Cabazitaxel albumin composition and use thereof

Abstract

The present invention belongs to the technical field of anti-tumor medicine. Provided are a cabazitaxel albumin composition and the use thereof. The cabazitaxel albumin composition comprises cabazitaxel and a human serum albumin, and does not contain a surfactant. The cabazitaxel albumin composition is a clear solution in a liquid state, which is administered by means of infusion for the treatment of a cancer patient. The dosage of the cabazitaxel infused to the patient is about 10-40 mg / m 2, preferably 20 mg / m 2 or 25 mg / m 2. The cabazitaxel albumin composition is optionally used in combination with a corticosteroid (such as prednisone), and is optionally administered repeatedly to the patient every 3 weeks as a new cycle. The cabazitaxel albumin composition has fewer adverse effects and a higher disease control rate for a patient with advanced solid tumors compared to the originally developed cabazitaxel injection.

Description

Cabazitaxel albumin composition and its use Technical Field

[0001] The present invention belongs to the field of anti-tumor technology, and in particular, relates to a cabazitaxel albumin composition and uses thereof. Background Art

[0002] Cancer treatment remains a key area of ​​research in today's medical field. As a serious threat to human health, continuous innovation in cancer treatment is crucial for improving cure rates and patient quality of life. Tumor treatment involves a variety of approaches, including surgery, radiotherapy, and chemotherapy, with chemotherapy being a common and effective method.

[0003] However, current cancer treatments still face a number of challenges. One of these is the limited effectiveness of treatments, particularly in certain tumor types. Tumor heterogeneity and drug resistance make some patients insensitive to existing treatments, resulting in unsatisfactory treatment outcomes. Therefore, there is an urgent need for novel treatments that can improve efficacy, alleviate patient suffering, and expand their scope of application.

[0004] Cabazitaxel is a semisynthetic taxane derivative developed by Sanofi-Aventis and approved in the US on June 17, 2010, in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received a docetaxel-containing regimen. Cabazitaxel injection (JEVTANA) is supplied as a kit containing (a) cabazitaxel injection, which contains 60 mg of cabazitaxel dissolved in 1.5 mL of polysorbate 80; and (b) a diluent containing approximately 5.7 mL of 13% (w / w) ethanol. Prior to administration, JEVTANA injection must first be mixed with the diluent, which dilutes cabazitaxel to 10 mg / mL. The diluent is then further diluted with either 0.9% sodium chloride solution or 5% dextrose solution for infusion.

[0005] Currently, cabazitaxel injection is widely used in the treatment of prostate cancer. Its ingredients and therapeutic mechanism have achieved some success to a certain extent. However, although cabazitaxel injection has shown relatively good therapeutic effects in some patients, its therapeutic effect still has limitations. According to research data (Heck MM, M, Horn T, et al. Compassionate use of abiraterone and cabazitaxel: first experiences in docetaxel-pretreated castration-resistant prostate cancer patients [J]. Der Urologe, 2012, 51: 390-397.) showed that cabazitaxel injection achieved only an 83.3% disease control rate (DCR) in patients with metastatic castration-resistant prostate cancer. This suggests that under current technological conditions, there is still room for improvement and innovation is needed.

[0006] In addition to therapeutic efficacy, safety is also an aspect of cancer treatment that requires special attention. A patient's quality of life depends not only on the effectiveness of treatment but also on the side effects and safety of treatment. Cabazitaxel injection may cause some discomfort and adverse reactions during treatment, posing a potential threat to the patient's physical health and quality of life. According to research data (Mukai H, Takahashi S, Nozawa M, et al. Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer [J]. Cancer chemotherapy and pharmacology, 2014, 73:703-710. and Nozawa M, Mukai H, Takahashi S, et al. Japanese phase I study of cabazitaxel in metastatic castration-resistant prostate cancer [J]. International journal of clinical oncology, 2015, 20:1026-1034.), cabazitaxel injection has been associated with grade 3 / 4 adverse reactions in Asian (Japanese) patients, posing additional health risks to patients. This not only increases the complexity of treatment but also impacts patients' quality of life. Therefore, a safer formulation with fewer side effects is urgently needed for the treatment of prostate cancer.

[0007] Therefore, the current field of prostate cancer treatment urgently needs a novel formulation that can improve therapeutic efficacy, alleviate patient suffering, and demonstrate superior safety. Such a formulation needs to overcome the limitations of current treatments and provide patients with a more effective and safer treatment option. Against this backdrop, the invention of cabazitaxel albumin solution injection for prostate cancer has emerged, injecting new hope into the field of prostate cancer treatment. By achieving a 100% disease control rate (DCR) in prostate cancer treatment, cabazitaxel albumin solution injection demonstrates significant therapeutic advantages, opening up new treatment possibilities for cancer patients. Furthermore, cabazitaxel albumin solution injection's superior safety profile makes it a highly anticipated innovative treatment option, particularly with its relatively low incidence of grade 3 / 4 adverse reactions, including decreased neutrophil count and febrile neutropenia, in Asian populations, offering a safer treatment option for Asian patients. Therefore, the development and application of cabazitaxel albumin solution injection will bring new hope to the field of prostate cancer treatment and become a significant breakthrough in future prostate cancer treatment. Summary of the Invention

[0008] The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.

