion bag or bottle of a second aqueous composition comprising a solution comprising HSA and a parenterally acceptable carrier;
  • human serum albumin solution such as 20%, 25% or 5% human serum albumin solution for infusion (w/v) used clinically
  • parenterally acceptable carrier such as normal saline solution or glucose solution
  • the infusion bag or bottle usually does not require human mixing or agitation during the injection (e.g. the method includes injecting the first liquid injecting the composition into an infusion bag or bottle containing the second aqueous composition without artificially mixing the composition and/or without agitating the infusion bag or bottle (e.g., by keeping the infusion bag or bottle stationary); and
  • the formulation thus obtained can be dosed with docetaxel at the necessary dosage level, e.g., from about 50 mg/m to about 150 mg/ m , to a cancer patient based on the individual patient's body surface area (“BSA”) medication.
  • BSA body surface area
  • the formulation can be dosed at 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 of docetaxel Dosing.
  • the invention also 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.
  • the method comprises parenterally administering to a subject in need thereof a therapeutically effective amount of a liquid infusion formulation of the invention.
  • the formulation may comprise or may be configured to be about 50 mg/m 2 , about 60 mg/m 2 , about 75 mg/m 2 , about 90 mg/m 2 , about 100 mg based on the patient's BSA (body surface area) /m 2 or about 120 mg/m 2 dose of docetaxel was administered to the patient .
  • BSA body surface area
  • body surface area refers to the measured or calculated surface area of the human body. This measurement is often used as an indicator of metabolic mass rather than body weight.
  • the table below shows body surface area for typical heights and weights. Calculate with DuBois&DuBois formula: (weight (kg)) 0.425 ⁇ (height (cm)) 0.725 ⁇ 0.007184. Weight is on the horizontal axis, first in pounds and then in kilograms. Height is the vertical axis, first in inches and then in centimeters. The result is body surface area in square meters. Typical BSAs are provided in the table below.
  • cancer patients have an average BSA of about 1.73 m 2 .
  • the infusion bag or bottle when the formulation described herein is infused into a patient, contains the required dose of docetaxel according to the patient's body surface area after injection of a predetermined amount of the first liquid composition, for example containing About 75mg/ m2 of docetaxel.
  • multiple infusion bags or bottles are used to prepare the required infusion formulation containing the dose of docetaxel required for one infusion to the patient.
  • the dose of docetaxel in the infusion bag is about 150 mg.
  • the infusion time is from about 1 hour to about 2 hours. In some embodiments, the infusion time is about 1 hour.
  • the fluid infusion flow rate can be determined and/or adjusted according to the desired infusion time (eg, 1 hour).
  • one infusion bag or bags eg, 2 infusion bags
  • the desired dose for example a dose of about 75 mg/ m2
  • the concentration of docetaxel in the infusion bag is from about 0.1 mg/ml to about 0.5 mg/ml.
  • the concentration of docetaxel in the infusion bag is from about 0.15 mg/ml to about 0.4 mg/ml.
  • 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 infusion solution can be determined according to the concentration of docetaxel in the infusion bag. For example, if the required dose is an infusion (treatment) of 120 mg of docetaxel and the concentration of docetaxel in the infusion bag is 0.25 mg/ml, the total volume of infusion solution in the infusion bag will be 480 ml.
  • the amount of infusion solution required by the patient for one infusion can be contained in one infusion bag or a plurality of infusion bags (eg, 2 infusion bags).
  • one infusion bag may contain about 450 mL of an infusion solution containing about 90 mg of docetaxel at a docetaxel concentration of about 0.20 mg/ml.
  • two infusion bags can contain a total of about 600 mL of an infusion solution containing about 150 mg of docetaxel at a concentration of about 0.25 mg/mL of docetaxel.
  • cancer is selected from the group consisting of sarcoma, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, teratoma, non-small cell lung cancer (NSCLC), bronchial Squamous cell carcinoma, small cell undifferentiated carcinoma, large cell undifferentiated carcinoma, adenocarcinoma, alveolar bronchiole carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal carcinoma, Esophageal carcinoma, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, gastric carcinoma, carcinoma, lymphoma, leiomyosarcoma, pancreatic carcinoma, ductal
  • the cancer is a solid tumor cancer.
  • solid tumors include: breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, and melanoma.
  • 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., squamous cell carcinoma of the head and neck) .
  • the methods of the present invention for treating cancer comprise administering docetaxel in combination with another anticancer therapeutic agent.
  • additional anticancer therapeutic agents include doxorubicin, cyclophosphamide, cisplatin, prednisone, and fluorouracil, or combinations thereof. These additional anticancer therapeutic agents may be administered sequentially (before or after) or simultaneously with the docetaxel formulation of the present claims. In some embodiments, the additional anticancer therapeutic agent may be administered at a dose of about 50 mg/m 2 to about 750 mg/m 2 according to the exact diagnosis of the patient and the recommendation of the treating physician.
  • the 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:
  • Docetaxel dose as required eg, 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 according to the patient's BSA m2 dose of docetaxel
  • dose eg, 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 according to the patient's BSA m2 dose of docetaxel
  • the 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:
  • a dose containing the desired docetaxel e.g. about 50 mg/m 2 , about 60 mg/m 2 according to the patient's BSA , about 75 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , or about 120 mg/m 2 of docetaxel dosage
  • a dose containing the desired docetaxel e.g. about 50 mg/m 2 , about 60 mg/m 2 according to the patient's BSA , about 75 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , or about 120 mg/m 2 of docetaxel dosage
  • step (i) administering the preparation obtained in step (i) to subjects in need according to the required dose of docetaxel.
  • a desired dose of docetaxel is included (e.g., 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 a docetaxel dose of about 120 mg/m 2 ) can be prepared in multiple infusion bags or bottles (eg, in 2 infusion bags or bottles).
  • kits for preparing the formulations for infusion described herein comprising: a first container containing a composition comprising docetaxel; and a second container containing a composition comprising human serum albumin.
  • the kit comprises a first container comprising a liquid composition comprising docetaxel and a second container comprising a liquid composition comprising human serum albumin.
  • the kit includes a first container containing a liquid composition comprising docetaxel and ethanol and a second container containing a liquid composition comprising human serum albumin.
  • the kit includes 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.
  • the kit includes 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.
  • the kit comprises a first container comprising a liquid composition comprising docetaxel, citric acid and ethanol and a solution comprising human serum albumin (e.g., 20%, 25% or 5% (w/v )) for the second container.
  • both the liquid composition in the first container and the liquid composition in the second container are sterile solutions.
  • the ethanol contained in the first container is absolute ethanol.
  • the first container contains a liquid composition comprising docetaxel and ethanol.
  • the first container contains a liquid composition comprising docetaxel, acid, and ethanol.
  • the first container contains a liquid composition comprising docetaxel, an organic acid, and ethanol.
  • the first container contains a liquid composition comprising docetaxel, ethanol, and other organic solvents (eg, alcohols such as propylene glycol or polyethylene glycol 300, etc.).
  • the first container contains a liquid composition comprising docetaxel, citric acid, and ethanol.
  • the first container contains an ethanolic solution comprising docetaxel. In some embodiments, the first container contains an ethanolic solution comprising docetaxel and citric acid. In some embodiments, the concentration of citric acid in the first container is from about 0.005 mg/ml to about 10 mg/ml. In some embodiments, the concentration of citric acid in the first container is from about 0.01 mg/ml to about 2 mg/ml. In some embodiments, the concentration of citric acid in the first container is from about 0.01 mg/ml to about 1 mg/ml. In some embodiments, the concentration of citric acid in the first container is from about 0.02 mg/ml to about 0.5 mg/ml. In some embodiments, the concentration of citric acid in the first container is from about 0.02 mg/ml to about 0.2 mg/ml.
  • the amount of docetaxel contained in the first container is from about 10 mg to about 300 mg of docetaxel. In some embodiments, the amount of docetaxel contained in the first container is from 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 from about 0.5 ml to about 50 ml of ethanol. In some embodiments, the amount of ethanol contained in the first container is from about 1 ml to about 20 ml of ethanol.
  • the amount of ethanol contained in the first container is from about 1 ml to about 10 ml of ethanol. In some embodiments, the amount of ethanol contained in the first container is from about 1 ml to about 5 ml of ethanol. In some embodiments, the amount of ethanol contained in the first container is from about 5 ml to about 10 ml of ethanol. In some embodiments, the concentration of docetaxel in the first container is from about 5 mg/ml to about 100 mg/ml. In some embodiments, the concentration of docetaxel in the first container is from 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.
  • an injectable pharmaceutical product comprising a first liquid composition described herein is contained in a first container.
  • the injectable pharmaceutical formulation product of the first liquid composition described herein is contained in the first container in an amount of from about 0.5 milliliters to about 30 milliliters.
  • the injectable pharmaceutical formulation product of the first liquid composition described herein is contained in the first container in an amount of from about 1 milliliter to about 20 milliliters.
  • the injectable pharmaceutical product of the first liquid composition described herein is contained in the first container in an amount of from about 1 milliliter to about 10 milliliters.
  • the injectable pharmaceutical formulation product of the first liquid composition described herein is contained in the first container in an amount of about 1 milliliter, about 2 milliliters, about 4 milliliters, about 6 milliliters, and about 8 milliliters.
  • the first container comprises about 80 mg of docetaxel. In some embodiments, the first container comprises about 80 mg docetaxel and about 4 ml ethanol.
  • the second container contains a liquid composition comprising human serum albumin. In some embodiments, the second container contains a solution of human serum albumin. In some embodiments, the second container contains a solution of human serum albumin, wherein the concentration of human serum albumin in the solution is from about 1% to about 25% (w/v). In some embodiments, the second container contains a solution of human serum albumin, wherein the concentration of human serum albumin in the solution is from about 5% to about 25% (w/v). In some embodiments, the second container contains a solution of human serum albumin for infusion. In some embodiments, the second container contains a 20% human serum albumin solution (w/v) for infusion.
  • 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.
  • 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.
  • 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 comprises about 80 mg docetaxel and about 4 ml ethanol.
  • the 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 kit includes a first container containing about 80 mg of docetaxel and a second container containing about 10 g of human serum albumin.
  • the desired amount of the first liquid composition is withdrawn from one or more first containers with a syringe and injected into an infusion bag or bottle containing a corresponding amount of the second aqueous composition to prepare the infusion described herein. Preparation for injection.
  • the present invention provides for the preparation of a docetaxel composition for infusion for the treatment of cancer (e.g., breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer) in a subject.
  • cancer e.g., breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, head and neck cancer
  • An embodiment of the preparation method is as follows:
  • human serum albumin solution such as commercially available and clinically used 20%, 25% or 5% human serum albumin solution for infusion (w/v) from one or more second containers with a syringe )
  • an acceptable carrier for parenteral administration such as physiological saline solution or glucose solution
  • the first and second steps of preparation can be performed simultaneously or in a different order.
  • the infusion preparation containing the dose of docetaxel required for infusion obtained in the fourth step can be infused and administered to subjects in need.
  • docetaxel is administered to a cancer patient at a dose of from about 50 mg/ m2 to about 150 mg/ m2 based on the body surface area ("BSA") of the individual patient.
  • the formulation can be dosed at 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 of docetaxel Dosing.
  • the formulation can be administered at a dose of docetaxel of about 75 mg/ m2 .
  • the kit further includes instructions for preparing the infusion formulation (composition) described herein.
  • Winthrop (docetaxel) injection is An authorized generic of Docetaxel, available from Winthrop US, a subsidiary of Sanofi-Aventis US, is a solution of docetaxel at 20 mg/mL in ethanol and polysorbate 80.
  • a 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 citric acid to adjust the pH.
  • each patient was infused with the final infusion solution of the reference preparation with a concentration of 0.3 mg/ml and a dose of 75 mg/ m2 of docetaxel.
  • the preparation method of the infusion solution (preparation) of the reference preparation is as follows:
  • the dose of docetaxel in the infusion bag is about 150 mg.
  • the docetaxel infusion solution should be administered as a 1-hour infusion completed intravenously at ambient room temperature (below 25°C) and under light conditions.
  • BH009 is developed as a polysorbate 80-free docetaxel injection product.
  • BH009 is prepared as a sterile injectable product (20 mg/ml solution of docetaxel in ethanol).
  • the BH009 drug kit includes a vial containing 80mg (docetaxel)/4ml BH009 drug (docetaxel injection) and a commercially available 20% human albumin solution (50ml ) vials.
  • Each 4ml of BH009 medicine (docetaxel injection) contains 80mg of docetaxel (anhydrous) and 3156mg of absolute ethanol, and citric acid is used to adjust the pH.
  • each patient was infused with an infusion solution containing docetaxel at a concentration of 0.25 mg/ml and a dose of 75 mg/m 2 of the test preparation.
  • the volume ratio of the BH009 medicine (docetaxel injection) used in the preparation, 20% human albumin solution and 0.9% sodium chloride injection for infusion is 1: 7.5:71.5 (v/v).
  • the preparation method of the infusion solution (preparation) of the test preparation is as follows:
  • the dose of docetaxel in the infusion bag is about 150 mg.
  • ⁇ Use a syringe to inject 56.25ml of 20% human albumin solution for infusion into an infusion bag or bottle containing 536.25ml of 0.9% sodium chloride solution.
  • the resulting albumin-saline solution is then thoroughly mixed by gently manually inverting the infusion bag or bottle up and down about 10 times.
  • ⁇ BH009 infusion solution (test formulation) should be administered intravenously as a 1-hour infusion at ambient room temperature (below 25°F) and light.
  • a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the assessment of total docetaxel in human plasma using a liquid-liquid extraction technique.
  • the method utilizes triple quadrupole mass spectrometry in electrospray positive ionization mode to monitor docetaxel.
  • docetaxel-d9 was used as an internal standard (IS).
  • extraction solvent use mobile phase buffer (aqueous solution containing 0.1% v/v of acetic acid) on chromatographic column (model, Gemini5 ⁇ m C18 150x4.6mm): methanol, 30:70v/v in isogradient Separation at a flow rate of 1.000 mL/min under conditions.
  • Quantification of docetaxel and docetaxel-d9 was performed using multiple reaction monitoring mode (MRM).
  • MRM multiple reaction monitoring mode
  • the method is suitable for the determination of total docetaxel in K 3 EDTA human plasma within the linear range of 10.000ng/mL (LLOQ) to 6000.000ng/mL (ULOQ) using 0.200mL of human plasma.
  • LLOQ 10.000ng/mL
  • UOUQ 6000.000ng/mL
  • the reliability of the method was verified for the analysis of 10-fold diluted samples (up to 27000.000ng/mL).
  • a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the assessment of free docetaxel in human plasma was developed using a liquid-liquid extraction technique.
  • the method utilizes triple quadrupole mass spectrometry in electrospray positive ionization mode to monitor docetaxel.
  • docetaxel-d9 was used as an internal standard (IS).
  • IS internal standard
  • Plasma samples were filtered by an ultrafiltration device (centrifugal filter 1.0 mL, 30 KDa) for direct measurement of unbound docetaxel concentrations.
  • docetaxel is extracted with an extraction solvent, use mobile phase buffer (aqueous solution containing 0.1% v/v of acetic acid):methanol, 30:70v/v on a chromatographic column (model, Gemini 5 ⁇ m C18 150x4.6mm) Separation at a flow rate of 1.000 mL/min under gradient conditions.
  • Quantification of docetaxel and docetaxel-d9 was performed using multiple reaction monitoring mode (MRM).
  • MRM multiple reaction monitoring mode
  • the method is suitable for the determination of free docetaxel in K3EDTA human plasma within the linear range of 10.000ng/mL (LLOQ) to 600.000ng/mL (ULOQ) with 0.200mL of human plasma. The reliability of the method was verified for the analysis of 10-fold diluted samples (up to 8000.000ng/mL).
  • Inclusion criteria age ⁇ 18 years old, gender is not limited; patients with solid tumors confirmed by histology or cytology, plan to receive docetaxel monotherapy at a dose of 75mg/m 2 , or have already received docetaxel monotherapy Treatment (these drugs are limited to or approved for marketing The generic drug of the drug), and the dose is 75mg/m 2 , and the solid tumor patients who continue to receive ⁇ 2 courses of treatment at the same dose according to the actual treatment plan; ECOG physical status score is 0 or 1, and the expected survival time ⁇ 3 months; with sufficient hematopoietic, renal and liver functions (bone marrow function: ANC ⁇ 1500/mm 3 , platelet count ⁇ 100,000/mm 3 , hemoglobin>9.0g/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; full Dose anticoagulant; patient recovered from adverse events related to prior anticancer therapy to grade 0-1 (according to CTCAE 5.04 criteria), except alopecia and endocrine disease controlled by hormone replacement therapy.
  • Exclusion criteria Allergic or atopic 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 (such as tuberculosis, sepsis, or opportunistic infection), severe pleural effusion, and/or peripheral neuropathy ⁇ grade 2; hepatitis B surface antigen and hepatitis C (HCV) Viral antibody-positive patients, HIV-infected patients, patients with known brain metastases or neurological symptoms due to brain metastases; pregnant or lactating women, etc.
  • 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 (such as tuberculosis,
  • Cycle I (Day 1): On the first day of chemotherapy, the patient will receive an intravenous infusion of 75 mg/m 2 of docetaxel (test preparation or reference preparation).
  • Cycle II (Day 22): On Day 1 of the start of the second chemotherapy, patients will be cross-administered with another docetaxel formulation 75 mg/m 2 (test formulation or reference formulation). All patients should be given oral corticosteroids, such as dexamethasone 16 mg/day (e.g., 8 mg/time, twice daily) 1 day before docetaxel administration, for 3 days to reduce the incidence and severity of fluid retention. and severity of allergic reactions.
  • dexamethasone 16 mg/day e.g., 8 mg/time, twice daily
  • prophylactic granisetron antiemetic
  • ondansetron antiemetic 4-8 mg IV prior to study drug infusion (approximately 30 minutes prior to dosing) .
  • Prophylactic antiallergic treatment and G-CSF were allowed at the discretion of the investigator.
  • the preventive treatment and dosage should be the same before administration of the two cycles.
  • test preparation BH009 and the reference preparation Winthrop (docetaxel) injection (for authorized generic drug) is bioequivalent in patients with advanced solid tumors.
  • the 90% confidence intervals for AUC0 -t , AUC0 - ⁇ , and Cmax for total docetaxel were 91.89%-107.18%, 91.10%-106.04%, and 92.18%-108.00%, respectively; AUC for free docetaxel
  • the 90% confidence intervals for 0-t , AUC 0- ⁇ and C max were 89.98%-103.15%, 90.24%-102.75% and 85.22%-101.70%, respectively.
  • the 90% confidence intervals for AUC 0-t , AUC 0- ⁇ and C max for total and free docetaxel were all within the bioequivalence (BE) range (80%-125%).
  • the safety analysis data showed that the test preparation BH009 was well tolerated in the human body; the incidence of hematological toxicity in the test preparation group (BH009) was significantly lower than that in the reference preparation group (Winthrop (docetaxel) injection) (See Table 6).
  • the most common grade 3/4 toxicities in the trial were neutropenia, anemia, lymphopenia, and leukopenia, and the grade 3/4 hematological toxicity in the test formulation group was significantly reduced compared with the reference formulation group (R /T: 15.9% vs 2.3%), especially in neutropenia 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%.
  • Table 4 BE results of the main pharmacokinetic parameters of the total docetaxel of the test preparation BH009 and the reference preparation Winthrop (docetaxel) injection
  • Table 5 BE results of the main pharmacokinetic parameters of free docetaxel of the test preparation BH009 and the reference preparation Winthrop (docetaxel) injection

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Abstract

本申请提供了含有多西他赛和人血清白蛋白的药物组合物。该组合物具有不包含任何聚山梨酯80表面活性剂的优势，并且可以用于以75mg/m 2的剂量向患者输注多西他赛。该组合物可用于治疗癌症，例如乳腺癌、非小细胞肺癌、前列腺癌、胃癌或头颈癌。

Description

多西他赛组合物和方法 技术领域
本发明涉及用于治疗癌症的多西他赛制剂。本发明尤其涉及含有多西他赛和人血清白蛋白(“HSA”)的制剂，其可用于治疗患有乳腺癌、非小细胞肺癌、前列腺癌(例如去势抵抗性前列腺癌)、胃癌(例如腺癌)或者头颈癌(如头颈部鳞状细胞癌)的患者。
背景技术
许多肠道外用药物不溶于水，因此向患者给药时与有刺激性的、引起过敏症的或有毒的增溶剂、表面活性剂、溶剂和/或乳化剂一起配制。参见例如Briggs et al.,Anesthesis 37,1099(1982)和Waugh et al.,Am.J.Hosp.Pharmacists,48,1520(1991))。而且，这些药物中的许多药物，尤其那些通过静脉内给药的药物，引起不良副作用例如静脉刺激、静脉炎、注射时灼痛和疼痛、静脉血栓形成、外渗和其他给药相关的副作用。
紫杉烷类在各种实体瘤的治疗中发挥着重要作用。作为第二代半合成紫杉烷衍生物，多西他赛在抑制微管解聚是紫杉醇的约两倍活性，并且具有改变某些类别微管的独特能力，这与目前临床应用的大多数纺锤体毒物不同。然而，多西他赛具有非常差的水溶性。市售的两瓶装多西他赛制剂
Figure PCTCN2022078020-appb-000001
的临床静脉给药是配制成一个高浓度溶液，该高浓度溶液每毫升含有40mg多西他赛和1040mg聚山梨酯80。该浓溶液在给药前必须用盐水中含有13％乙醇的溶剂小心稀释。据报道，多西他赛临床使用与不可预测(急性)超敏反应和累积液体潴留的发生有关。参见例如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。这些副作用部分归因于聚山梨酯80的存在。聚山梨酯80是一种合成的非离子表面活性剂，用作药物制剂中的稳定剂。在未接受前药的患者中，具有聚山梨酯80的多西他赛(Taxotere)的超敏反应报告率估计为30％。在使用前药时，具有聚山梨酯80的多西他赛(Taxotere)的超敏反应报告率范围从8％到13％。参见Taxotere处方信息。据报道，在给予预防疗法后，因含聚山梨酯80的多西他赛过敏反应的死亡事故仍然发生。这增加了研制不含聚山梨酯80的多西他赛制剂的重要性。
目前，在主要医药市场(例如美国、欧盟、中国和日本)尚未批准不含聚山梨酯80的多西他赛产品用于临床。迫切需要研发新的不含聚山梨酯80的具有更好的临床应用安全性的多西他赛产品。本发明中描述的制剂和方法有助于满足这个需求。
发明概述
目前市售的
Figure PCTCN2022078020-appb-000002
制剂包括单瓶装制剂或两瓶装制剂(包含注射剂和稀释剂)。单瓶装制剂是一个包含多西他赛在聚山梨酯80和乙醇中的溶液。两瓶装制剂包含一个多西他赛在聚山梨酯80中的溶液和一个其中含有乙醇水性溶液的溶剂的西林瓶。
虽然单瓶装和两瓶装形式的Taxotere都各有优缺点，但两种制剂都含有大量的聚山梨酯80，这会给一些患者导致严重超敏反应，并且与
Figure PCTCN2022078020-appb-000003
制剂最常见的不良事件有关。有利地，本发明的制剂不使用任何有毒表面活性剂制备，但它们与商业化的
Figure PCTCN2022078020-appb-000004
制剂 具有生物等效。因为如此，该制剂在临床使用中允许实现与
Figure PCTCN2022078020-appb-000005
制剂相同或相似的治疗效果，同时避免
Figure PCTCN2022078020-appb-000006
制剂中聚山梨酯表面活性剂引起的相关不良事件。特别地，该制剂允许以约75mg/m 2剂量的多西他赛给药，以治疗多种癌症，例如乳腺癌、非小细胞肺癌、前列腺癌、胃癌或头颈癌。此外，本权利要求中的制剂仅包含容易获得、相对便宜的成分，例如人血清白蛋白、乙醇和柠檬酸，所有这些成分分别由监管机构例如FDA或EMA批准用于药物使用。
在WO2021/158632中描述了包含多西他赛、人血清白蛋白和乙醇的制剂。
在一个总体方面，本发明提供了包括多西他赛和人血清白蛋白的输注用药物组合物，
其中该组合物是通过将包含多西他赛和乙醇的第一液体组合物注入到含有包含在肠道外给药可接受载体中的人血清白蛋白的第二水性组合物的输注袋或瓶中制备而成，
其中该组合物不含聚山梨酯80，
其中该组合物通过输注给药用于治疗诊断为选自乳腺癌、非小细胞肺癌、前列腺癌、胃癌和头颈癌的实体瘤的患者，
其中输注给有此需要的所述患者的多西他赛剂量为约75mg/m 2，以及
其中该组合物是在输注给所述患者前24小时内制备的。
在一些实施方式中，该组合物是在输注给所述患者前4小时内制备的。
在一些实施方式中，第一液体组合物是无菌溶液。
在一些实施方式中，第二水性组合物是无菌溶液。
在一些实施方式中，该组合物中多西他赛的浓度为约0.05mg/ml至约0.5mg/ml。
在一些实施方式中，该组合物中多西他赛的浓度为约0.1mg/ml至约0.4mg/ml。
在一些实施方式中，该组合物中多西他 赛的浓度为约0.20mg/ml。
在一些实施方式中，该组合物中多西他 赛的浓度为约0.25mg/ml。
在一些实施方式中，该组合物中多西他 赛的浓度为约0.30mg/ml。
在一些实施方式中，该组合物中人血清白蛋白的浓度为约0.01％至约20％(w/v)。
在一些实施方式中，该组合物中人血清白蛋白的浓度为约0.1％至约10％(w/v)。
在一些实施方式中，该组合物中人血清白蛋白的浓度为约0.2％至约5％(w/v)。
在一些实施方式中，该组合物中人血清白蛋白的浓度为约0.5％至约2.5％(w/v)。
在一些实施方式中，该组合物是澄明水性输注溶液。
在一些实施方式中，该组合物按每3周1个新的周期重复给药用于所述患者。
在一些实施方式中，该组合物 按多西他赛剂量为75mg/m 2给药。
在一些实施方式中，该组合物给药用于治疗诊断为乳腺癌的所述患者。
在一些实施方式中，该组合物给药用于治疗被诊断为局部晚期或转移性乳腺癌的所述患者。
在一些实施方式中，该组合物给药用于乳腺癌的辅助治疗。
在一些实施方式中，该组合物给药用于治疗诊断为非小细胞肺癌的所述患者。
在一些实施方式中，该组合物给药用于治疗诊断为局部晚期或转移性非小细胞肺癌的所述患者。
在一些实施方式中，该组合物给药用于治疗诊断为前列腺癌的所述患者。
在一些实施方式中，该组合物给药用于治疗诊断为转移性去势抵抗性前列腺癌的所述患者。
在一些实施方式中，该组合物给药用于治疗诊断为胃癌的所述患者。
在一些实施方式中，该组合物给药用于治疗诊断为晚期胃腺癌的患者，包括胃食管结合部肿瘤患者。
在一些实施方式中，该组合物给药用于治疗患有头颈癌的所述患者。
在一些实施方式中，该组合物给药用于局部晚期头颈部鳞状细胞癌的诱导治疗。
除非另有定义，本文中使用的所有技术和科学术语都具有与本申请所属领域普通技术人员通常理解相同的含义。本文中描述的方法和材料用于本申请；另外，本领域中已知的合适的方法和材料也可以使用。材料、方法和实施例只是解释性的，并不意在限制。本文中所提及的所有出版物、专利申请、专利、序列、数据库条目和其他参考资料全文以引用方式并入。如有冲突，以本说明书包括定义为准。
本申请的其他特点和优点将从以下详述和图表以及从权利要求中显现。
附图说明
图1是BH009和Winthrop(Taxotere授权仿制药)(多西他赛)注射剂用于晚期实体瘤患者给药后总多西他赛平均浓度与时间曲线的线图。
图2是BH009和Winthrop(Taxotere授权仿制药)(多西他赛)注射剂用于晚期实体瘤患者给药后游离多西他赛平均浓度与时间曲线的线图。关于图1和图2，“R”代表参比制剂(Winthrop注射剂)，“T”代表受试制剂(BH009)。
发明详述
在一个总体方面，本文提供的是含有多西他赛和人血清白蛋白的药物制剂。该制剂一般可以通过肠道外途径向有此需要的受试者给药。术语“肠道外”是指选自皮下注射(“SC”)、静脉注射(“IV”)、肌肉注射(“IM”)、皮内注射(“ID”)、腹腔注射(“IP”)等的途径。在一个实施例中，如本文所述，该制剂可以通过静脉输注例如通过输注袋或瓶向受试者给药。
在一些实施方式中，该制剂包括多西他赛、人血清白蛋白、酸、乙醇和液体载体(例如肠道外给药可接受的载体)。在一些实施方式中，该制剂包括多西他赛、人血清白蛋白、柠檬酸、乙醇和液体载体(例 如肠道外给药可接受的载体)。在一些实施方式中，该制剂包含在输注袋或瓶中。在一些实施方式中，该制剂在输注袋或瓶中制备得到。
在一些实施方式中，该制剂的pH值为约4至约9.5。在一些实施方式中，该制剂的pH值为约5至约9。在一些实施方式中，该制剂的pH值为约6至约8。在一些实施方式中，该制剂的pH值为约6.5至约7.5。在一些实施方式中，该制剂的pH值为约4至约9。在一些实施方式中，该制剂的pH值为约5至约8.5。在一些实施方式中，该制剂的pH值为约6至约7.5。
在一些实施方式中，该制剂基本上没有任何表面活性剂。在一些实施方式中，该制剂基本上没有聚山梨酯80。在一些实施方式中，该制剂含有不超过约1ppm或约1ppb的表面活性剂(例如聚山梨酯80)。在一些实施方式中，该制剂不含聚山梨酯80。在一些实施方式中，所述药物制剂不包含脂质(例如大豆油)。
如本文中使用的术语“多西他赛”是指具有CAS No.114977-28-5和以下化学结构的化合物：
Figure PCTCN2022078020-appb-000007
或其药学上可接受的盐。多西他赛是白色至近乎白色粉末。该化合物具有高度的亲酯性且几乎不溶于水。多西他赛是一种适用于治疗乳腺癌、非小细胞肺癌、激素难治性前列腺癌、胃腺癌和头颈部鳞状细胞癌的微管抑制剂。本文使用的术语“多西他 赛”包括多西他赛化合物游离碱或游离酸(例如，如上描绘的化学结构，或其任何互变异构体)的任何药学上可接受的盐。通常地，药学上可接受的盐是那些保留所指化合物所要的生物活性并表现出最小的不良毒理作用的盐。这些药学上可接受的盐可以在化合物的最后分离和纯化过程中原位制备，或者单独地将游离酸或游离碱形式的纯化的化合物分别与合适的碱或酸反应而制备。该盐可以赋予分子更大的稳定性或溶解性，从而使得在当前权利要求范围内的制剂的制备更加便利。多西他赛的药学上可接受的酸加成盐的合适实例包括胆汁酸加成盐、盐酸盐、氢溴酸盐、硝酸盐、硝酸甲酯盐、硫酸盐、硫酸氢盐、氨基磺酸盐、磷酸盐、醋酸盐、羟基醋酸盐、苯醋酸盐、丙酸盐、丁酸盐、异丁酸盐、戊酸盐、马来酸盐、羟基马来酸盐、 丙烯酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、水杨酸盐、对氨基水杨酸盐、乙醇酸盐、乳酸盐、庚酸盐、邻苯二甲酸盐、草酸盐、琥珀酸盐、苯甲酸盐、邻乙酰氧基苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、扁桃酸盐、丹宁酸盐、甲酸盐、硬脂酸盐、抗坏血酸盐、棕榈酸盐、油酸盐、丙酮酸盐、双羟萘酸盐、丙二酸盐、月桂酸盐、戊二酸盐、谷氨酸盐、丙酸酯十二烷基硫酸盐、甲基磺酸盐(甲磺酸盐)、乙基磺酸盐(乙磺酸盐)、2-羟基乙烷磺酸盐，苯基磺酸盐(苯磺酸盐)、对氨基苯基磺酸盐、对甲苯基磺酸盐(甲苯磺酸盐)、萘-2-磺酸盐、乙二磺酸盐、二硫化氢盐、酒石酸氢盐、葡萄糖酸盐、葡糖醛酸盐、对溴苯基磺酸盐、碳酸盐、焦硫酸盐、亚硫酸盐、亚硫酸氢盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、癸酸盐、辛酸盐、癸酸盐、丙炔酸盐、癸二酸盐、癸二酸盐、丁炔-1,4-二酸盐、己炔-l,6-二酸盐、对苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯基丙酸盐、苯基丁酸盐、β-羟基丁酸盐、乙醇酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和2,5-二羟基苯甲酸盐。药学上可接受的碱加成盐的合适实例包括碱金属包括钠、钾和锂的氢氧化物；碱土金属例如钙和镁的氢氧化物；其他金属例如铝和锌的氢氧化物；氨，有机胺例如未取代或羟基取代的单烷基、二烷基或三烷基胺，二环己基胺；三丁胺；吡啶；N-甲基、N-乙基胺；二乙胺；三乙胺；单、双或三-(2-羟基-(C1-C6)-烷基)胺，例如N,N-二甲基-N-(2-羟乙基)胺或三-(2-羟乙基)胺；N-甲基-D-葡糖胺；吗啉；硫代吗啉；哌啶；吡咯烷；以及氨基酸例如精氨酸或赖氨酸。
在一些实施方式中，多西他赛可以包括1、2或3当量的水合溶剂化物。在一些实施方式中，多西他赛是包括三当量水的溶剂化物。在一些实施方式中，多西他赛是多西他赛三水合物、多西他赛一水合物或多西他赛无水物。在一些实施方式中，多西他赛含有一当量丙酮溶剂化物。在一些实施方式中，多西他赛可以是例如在WO2010091650或US2012007167中披露的多西他赛溶剂化物的任何一种，其披露内容全文以引用方式并入本文中。在一些实施方式中，多西他赛是结晶的。在一些实施方式中，多西他赛是例如WO2012115402、US8410294、US20100197944、US20100099897、US8357811、US20100160653或US20070142457中披露的任何一种结晶形式，其披露内容全文以引用方式并入本文中。在一些实施方式中，多西他赛是非结晶的。在一些实施方式中，多西他赛是例如在WO2008102374中披露的任何一种非晶形式，其披露内容全文以引用方式并入本文中。
在一些实施方式中，该制剂中多西他赛的浓度为从约0.05mg/ml至约1mg/ml、从约0.1mg/ml至约0.8mg/ml、从约0.05mg/ml至约0.75mg/ml、从约0.1mg/ml至约0.5mg/ml、从约0.1mg/ml至约0.35mg/ml、从约0.15mg/ml至约0.4mg/ml、从约0.2mg/ml至约0.3mg/ml、从约0.2mg/ml至约0.4mg/ml、从约0.2mg/ml至约0.35mg/ml、从约0.25mg/ml至约0.35mg/ml或从约0.5mg/ml至约0.75mg/ml。在一些实施方式中，该制剂中多西他赛的量(或浓度)为约0.05mg/ml、约0.1mg/ml、约0.15mg/ml、约0.2mg/ml、约0.25mg/ml、约0.3mg/ml、约0.35mg/ml、约0.4mg/ml、约0.45mg/ml、约0.5mg/ml、约0.6mg/ml、约0.74mg/ml、约0.75mg/ml、约0.8mg/ml或约1mg/ml。在一些实施方式中，该制剂包含从约10mg至约300mg、从约20mg至约200mg、从约50mg至约250mg、从约60mg至约 240mg、从约100mg至约200mg、从约120mg至约200mg或从约100mg至约175mg的多西他赛。在一些实施方式中，该制剂包含约20mg、约40mg、约80mg、约120mg、约150mg、约160mg、约175mg、约200mg或约250mg的多西他赛。在一些实施方式中，该制剂，例如基于患者个人的体表面积(“BSA”)，包含相当于从约50mg/m 2至约150mg/m 2给药剂量的多西他赛。在一些实施方式中，该制剂，例如基于患者个人的体表面积(“BSA”)，包含相当于约50mg/m 2、约60mg/m 2、约75mg/m 2、约90mg/m 2、约100mg/m 2或约120mg/m 2给药剂量的多西他赛。例当患者的体表面积为2.0，多西他赛给药剂量为约75mg/m 2时，该制剂包含约150mg多西他赛。
如本文中使用的，术语“人血清白蛋白”是指天然和重组人血清白蛋白。在一些实施方式中，人血清白蛋白是天然人血清白蛋白。在一些实施方式中，人血清白蛋白是重组人血清白蛋白。
天然人血清白蛋白和其他血浆蛋白可以通过改变pH和添加乙醇从人体血浆沉淀，这被称为Cohn分馏过程(Cohn EJ et al.,J.Am.Chem.Soc.1946；68:459-475)。通过控制pH和乙醇含量，可以生产半纯化的血浆蛋白馏分。在Cohn过程中，最后沉淀的蛋白质之一是天然人血清白蛋白。沉淀后，得到粗制天然人血清白蛋白的湿糊状物。随后的生物加工步骤(纯化、过滤、巴氏灭菌等)，可用于生产商业用途的纯化、稳定形式的天然人血清白蛋白(Lin JJ et al.,Pharmaceutical Research 2000；17:391-6)。重组人血清白蛋白是高度纯化的无动物成分、无病毒和无朊病毒的产品，其作为天然人血清白蛋白的替代品，两者在结构上是相同的(Bosse D et al.,J.Clin.Pharmacol.2005；45:57-67)。通过原核和真核的各种宿主生产重组人血清白蛋白(Chen Z et al.,Biochimica et Biophysica Acta 2013；1830:5515-5525)。
人血清白蛋白(HSA)是相对分子量(M r)为65K的高度可溶性球状蛋白，由585个氨基酸组成。HSA是血浆中最丰富的蛋白质，占人体血浆胶体渗透压的70-80％。HSA的氨基酸序列含有总共17个二硫桥、一个游离巯基(Cys34)和单个色氨酸(Trp214)。静脉内使用HSA溶液已表明可用于预防和治疗低血容量性休克(参见例如Tullis,JAMA,237,355-360,460-463,(1977)和Houser et al.,Surgery,Gynecology and Obstetrics,150,811-816(1980))，并与换血疗法联合治疗新生儿高胆红素血症(参见例如Finlayson,Seminars in Thrombosis and Hemostasis,6,85-120,(1980))。
本文中的人血清白蛋白也可以是人血清白蛋白溶液。适合的人血清白蛋白溶液包括但不限于市售的输注用人血清白蛋白溶液。市售的输注用血清白蛋白溶液包括药学上可接受的稳定剂如N-乙酰色氨酸钠、辛酸钠、氯化钠、碳酸氢钠、氢氧化钠或醋酸等或其混合物。在一些实施方式中，人血清白蛋白溶液可以通过用肠道外给药可接受的载体稀释市售的输注用人血清白蛋白溶液来制备。
或者，人血清白蛋白可以通过将溶于水中的人血清白蛋白粉末与在市售的白蛋白产品中含有的其他药学上可接受的稳定剂混合来制备。
在一些实施方式中，人血清白蛋白是市售的输注用人血清白蛋白溶液。在一些实施方式中，人血清白蛋白溶液是市售的输注用人血清白蛋白溶液。在一些实施方式中，人血清白蛋白溶液包含市售的输注用人血清白蛋白溶液。在一些实施方式中，市售的输注用人血清白蛋白溶液用作人血清白蛋白的来源。在一些实施方式中，输注用人血清白蛋白溶液是5％人血清白蛋白溶液(w/v)。在一些实施方式中，输注用人血清白蛋白溶液是20％人血清白蛋白溶液(w/v)。在一些实施方式中，输注用人血清白蛋白溶液是25％人血清白蛋白溶液(w/v)。在一些实施方式中，人血清白蛋白溶液是一个水性溶液，通过稀释市售的输注用人血清白蛋白来制备得到。
在一些实施方式中，该制剂中人血清白蛋白的浓度为从约0.1％至约20％(w/v)、从约0.05％至约10％(w/v)、从约0.05％至约5％(w/v)、从约0.05％至约3％(w/v)、从约0.02％至约3％(w/v)、从约0.2％至约10％(w/v)、从约0.5％至约15％(w/v)、从约0.5％至约5％(w/v)、从约1％至约10％(w/v)或从约1％至约3％(w/v)。在一些实施方式中，该制剂中人血清白蛋白的浓度为约0.05％(w/v)、约0.1％(w/v)、约0.25％(w/v)、约0.5％(w/v)、约1％(w/v)、约2％(w/v)、约3％(w/v)、约5％(w/v)、约10％(w/v)、约15％(w/v)或约20％(w/v)。在一些实施方式中，该制剂包含从约1g至约50g、从约2g至约40g、从约1g至约10g、从约2g至约20g、从约1g至约5g或从约5g至约10g的人血清白蛋白。
在一些实施方式中，该制剂中人血清白蛋白与多西他赛的重量比为从约20:1至约200:1或从约20:1至约100:1。在一些实施方式中，人血清白蛋白与多西他赛的重量比为约20:1、约30:1、约40:1、约50:1、约75:1、约90:1、约95:1、约100:1或约150:1。
在一些实施方式中，该制剂中液体载体(例如肠道外给药可接受的载体)的量为从约10mL至约2L、从约50mL至约1L、从约100mL至约1L、从约250mL至约1L、从约100mL至约500mL或从约250mL至约500mL。液体载体的合适的实例包括水(例如无菌水)、生理盐水(例如0.9wt.％的NaCl水溶液)或葡萄糖溶液(例如5wt.％的葡萄糖溶液)。
在一些实施方式中，该制剂是澄明的(例如透明的)输注溶液，而不是纳米颗粒悬浮液。在一些实施方式中，该制剂是澄明溶液。在一些实施方式中，澄明输注溶液保持澄明无沉淀至少1小时、至少2小时、至少3小时、至少4小时、至少6小时或至少8小时。在一些实施方式中，当澄明溶液保持在约15-30时，澄明输注溶液保持澄明无沉淀至少1小时、至少2小时、至少3小时、至少4小时或至少6小时。在一些实施方式中，当澄明溶液保持在约18-25时，澄明输注溶液保持澄明无沉淀至少1小时、至少2小时、至少3小时、至少4小时或至少6小时。在一些实施方式中，当澄明溶液保持在约2-8时，澄明溶液保持澄明且无沉淀至少2小时、至少4小时、至少6小时、至少8小时、至少12小时或至少24小时。在一些实施方式中，当澄明溶液保持在环境温度下，澄明输注溶液保持澄明无沉淀至少1小时、至少2小时、至少4小时、至少6小时或至少8小时。
在一些实施方式中，该制剂(澄明输注溶液)中的至少约30％、至少约40％、至少约50％、至少约60％或至少约70％的多西他赛为游离(未结合)多西他赛。游离(未结合) 多西他赛是指输注组合物(溶液)中未结合(例如非共价结合)到人血清白蛋白的那部分多西他赛。在一个实施方式中，通过30kDa膜超滤来测量在肠道外给药的输注组合物(溶液)中的游离(未结合)多西他赛的量。通过动态光散射(DLS)测量，该肠道外给药的输注组合物(溶液)与相对应的人血清白蛋白盐水溶液相比在DLS中具有几乎相同的特征。在一些实施方式中，1mL的该制剂(例如用于肠道外给药的输注组合物)包含不超过50个尺寸大于10μm的颗粒、不超过100个尺寸大于10μm的颗粒、不超过150个尺寸大于10μm的颗粒或不超过200个尺寸大于10μm的颗粒。在一些实施方式中，1ml的该制剂(例如用于肠道外给药的输注组合物)包括不超过5个尺寸大于25μm的颗粒、不超过10个尺寸大于25μm的颗粒、不超过5个尺寸大于15μm的颗粒或不超过20个尺寸大于25μm的颗粒。
在一些实施方式中，该制剂包括有机酸。有机酸的实例包括柠檬酸、乙酸、甲酸、天冬氨酸、谷氨酸、抗坏血酸、苯甲酸、酒石酸、乳酸、马来酸和琥珀酸或其药学上可接受的盐。在一些施行方式中，该制剂包含柠檬酸。在一些施行方式中，该制剂包含从约0.001mg/ml至约2mg/ml的柠檬酸、从约0.005mg/ml至约1mg/ml的柠檬酸或从约0.01mg/ml至约0.5mg/ml的柠檬酸。不受任何特定理论约束地，将有机酸(例如柠檬酸)添加到制剂中被认为是用于产生或保持制剂(例如输注溶液)所需合适的pH。在一些实施方式中，用作肠道外给药的该输注组合物的pH值为从约4至约9.5、从约5至约9、从约6至约8、从约6.5至约7.4、从约4至约9、从约5至约8.5或从约6至约7.5。
在一些实施方式中，该制剂包含有机溶剂或多种有机溶剂的组合。在一些实施方式中，有机溶剂是醇。醇的合适实例包括乙醇、丙二醇和聚乙二醇300等。在一些实施方式中，有机溶剂是乙醇。在一些实施方式中，多西他赛的用于肠道外给药的输注组合物中乙醇的量不超过约10％(v/v)、约5％(v/v)、约2％(v/v)、约1.75％(v/v)、约1.5％(v/v)或约1.4％(v/v)。
在一些实施方式中，该制剂(例如该用于肠道外给药的输注组合物)由第一液体组合物和第二水性组合物制备，如本文进一步描述。在一些实施方式中，该制剂在输注到癌症患者前少于24小时、少于12小时、少于8小时、少于6小时，少于4小时或少于1小时制备完成。在将第一液体组合物注入到包含第二水性组合物的输注袋或瓶中，接着将第一液体组合物和第二水性组合物混合均匀后，得到在肠道外给药可接受载体中的包含人血清白蛋白、多西他赛、柠檬酸和乙醇的澄明无沉淀的输注溶液。
在一些实施方式中，本发明提供了包括剂量为约75mg/m 2的多西他赛和人血清白蛋白的输注用药物组合物，其中该组合物不含聚山梨酯80。在一些实施方式中，本发明提供了包括剂量为约50mg至约200mg的多西他赛和人血清白蛋白的输注用药物组合物，其中该组合物不包含聚山梨酯80。在一些实施方式中，该组合物是输注到所述患者前24小时内制备的。在一些实施方式中，本发明提供了由第一液体组合物和第二水性组合物制备的药物组合物，如进一步描述所述。
制备药物制剂的方法
在一些实施方式中，本发明提供了一种制备包括多西他赛和人血清白蛋白的制剂(例如输注用药物组合物)的方法，该方法包括混合如下两个组合物，(a)包含多西他赛和乙醇的第一液体组合物；和(b)包含人血清白蛋白和肠道外给药可接受载体的第二水性组合物。在一些实施方式中，第一液体组合物和第二水性组合物均不包含聚山梨酯80、表面活性剂或脂质(例如大豆油)。在一些实施方式中，这两个组合物在输注或给药用到患者前少于约24小时、约8小时、约4小时或约1小时相混合。在一些实施方式中，两个组合物的混合是在输注袋或瓶里完成的。例如，当第二水性组合物包含在输注袋或瓶中，第一液体组合物注入到包含有第二水性组合物的输注袋或瓶中。在一些实施方式中，使用注射器将第一液体组合物注射到包含有第二水性组合物的输注袋或瓶中。
在一些实施方式中，第一液体组合物包含多西他赛和乙醇。在一些实施方式中，第一液体组合物包含多西他赛、乙醇和其他有机溶剂(例如丙二醇、聚乙二醇300等)。在一些实施方式中，第一液体组合物进一步包含酸(例如柠檬酸)。优选地有机酸选自由柠檬酸、乙酸、甲酸、抗坏血酸、苯甲酸、酒石酸、乳酸、马来酸、琥珀酸或其药学上可接受的盐组成的组。在一些实施方式中，第一液体组合物是含有多西他赛的乙醇溶液。在一些实施方式中，第一液体组合物中多西他赛和柠檬酸的重量比为从约5000:1至约1:1、从约2000:1至约1:1、从约1000:1至约1:1、从约500:1至约1:1、从约5000:1至约5:1、从约2000:1至约5:1、从约1000:1至约5:1、从约500:1至约5:1、从约5000:1至约10:1、从约2000:1至约10:1、从约1000:1至约10:1、从约500:1至约10:1、从约2000:1至约100:1、从约1000:1至约100:1、从约500:1至约100:1或从约500:1至约200:1。在一些实施方式中，第一液体组合物中多西他赛和柠檬酸的重量比为约1000:1、约500:1、约200:1或约100:1。在一些实施方式中，第一液体组合物中柠檬酸的浓度为从约0.005mg/ml至约10mg/ml、从约0.01mg/ml至约2mg/ml、从约0.01mg/ml至约1mg/ml、从约0.02mg/ml至约0.5mg/ml、从约0.02mg/ml至约0.2mg/ml。在一些实施方式中，第一液体组合物通过将多西他赛(和/或柠檬酸)溶解在醇(例如乙醇和/或丙二醇)中而制备。在一些实施方式中，醇(例如乙醇和/或丙二醇)中多西他赛的浓度为从约1mg/ml至约200mg/ml、从约5mg/ml至约100mg/ml、从约5mg/ml至约40mg/ml、从约10mg/ml至约50mg/ml、从约10mg/ml至约20mg/ml、从约10mg/ml至约30mg/ml。在一些实施方式中，醇(例如乙醇和/或丙二醇)中多西他赛的浓度为约10mg/ml、约15mg/ml、约20mg/ml或约30mg/ml。在一些实施方式中，第一液体组合物中多西他赛的量为从约10mg至约300mg或从约20mg至约200mg。在一些实施方式中，第一液体组合物中多西他赛的量为约20mg、约40mg、约60mg、约80mg、约100mg、约120mg或约160mg。在一些实施方式中，第一液体组合物中乙醇的量为从约0.5ml至约50ml、从约1ml至约20ml、从约1ml至约10ml或从约3ml至约6ml。
通常地，第一液体组合物是可注射用的组合物(例如是为了注射到包括含有人血清白蛋白的水性组合物的输注袋或瓶中而制成或调整的)。在一些实施方式中，第一液体组合物是一个可注射用的药物制剂。可注射的药物组合物(药物制剂)中多西他赛的浓度可以为从约5mg/ml至约40mg/ml或从约10mg/ml至约20mg/ml。在一些实施方式中，可注射的药物组合物(药物制剂)中多西他赛的浓度为约10mg/ml、约15mg/ml或约20mg/ml。在一些实施方式中，可注射的药物组合物(第一液体组合物)的pH为从约3至约9、从约3 至8、从约3至7、从约3至6.5、从约3.5至6.5、从约3.5至6、从约3.5至约5.5或从约4至约5。在一个实施例中，为了测量可注射药物制剂的pH值，将可注射的药物制剂与生理盐水按1:1的比例(v/v)混合以获得水性溶液，然后测试水性溶液的pH值。在一些实施方式中，包括第一液体组合物的可注射药物组合物(药物制剂)包含约20mg、约40mg、约80mg、约120mg或约160mg的多西他赛、柠檬酸和乙醇，其中可注射药物制剂中多西他赛的浓度为从约5mg/ml至约40mg/ml(例如约20mg/ml或约10mg/ml)，且该组合物的pH为从约3至约6.5或从约3.5至约5.5。
在一些实施方式中，第二水性组合物通过将人血清白蛋白溶液添加到肠道外给药可接受的载体中来制备。例如，第二水性组合物通过将适量人血清白蛋白溶液添加到包含有合适量的肠道外给药可接受载体(例如生理盐水溶液或葡萄糖溶液)的输注袋或瓶中来制备。在一些实施方式中，第二水性组合物通过将20％、25％或5％的市售输注用人血清白蛋白溶液(w/v)添加到生理盐水溶液或葡萄糖溶液中来制备。在一些实施方式中，第二水性组合物中人血清白蛋白的浓度为从约0.1％至约20％(w/v)、从约0.5％至约10％(w/v)、从约0.5％至约15％(w/v)、从约0.5％至约5％(w/v)、从约1％至约10％(w/v)或从约1％至约3％(w/v)。在一些实施方式中，第二水性组合物包含从约1g至约50g的人血清白蛋白、从约1g至约20g、从约2g至约10g或从约2g至约20g的人血清白蛋白。在一些实施方式中，第二水性组合物的体积为从约100ml至约1L。在一些实施方式中，第二水性组合物的体积为从约250ml至约1L。在一些实施方式中，第二水性组合物的体积为从约250ml至约500ml。
通常地，在包含第二水性组合物的输注袋或瓶中注射入第一液体组合物是快速的。在一些实施方式中，注射时间不超过60秒、不超过30秒、不超过15秒、不超过10秒、不超过5秒、或不超过3秒。通常地，在向包含第二水性组合物的输注袋或瓶中注射入第一液体组合物的注射过程中不需要人为的晃动或搅动(例如故意搅拌)。完成在向输注袋或瓶中注射入第一液体组合物后，将第一液体组合物和第二水性组合物混合均匀(例如轻轻用手倒转包含该组合物的袋)，以获得澄明无沉淀的输注溶液。在一些实施方式中，含有第二水性组合物的输注袋或瓶在注射过程中保持静止。在一些实施方式中，在注射过程中第一液体组合物注射到第二水性组合物的液体表面下。在一些实施方式中，注射完成后，输注袋或瓶重复地轻轻倒转以均匀混合第一液体组合物和第二水性组合物。通过简单地轻轻倒转输注袋或瓶(例如约5-30次)，可以得到澄明无沉淀的输注溶液。混合时间可以是例如从约5秒至约10分钟、从约5秒至约3分钟、从约5秒至约2分钟或从约0.1分钟至约1分钟。将第一液体组合物注射到包含第二水性组合物的输注袋或瓶中，然后将第一液体组合物和第二水性组合物混合均匀后，得到在肠道外给药可接受的载体中的包含人血清白蛋白、多西他赛、乙醇和柠檬酸的澄明无沉淀的输注溶液。在一些实施方式中，在注射过程中，不需要人为搅动(例如搅拌)用来混合该组合物。在一些实施方式中，在从约15至约30、从约15至约25或从约20至约25的温度下完成将第一液体组合物注射到含有第二水性组合物的输注袋或瓶中。在一些实施方式中，在环境温度下完成将第一液体组合物注射到含有第二水性组合物的输注袋或瓶中。
在一些实施方式中，本发明提供了如本文所述的澄明(例如无沉淀)的用于肠道外给药多西他赛输注组合物的制备方法。该制备方法的一个实施方式如下：
1)在乙醇或者包括乙醇的混合溶剂(例如乙醇和PEG300或乙醇和PEG400的混合溶剂)中溶解多西他赛和酸(例如柠檬酸)用来制备第一液体组合物；
2)加入人血清白蛋白溶液(例如市售和临床使用的20％、25％或5％的输注用人血清白蛋白溶液(w/v))到包含肠道外给药可接受载体(例如生理盐水溶液或葡萄糖溶液)的输注袋或瓶中以制备第二水性组合物；
3)将第一液体组合物注射入含有第二水性组合物的输注袋或瓶中；在注入过程中，输注袋或瓶通常不需要人为混合或搅动；
4)在完成将第一液体组合物注射入输注袋或瓶后，将第一液体组合物和第二水性组合物混合均匀(例如用手轻轻倒转含有组合物的输注袋或瓶)以得到澄明无沉淀的输注溶液。
该方法的一个实施方式如下，例如该方法包括:
1)在乙醇或者包括乙醇的混合溶剂(例如乙醇和PEG300或乙醇和PEG400的混合溶剂)中溶解多西他赛和酸(例如柠檬酸)以制备第一液体组合物(例如该方法包括得到包含在乙醇或包括乙醇的混合溶剂中多西他赛和酸的溶液的第一液体组合物)；
2)加入人血清白蛋白溶液(例如临床使用的20％、25％或5％的输注用人血清白蛋白溶液(w/v))到含有肠道外给药可接受载体(例如生理盐水溶液或葡萄糖溶液)的输注袋或瓶中以制备第二水性组合物(例如该方法包括得到包含含有HSA和肠道外给药可接受载体的溶液的第二水性组合物的输注袋或瓶)；
3)将第一液体组合物注射入含有第二水性组合物的输注袋或瓶中；在注射过程中，输注袋或瓶通常不需要人为混合或搅动(例如该方法包括将第一液体组合物注射入包含第二水性组合物的输注袋或瓶中，不人为混合组合物和/或不搅动输注袋或瓶(例如通过保持该输注袋或瓶静止)；以及
4)在完成将第一液体组合物注射入输注袋或瓶后，将第一液体组合物和第二水性组合物混合均匀(例如用手轻轻倒转含有组合物的输注袋或瓶)以得到澄明无沉淀的输注溶液。制备的第一步和第二步可以同时或以不同的顺序完成。一旦混合完成，由此获得的制剂就可以在必要的剂量水平下例如根据个体患者的体表面积(“BSA”)按约50mg/m 2至约150mg/m 2剂量的多西他赛向癌症患者给药。在一些实施方式中，该制剂可以按约50mg/m 2、约60mg/m 2、约75mg/m 2、约90mg/m 2、约100mg/m 2或约120mg/m 2的多西他赛剂量给药。
治疗癌症的方法
本发明也提供了治疗癌症的方法，该方法包括用治疗上有效量的本文所述的任何组合物或制剂向有这种需要的受试者给药。在一些实施方式中，该方法包括用治疗上有效量的本发明的液体输注制剂向有这种需要的受试者通过肠道外给药。在一些实施方式中，该制剂可以包含或可以被配置为根据患者的BSA(体表面积)按约50mg/m 2、约60mg/m 2、约75mg/m 2、约90mg/m 2、约100mg/m 2或约120mg/m 2剂量的多西他 赛向患者给药。
如本文中使用的，术语“体表面积”或“BSA”是指测量或计算的人体表面积。这种测量通常被用作代谢量而不是体重的指标。下表显示了典型身高和体重的体表面积。用DuBois&DuBois公式进行计算：(体重(kg)) 0.425×(身高(cm)) 0.725×0.007184。体重是横轴，先按英镑，然后按千克。身高是竖轴，先按英寸，然后按厘米。结果是按平方米的体表面积。典型的BSA在下表中提供。
Figure PCTCN2022078020-appb-000008
在一个实施例中，癌症患者的平均BSA为约1.73m 2。
在一些实施方式中，当本文描述的制剂被输注到患者时，输注袋或瓶在注入了预定量的第一液体组合物后含有根据患者体表面积所需多西他赛剂量，例如含有约75mg/m 2的多西他赛。在一些实施方式中，使用多个输注袋或瓶来准备所需的输注制剂，其包含给患者一次输注所需多西他赛的剂量。在一个实施例中，对于一个BSA约2m 2的癌症患者，输注袋中多西他赛的剂量为约150mg。在一些实施方式中，输注时间为约1小时至约2小时。在一些实施方式中，输注时间为约1小时。液体输注流速可以根据想要的输注时间(例如1小时)来确定和/或调整。在其他实施方式中，一个输注袋或多个输注袋(例如2个输注袋)可以含有一次输注所需剂量的多西他赛的量。在这种情况下，所需的剂量，例如约75mg/m 2的剂量，可以通过在想要的输注时间(例如1小时)内调整输注速率(滴速)来 向患者给药。在一些实施方式中，输注袋中多西他 赛的浓度为从约0.1mg/ml至约0.5mg/ml。在一些实施方式中，输注袋中多西他 赛的浓度为从约0.15mg/ml至约0.4mg/ml。在一些实施方式中，输注袋中多西他 赛的浓度为约0.2mg/ml、约0.25mg/ml、约0.30mg/ml或约0.35mg/ml。输注溶液的体积量可以根据输注袋中多西他 赛的浓度而确定。例如，如果所需剂量为一次输注(治疗)120mg多西他 赛且输注袋中多西他 赛的浓度为0.25mg/ml，输注袋中输注溶液总体积将达到480ml。根据输注溶液的体积和输注袋的尺寸，患者一次输注所需量的输注溶液可以包含在一个输注袋或多个输注袋(例如2个输注袋)中。例如一个输注袋可以包含约450mL含有约90mg多西他赛、多西他赛浓度为约0.20mg/ml的输注溶液。在另一个实施例中，两个输注袋可以总共包含约600mL含有约150mg多西他赛、多西他赛浓度为约0.25mg/mL的输注溶液。
在一些实施方式中，“癌症”选自肉瘤、血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤、畸胎瘤、非小细胞肺癌(NSCLC)、支气管鳞状细胞癌、小细胞未分化癌、大细胞未分化癌、腺癌、肺泡细支气管癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤性错构瘤、间皮瘤、胃肠道癌、食管癌、鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤、胃癌、癌、淋巴瘤、平滑肌肉瘤、胰腺癌、导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、舒血管肠肽瘤、小肠癌、腺癌、淋巴瘤、类癌瘤、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤、大肠或结肠癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤、泌尿生殖道癌、肾腺癌、维尔姆斯瘤(肾母细胞瘤)、淋巴瘤、白血病、膀胱癌、尿道癌、鳞状细胞癌、移行细胞癌、前列腺癌、睾丸癌、精原细胞瘤、畸胎瘤、胚胎性癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤、肝癌、肝癌肝细胞癌、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤、骨癌、骨原性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)，多发性骨髓瘤、恶性骨巨细胞瘤、脊索瘤、骨软骨瘤(骨软骨外生骨疣)、良性软骨瘤、软骨母细胞瘤、软骨粘液纤维瘤、骨样骨巨细胞瘤、神经系统癌、颅骨癌、骨瘤、血管瘤、肉芽肿瘤、黄瘤、变形性骨炎、脑膜瘤癌、神经胶质瘤、脑癌、星形细胞瘤、髓母细胞瘤、胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形性胶质母细胞瘤、少突胶质细胞瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤、脊髓癌、神经纤维瘤、脑膜瘤、胶质瘤、肉瘤、妇科癌症、子宫癌、子宫内膜癌、宫颈癌、宫颈肿瘤、癌前宫颈发育不良、卵巢癌、卵巢肿瘤、浆液性囊腺癌、粘液性囊腺癌、未分类癌、颗粒卵泡膜细胞瘤、卵巢支持-间质细胞肿瘤、无性细胞瘤、恶性畸胎瘤、外阴癌、鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤、阴道癌、透明细胞癌、鳞状细胞癌、葡萄状肉瘤、胚胎性横纹肌肉瘤、输卵管癌、血液癌、血癌、急性髓系白血病(AML)、慢性髓系白血病(CML)、急性淋巴细胞白血病(ALL)、慢性淋巴细胞白血病、慢性淋巴细胞白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征、霍奇金淋巴瘤、非霍奇金淋巴瘤(恶性淋巴瘤)、瓦尔登斯特伦巨球蛋白血症、皮肤癌、恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、葡萄胎发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕疙瘩、牛皮癣、肾上腺癌和神经母细胞瘤。
在一些实施方式中，癌症是实体瘤癌。一些实体瘤的实例包括：乳腺癌、前列腺癌、肺癌、肝癌、胰腺癌和黑色素瘤。在一些实施方式中，癌症选自乳腺癌、非小细胞肺癌、前列腺癌(例如去势抵抗性前列腺癌)、胃癌(例如腺癌)和头颈部癌(例如头颈部鳞状细胞癌)。
在一些实施方式中，本发明治疗癌症的方法包括多西他赛和另外的抗癌治疗药物联合给药。另外的抗癌治疗药物的合适的实例包括阿霉素、环磷酰胺、顺铂、强的松和氟尿嘧啶或其组合。这些另外的抗癌治疗药物可以与当前权利要求的多西他赛制剂按顺序地(前或后)或同时给药。在一些实施方式中，另外的抗癌治疗药物可以根据患者的确切诊断和治疗医生的建议按约50mg/m 2至约750mg/m 2的剂量给药。
在一些实施方式中，本发明提供了在受试者中治疗癌症(例如乳腺癌、非小细胞肺癌、前列腺癌、胃癌、头颈部癌)的方法，该方法包括：
i)混合本文中描述的第一液体组合物和本文中描述的第二水性组合物以得到包含多西他赛的输注用制剂；以及
ii)按所需多西他赛剂量(例如根据患者的BSA用约50mg/m 2、约60mg/m 2、约75mg/m 2、约90mg/m 2、约100mg/m 2或约120mg/m 2的多西他赛剂量)向有此需要的受试者用步骤(i)得到的制剂输注给药。
在一些实施方式中，本发明提供了在受试者中治疗癌症(例如乳腺癌、非小细胞肺癌、前列腺癌、胃癌、头颈癌)的方法，该方法包括：
i)混合本文中描述的第一液体组合物和本文中描述的第二水性组合物以得到包含所需多西他赛剂量(例如根据患者的BSA用约50mg/m 2、约60mg/m 2、约75mg/m 2、约90mg/m 2、约100mg/m 2或约120mg/m 2的多西他赛剂量)的输注用制剂；以及
ii)按所需多西他赛剂量向有此需要的受试者用步骤(i)得到的制剂输注给药。
在一些实施方式中，包含所需多西他 赛剂量 (例如根据患者的BSA用约50mg/m 2、约60mg/m 2、约75mg/m 2、约90mg/m 2、约100mg/m 2或约120mg/m 2的多西他 赛剂量)的输注用制剂可以在多个输注袋或瓶中(例如在2个输注袋或瓶中)制备。
试剂盒
此外，本文提供用于制备本文描述的输注用制剂的试剂盒，其包括：含有包含多西他赛的组合物的第一容器；和含有包含人血清白蛋白的组合物的第二容器。在一些实施方式中，该试剂盒包括含有包含多西他赛的液体组合物的第一容器和含有包含人血清白蛋白的液体组合物的第二容器。在一些实施方式中，该试剂盒包括含有包含多西他赛和乙醇的液体组合物的第一容器和含有包含人血清白蛋白的液体组合物的第二容器。在一些实施方式中，该试剂盒包括含有包含多西他赛、柠檬酸和乙醇的液体组合物的第一容器和含有包含人血清白蛋白的液体组合物的第二容器。在一些实施方式中，该试剂盒包括含有包含多西他赛、柠檬酸和无水乙醇的液体组合物的第一容器和含有包含人血清白蛋白的液体组合物的第二容器。在一些实施方式中，该试剂盒包括含有包含多西他赛、柠檬酸和乙醇的液体 组合物的第一容器和含有人血清白蛋白溶液(例如20％、25％或5％(w/v))的第二容器。在一些实施方式中，第一容器中和第二容器中的液体组合物都是无菌溶液。
在一些实施方式中，第一容器中包含的乙醇是无水乙醇。在一些实施方式中，第一容器含有包含多西他赛和乙醇的液体组合物。在一些实施方式中，第一容器含有包含多西他赛、酸和乙醇的液体组合物。在一些实施方式中，第一容器含有包含多西他赛、有机酸和乙醇的液体组合物。在一些实施方式中，第一容器含有包含多西他赛、乙醇和其他有机溶剂(例如醇如丙二醇或聚乙二醇300等)的液体组合物。在一些实施方式中，第一容器含有包含多西他赛、柠檬酸和乙醇的液体组合物。在一些实施方式中，第一容器含有包含多西他赛的乙醇溶液。在一些实施方式中，第一容器含有包含多西他赛和柠檬酸的乙醇溶液。在一些实施方式中，第一容器中柠檬酸的浓度为约0.005mg/ml至约10mg/ml。在一些实施方式中，第一容器中柠檬酸的浓度为约0.01mg/ml至约2mg/ml。在一些实施方式中，第一容器中柠檬酸的浓度为约0.01mg/ml至约1mg/ml。在一些实施方式中，第一容器中柠檬酸的浓度为约0.02mg/ml至约0.5mg/ml。在一些实施方式中，第一容器中柠檬酸的浓度为约0.02mg/ml至约0.2mg/ml。
在一些实施方式中，第一容器中包含的多西他赛的量为从约10mg至约300mg的多西他赛。在一些实施方式中，第一容器中包含的多西他赛的量为从约20mg至约200mg的多西他赛。在一些实施方式中，第一容器中包含的多西他赛的量为约20mg、约40mg、约60mg、约80mg、约100mg、约120mg或约160mg的多西他赛。在一些实施方式中，第一容器中包含的乙醇的量为从约0.5ml至约50ml的乙醇。在一些实施方式中，第一容器中包含的乙醇的量为从约1ml至约20ml的乙醇。在一些实施方式中，第一容器中包含的乙醇的量为从约1ml至约10ml的乙醇。在一些实施方式中，第一容器中包含的乙醇的量为从约1ml至约5ml的乙醇。在一些实施方式中，第一容器中包含的乙醇的量为从约5ml至约10ml的乙醇。在一些实施方式中，第一容器中多西他赛的浓度为从约5mg/ml至约100mg/ml。在一些实施方式中，第一容器中多西他赛的浓度为从约10mg/ml至约40mg/ml。在一些实施方式中，第一容器中多西他赛的浓度为约20mg/ml。
在一些实施方式中，第一容器中包含本文描述的第一液体组合物的可注射药物制剂产品。在一些实施方式中，第一容器中包含从约0.5毫升到约30毫升量的本文描述的第一液体组合物的可注射药物制剂产品。在一些实施方式中，第一容器中包含从约1毫升到约20毫升量的本文描述的第一液体组合物的可注射药物制剂产品。在一些实施方式中，第一容器中包含从约1毫升到约10毫升量的本文描述的第一液体组合物的可注射药物制剂产品。在一些实施方式中，第一容器中包含约1毫升，约2毫升，约4毫升，约6毫升和约8毫升量的本文描述的第一液体组合物的可注射药物制剂产品。在一些实施方式中，第一容器包括约80mg多西他赛。在一些实施方式中，第一容器包括约80mg多西他赛和约4ml乙醇。
在一些实施方式中，第二容器含有包含人血清白蛋白的液体组合物。在一些实施方式中，第二容器含有人血清白蛋白溶液。在一些实施方式中，第二容器含有人血清白蛋白溶液，其中人血清白蛋白在溶液中的浓度为约1％至约25％(w/v)。在一些实施方式中，第二容器含有人血清白蛋白溶液，其中人血清白蛋白在溶液中的浓度为约5％至约25％ (w/v)。在一些实施方式中，第二容器含有输注用的人血清白蛋白溶液。在一些实施方式中，第二容器含有输注用的20％人血清白蛋白溶液(w/v)。在一些实施方式中，第二容器含有输注用的25％人血清白蛋白溶液(w/v)。在一些实施方式中，第二容器含有输注用的5％人血清白蛋白溶液(w/v)。在一些实施方式中，第二容器含有包含约1g至约50g人血清白蛋白的液体组合物。在一些实施方式中，第二容器含有包含约1g至约30g人血清白蛋白的液体组合物。在一些实施方式中，第二容器含有包含约1g至约20g人血清白蛋白的液体组合物。在一些实施方式中，第二容器含有包含约1g至约10g人血清白蛋白的液体组合物。在一些实施方式中，第二容器含有包含约2g至约6g人血清白蛋白的液体组合物。在一些实施方式中，第二容器含有包含约2g、为约4g、为约6g、为约8g、约10克、约12g或约16g人血清白蛋白的液体组合物。
在一些实施方式中，第一容器包含约80mg多西他赛。在一些实施方式中，第一容器包含约4ml乙醇。在一些实施方式中，第一容器包含约80mg多西他赛和约4ml乙醇。
在一些实施方式中，该试剂盒包括含有约80mg多西他赛的第一容器和含有约2g至约10g人血清白蛋白的第二容器。在一些实施方式中，该试剂盒包括含有约80mg多西他赛的第一容器和含有约10g人血清白蛋白的第二容器。
在一些实施方式中，用注射器从一个或多个第一容器中取出所需量的第一液体组合物并注入含有相应量第二水性组合物的输注袋或瓶中以制备本文描述的输注用制剂。
在一些实施方式中，本发明提供制备用于在受试者中治疗癌症(例如乳腺癌、非小细胞肺癌、前列腺癌、胃癌、头颈部癌)的输注用多西他赛组合物的方法。该制备方法的一个实施方式如下：
1)用注射器从一个或多个第二容器中抽取需要量的人血清白蛋白溶液(例如市售和临床使用的20％、25％或5％的输注用人血清白蛋白溶液(w/v))注入到包含有相应需要量的肠道外给药可接受载体(例如生理盐水溶液或葡萄糖溶液)的输注袋或瓶中，混匀后得到一个第二水性组合物；
2)用注射器从一个或多个第一容器中取出包含有所需多西他赛剂量的第一液体组合物；
3)将上述2)中注射器内抽取的第一液体组合物注射入上述1)中含有第二水性组合物的输注袋或瓶中；
4)在完成将第一液体组合物注入输注袋或瓶后，将第一液体组合物和第二水性组合物混合均匀(例如用手轻轻倒转含有组合物的输注袋或瓶)以得到一个澄明无沉淀的输注溶液。
制备的第一步和第二步可以同时或以不同的顺序完成。由此在第四步获得的含输注所需多西他赛剂量的输注制剂就可以向有此需要的受试者输注给药。例如根据个体患者的体表面积(“BSA”)按从约50mg/m 2至约150mg/m 2剂量的多西他赛向癌症患者给药。在一些实施方式中，该制剂可以按约50mg/m 2、约60mg/m 2、约75mg/m 2、约90mg/m 2、约 100mg/m 2或约120mg/m 2的多西他赛剂量给药。在一些实施方式中，该制剂可以按约75mg/m 2的多西他赛剂量给药。
在一些实施方式中，该试剂盒进一步包括制备本文描述的输注制剂(组合物)的用法说明。
实施例
材料与方法
Winthrop(多西他赛)注射剂，
Figure PCTCN2022078020-appb-000009
的授权仿制药(参比制剂):
Winthrop(多西他赛)注射剂是
Figure PCTCN2022078020-appb-000010
的授权仿制药，购自Sanofi-Aventis U.S.的一个子公司Winthrop U.S，是含20mg/mL的多西他赛在乙醇和聚山梨酯80中的溶液。一瓶Winthrop(多西他赛)注射剂含有20mg多西他赛(无水)、540mg聚山梨酯80和395mg无水乙醇(50％v/v)溶液，用柠檬酸来调节pH值。在本临床研究中，每位患者输注浓度为0.3mg/ml和剂量为75mg/m 2多西他赛的参比制剂的最终输注溶液。以BSA为2m 2的患者为例，参比制剂的输注溶液(制剂)的制备方法如下：
●对于一个BSA为约2m 2的癌症患者，输注袋中多西他赛的剂量为约150mg。为制备多西他赛浓度为0.3mg/ml的最终输注溶液，在制备中用到7.5ml的Winthrop(多西他赛)注射剂(20mg多西他赛/ml)和492.5ml的0.9％氯化钠注射剂。
●仅使用21号针头，用一个标定过的注射器在无菌条件下抽取7.5ml的Winthrop(多西他赛)注射剂(20mg多西他赛/ml)并通过单次注射(一次注射)注入含有492.5ml0.9％氯化钠溶液的输注袋或瓶中以产生最终浓度为0.3mg/ml多西他赛的输注溶液。轻轻地手动旋转来彻底混合输液。
●该多西他赛输注溶液应在环境室温下(25以下)和光照条件下作为1小时输注完成静脉输注给药。
BH009(受试制剂)：
BH009作为一个不含聚山梨酯80的多西他赛注射剂制剂产品而开发。BH009作为一个可注射的无菌产品(20mg/ml多西他赛在乙醇中的溶液)而制备。BH009药品试剂盒中包括一个包含80mg(多西他赛)/4ml的BH009药品(多西他赛注射剂)的西林瓶和一个装有市售10克输注用的20％人白蛋白溶液(50ml)的西林瓶。每4ml的BH009药品(多西他赛注射剂)含有80mg多西他赛(无水)和3156mg无水乙醇，用柠檬酸来调节pH。在此临床研究中，每位患者输注含浓度为0.25mg/ml和剂量为75mg/m 2多西他赛的受试制剂的输注溶液。在受试制剂的输注溶液的制备中，在制备中用到的BH009药品(多西他赛注射剂)、输注用20％人白蛋白溶液和0.9％氯化钠注射剂的体积比例为1:7.5:71.5(v/v)。以一个BSA为2m 2的患者为例，受试制剂的输注溶液(制剂)制备方法如下：
●对于一个BSA为约2m 2的癌症患者，输注袋中多西他赛的剂量为约150mg。为制备含多西他赛浓度为0.25mg/ml的受试制剂输注溶液，在制备中用到7.5ml的BH009 (20mg多西他赛/ml)、56.25ml输注用20％人白蛋白溶液和536.25ml的0.9％氯化钠注射剂。
●用注射器将56.25ml输注用20％人白蛋白溶液注入到一个含有536.25ml 0.9％氯化钠溶液的输注袋或瓶中。然后轻轻手动上下倒转输注袋或瓶约10次来彻底混合所得到的白蛋白-盐水溶液。
●仅使用21号针头，用一个标定过的注射器在无菌条件下抽取7.5ml的BH009药品溶液(20mg多西他赛/mL)并通过单次注射(一次快速注射)注入上述含有混合好的白蛋白-盐水溶液的输注袋或瓶中以得到一个最终多西他赛浓度为0.25mg/ml的输注溶液。单次注射完成后，立即轻轻用手上下倒转输注袋或瓶约20次(混合时间总共约为1分钟左右)来彻底混合均匀该输注液。得到的输注溶液为澄明溶液。
●BH009输注溶液(受试制剂)应在环境室温下(25以下)和光照条件下作为1小时输注完成静脉输注给药。
患者在血浆中未结合的多西他赛药物浓度和总多西他赛药物浓度将分别使用两种独立的验证过的分析方法定量测量，具体描述见下文。
测定人体K 3EDTA抗凝血浆中总多西他赛的液相色谱-质谱(LC-ESI-MS/MS)验证方法：
利用液-液萃取技术开发了用于评估人体血浆中总多西他赛的液相色谱-串联质谱(LC-MS/MS)方法。该方法利用三重四极质谱联用在电喷雾正离子模式下监测多西他赛。其中多西他赛-d9用作内标物(IS)。多西他赛用萃取溶剂提取后，在色谱柱(型号，Gemini5μm C18 150x4.6mm)上用流动相缓冲液(含醋酸0.1％v/v的水溶液)：甲醇，30:70v/v在等梯度条件下以1.000mL/分钟的流速分离。采用多反应监测模式(MRM)进行多西他赛和多西他赛-d9的定量分析。该方法适用于用0.200mL的人体血浆在10.000ng/mL(LLOQ)到6000.000ng/mL(ULOQ)线性范围内测定K 3EDTA人体血浆中的总多西他赛。该方法对于稀释浓度10倍的样品(达到27000.000ng/mL)分析的可靠性被验证。
测定人体K3EDTA抗凝血浆中游离多西他赛的液相色谱-质谱(LC-ESI-MS/MS)验证方法：
采用液-液萃取技术开发了评估人体血浆中游离多西他赛的液相色谱-串联质谱(LC-MS/MS)方法。该方法利用三重四极质谱联用在电喷雾正离子模式下监测多西他赛。其中多西他赛-d9用作内标物(IS)。使用
Figure PCTCN2022078020-appb-000011
超滤装置(离心过滤器1.0mL，30KDa)过滤血浆样本用于直接测量未结合的多西他赛的浓度。多西他赛用萃取溶剂提取后，在色谱柱(型号，Gemini 5μm C18 150x4.6mm)上用流动相缓冲液(含醋酸0.1％v/v的水溶液)：甲醇，30:70v/v在等梯度条件下以1.000mL/分钟的流速分离。采用多反应监测模式(MRM)进行多西他赛和多西他赛-d9的定量分析。该方法适用于用0.200mL的人体血浆在10.000ng/mL(LLOQ)到600.000ng/mL(ULOQ)线性范围内测定K3EDTA人体血浆中的游离多西他赛。该方法对于稀释浓度10倍的样品(达到8000.000ng/mL)分析的可靠性被验证。
实施例1
开展一个多中心、开放、随机、平衡、两次治疗、双周期、两序列、交叉、单剂量的生物等效性研究，其中患者接受受试制剂BH009或参比制剂
Figure PCTCN2022078020-appb-000012
(多西他赛)注射剂或
Figure PCTCN2022078020-appb-000013
的授权仿制药的治疗。
患者选择标准
入选标准：年龄≥18岁，性别不限；经组织学或细胞学证实为实体瘤患者，计划接受多西他赛单药治疗，剂量为75mg/m 2，或者已经接受多西他赛单药治疗(此类药物仅限于
Figure PCTCN2022078020-appb-000014
或已批准上市的
Figure PCTCN2022078020-appb-000015
的仿制药)，且剂量为75mg/m 2，并根据实际的治疗计划按相同给药剂量继续接受≥2个疗程治疗的实体瘤患者；ECOG体力状况评分为0或1，且预计生存期≥3个月；具有充分的造血、肾和肝功能(骨髓功能：ANC≥1500/mm 3，血小板计数≥100,000/mm 3，血红蛋白>9.0g/dl。肝功能：ALT/AST≤1.5×ULN，碱性磷酸酶≤2.5×ULN，总胆红素≤ULN。肾功能：血清肌酐≤1.5×ULN)；凝血酶原时间、国际标准化比值或活化部分凝血活酶时间<1.5×ULN；允许使用全剂量抗凝剂；患者从与先前抗癌治疗相关的不良事件中恢复到0-1级(按照CTCAE 5.04标准)，除了脱发和激素替代疗法控制的内分泌疾病。排除标准：对多西他赛及其辅料和/或相关物质(包括聚山梨酯80、紫杉醇、酒精、地塞米松和止吐药(格拉司琼或昂丹司琼)过敏或特异性反应者；或有严重心血管疾病、活动性感染(例如肺结核、败血症或机会性感染)、严重胸腔积液和/或周围神经病变≥2级的患者；乙型肝炎表面抗原和丙型肝炎(HCV)病毒抗体阳性者、HIV感染者、已知脑转移或因脑转移而出现神经症状的患者；妊娠期或哺乳期妇女等。
研究设计
临床研究中包括46例患者。周期I(第1天)：化疗开始的第1天，患者将静脉输注多西他赛75mg/m 2(受试制剂或参比制剂)。周期II(第22天)：在第2次化疗开始的第1天，患者将交叉给予另一种多西他赛制剂75mg/m 2(受试制剂或参比制剂)。所有患者均应在多西他赛给药前1天口服皮质类固醇，如地塞米松16mg/天(如8mg/次，每日两次)，为期3天，以降低体液潴留的发生率和严重程度以及过敏反应的严重程度。在两个周期里，所有患者都应在输注研究药物前给予预防性格拉司琼(止吐)2mg IV或昂丹司琼(止吐)4-8mg IV(大约在给药前30分钟)。研究人员可自行决定是否允许进行预防性抗过敏治疗和G-CSF。两个周期给药前的预防治疗和给药剂量应相同。将于静脉输注前0h，输注开始后0.500h、0.667h、0.833h，1.000h(输注结束时立即)，输注结束后0.083、0.167、0.333、0.500、1.000、2.000、3.000、6.000、8.000、12.000、24.000和48.000h分别采集静脉血6mL，用于药代动力学分析。使用两种单独验证的分析方法对总多西他赛和游离多西他赛的血浆浓度进行分析。利用得到游离多西他赛和总多西他赛的浓度-时间曲线，计算以下变量：主要变量：C max,AUC 0-t和AUC 0-∞；次要变量：T max,t 1/2,K el,V d,CL和AUC _％Extrap_obs。
对于游离多西他赛和总多西他赛，根据药代动力学参数C max、AUC 0-t和AUC 0-∞的几何最小二乘均值比(受试制剂(T)/参比制剂(R))的90％置信区间的统计结果，得出受 试制剂是否与参比制剂生物等效的结论。对于C max、AUC 0-t和AUC 0-∞的几何最小二乘均值比(T/R)的90％置信区间，生物等效性的可接受范围为80.00％-125.00％。
研究结果
研究期间共筛选了52例患者，其中有46例患者被随机，所有被随机的患者(N＝46)均包含在安全性分析集人群中(见表1)。共有5例患者退出临床研究，41例患者完成了完整的两个周期的研究。
对46例受试者采集的样本进行总多西他赛和游离多西他赛血浆药物浓度分析。根据统计分析的要求，药代动力学分析数据(N＝41)包括根据研究方案完成所有研究的受试者。总多西他赛和游离多西他赛的药代动力学参数见表2和表3。
由于41例患者中有1例患者在给药前(0h)的血药浓度超过了C max的5％，符合统计分析中规定的剔除标准，因此，在生物等效性分析数据中剔除了该患者的数据，最终合计有40例患者的数据被纳入BE分析组。总多西他赛和游离多西他赛的生物等效性分析结果见表4和表5。
研究结果显示，受试制剂BH009和参比制剂Winthrop(多西他赛)注射剂(为
Figure PCTCN2022078020-appb-000016
的授权仿制药)在晚期实体瘤患者中具有生物等效性。总多西他赛的AUC 0-t、AUC 0-∞和C max的90％置信区间分别为91.89％-107.18％、91.10％-106.04％和92.18％-108.00％；游离多西他赛的AUC 0-t、AUC 0-∞和C max的90％置信区间分别为89.98％-103.15％、90.24％-102.75％和85.22％-101.70％。总多西他赛和游离多西他赛的AUC 0-t、AUC 0-∞和C max的90％置信区间均在生物等效性(BE)范围(80％-125％)内。
安全性分析数据显示，受试制剂BH009在人体内具有良好的耐受性；受试制剂组(BH009)的血液学毒性发生率显著低于参比制剂组(Winthrop(多西他赛)注射剂)(见表6)。试验中最常见的3/4级毒性为中性粒细胞减少、贫血、淋巴细胞减少和白细胞减少，与参比制剂组相比，受试制剂组的3/4级血液学毒性显著降低(R/T:15.9％vs 2.3％)，尤其中白细胞减少症和中性粒细胞减少症(R/T:6.8％vs 0.0％,4.6％vs 0.0％)。研究中发热性中性粒细胞减少症的发生率为0.0％。
BH009和Winthrop(多西他赛)注射液在晚期实体瘤患者中的总多西他赛及游离多西他赛的平均血浆药物浓度-时间曲线分别见图1和图2。
患者的人口统计学资料、药代动力学参数、总多西他赛和游离多西他赛的主要药代动力学参数的BE结果以及安全性统计数据总结如下。
表1：安全性人群的人口统计学特征
Figure PCTCN2022078020-appb-000017
Figure PCTCN2022078020-appb-000018
表2：受试制剂BH009和参比制剂Winthrop(多西他赛)注射剂的总多西他赛药代动力学参数(N＝41名患者)
Figure PCTCN2022078020-appb-000019
表3：受试制剂BH009和参比制剂Winthrop(多西他赛)注射剂的游离多西他赛药代动力学参数(N＝41名患者)
Figure PCTCN2022078020-appb-000020
表4：受试制剂BH009和参比制剂Winthrop(多西他赛)注射剂的总多西他赛主要药代动力学参数的BE结果
(N＝40名患者)
Figure PCTCN2022078020-appb-000021
Figure PCTCN2022078020-appb-000022
表5：受试制剂BH009和参比制剂Winthrop(多西他赛)注射剂的游离多西他赛主要药代动力学参数的BE结果
(N＝40名患者)
Figure PCTCN2022078020-appb-000023
表6：受试制剂BH009和参比制剂Winthrop(多西他赛)注射剂的安全性统计数据
Figure PCTCN2022078020-appb-000024
Figure PCTCN2022078020-appb-000025
其他实施方式
应理解，虽然本申请已经结合其详述进行了描述，但是前面的描述旨在说明而不是限制本申请的范围，本申请的范围由所附权利要求的范围界定。其他的方面、优势和改进均在以下权利要求的范畴内。

Claims (12)

  1. 包含多西他赛和人血清白蛋白的输注用的药物组合物，
    其中所述组合物是通过将包含多西他赛和乙醇的第一液体组合物注入到含有包含在肠道外给药可接受载体中的人血清白蛋白的第二水性组合物的输注袋或瓶中制备而成，
    其中所述组合物不含聚山梨酯80，
    其中所述组合物通过输注给药用于治疗诊断为选自乳腺癌、非小细胞肺癌、前列腺癌、胃癌和头颈癌的实体瘤的患者，
    其中输注给有此需要的所述患者的多西他赛剂量为约75mg/m 2，以及，
    其中所述组合物是在输注给所述患者前24小时内制备的。
  2. 如权利要求1所述的药物组合物，其中所述组合物是在输注给所述患者前4小时内制备的。
  3. 如权利要求1所述的药物组合物，其中所述组合物中多西他赛的浓度为约0.05mg/ml至约0.5mg/ml。
  4. 如权利要求1所述的药物组合物，其中所述组合物中人血清白蛋白的浓度为约0.01％至约20％(w/v)。
  5. 如权利要求1所述的药物组合物，其中所述组合物是澄明水性输注溶液。
  6. 如权利要求1所述的药物组合物，其中所述组合物按每3周1个新的周期重复给药用于所述患者。
  7. 如权利要求6所述的药物组合物，其中所述组合物按多西他赛剂量为75mg/m 2给药。
  8. 如权利要求1所述的药物组合物，其中所述组合物给药用于治疗诊断为前列腺癌的所述患者。
  9. 如权利要求1所述的药物组合物，其中所述组合物给药用于治疗诊断为乳腺癌的所述患者。
  10. 如权利要求1所述的药物组合物，其中所述组合物给药用于治疗诊断为非小细胞肺癌的所述患者。
  11. 如权利要求1所述的药物组合物，其中所述组合物给药用于治疗诊断为胃癌的所述患者。
  12. 如权利要求1所述的药物组合物，其中所述组合物给药用于治疗诊断为头颈癌的所述患者。
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