[0009] The present invention aims to solve the technical problems existing in the above-mentioned prior art. To this end, the present invention proposes a cabazitaxel albumin composition and its use. The cabazitaxel albumin composition is described in WO2017123760A1, WO2019204738A1, and WO2022056396A1. It is a clear solution in a liquid state and does not contain a surfactant (such as Tween 80). The contents of documents WO2017123760A1, WO2019204738A1, and WO2022056396A1 are all introduced into this article as part of the content of this article.

[0010] Specifically, the present invention provides the following embodiments:

[0011] In one aspect of the present invention, a cabazitaxel albumin composition is provided, comprising cabazitaxel and human serum albumin, and containing no surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered by infusion for treating cancer patients, and the cabazitaxel dose infused into the patient is about 10-40 mg / m 2 .

[0012] In some embodiments, the surfactant is Tween 80.

[0013] In some embodiments, the cabazitaxel dose is about 10-35 mg / m 2 , about 15-35 mg / m 2 , about 20-30 mg / m 2 , about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the cabazitaxel dose is about 25 mg / m 2 .

[0014] Another aspect of the present invention provides a cabazitaxel albumin composition, comprising cabazitaxel and human serum albumin, and containing no surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered by infusion for treating cancer patients, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 .

[0015] Another aspect of the present invention provides a cabazitaxel albumin composition, comprising cabazitaxel and human serum albumin, and containing no surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered by infusion for treating cancer patients, and the cabazitaxel dose infused into the patient is about 25 mg / m 2 .

[0016] In some embodiments, the cabazitaxel albumin composition contains about 5-40 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 10-40 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 20-40 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 25-35 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 30 mg of cabazitaxel.

[0017] In some embodiments, the cabazitaxel albumin composition is in a liquid dosage form; further, the liquid dosage form is an infusion solution; in some embodiments, the infusion solution is a sterile infusion solution; in some embodiments, the infusion solution is a parenteral infusion solution.

[0018] In some embodiments, the weight ratio of human albumin to cabazitaxel in the liquid dosage form is about 10: 1 to about 2000: 1, for example, about 10: 1 to about 500: 1, about 20: 1 to about 200: 1, about 50: 1 to about 300: 1, about 50: 1 to about 150: 1, about 150: 1, about 120: 1, about 100: 1, about 100: 1 to about 600: 1, about 100: 1 to about 300: 1. In some embodiments, the weight ratio of human albumin to cabazitaxel in the liquid dosage form is about 150: 1.

[0019] In some embodiments, the cabazitaxel albumin composition is a clear aqueous infusion solution.

[0020] In some embodiments, the infusion fluid is a clear aqueous infusion solution.

[0021] In some embodiments, the cabazitaxel albumin composition is a clear aqueous infusion solution, and the mass concentration of cabazitaxel in the cabazitaxel albumin composition is about 0.01 mg / mL to about 1 mg / mL, for example, about 0.01 mg / ml to about 0.25 mg / ml, about 0.02 mg / ml to about 0.2 mg / ml, about 0.03 mg / ml to about 0.15 mg / ml, about 0.05 mg / ml to about 0.1 mg / ml, about 0.08 mg / ml to about 0.1 mg / ml, about 0.05 mg / ml, about 0.06 mg / ml, about 0.08 mg / ml, about 0.10 mg / ml, about 0.12 mg / ml, about 0.16 mg / ml. In some embodiments, the cabazitaxel albumin composition is a clear aqueous infusion solution, and the mass concentration of cabazitaxel in the cabazitaxel albumin composition is about 0.08 mg / ml.

[0022] In some embodiments, the cabazitaxel albumin composition is a clear aqueous infusion solution, and the mass concentration of human serum albumin (g / ml) is about 0.1% to about 25%, for example, about 0.3% to about 20%, about 0.5% to about 10%, about 0.5% to about 5%, about 0.3% to about 1.5%, about 0.5% to about 1.2%, 0.2% to about 1.5%, about 1%, about 1.2%, about 1.5%. In some embodiments, the cabazitaxel albumin composition is a clear aqueous infusion solution, and the mass concentration of human serum albumin (g / ml) is about 1.2%.

[0023] In some embodiments, the cabazitaxel albumin composition further comprises one or more of ethanol, a parenterally acceptable carrier, an amino acid (e.g., arginine), and an organic acid. For example, the cabazitaxel albumin composition comprises cabazitaxel, human albumin, and an amino acid; the cabazitaxel albumin composition comprises cabazitaxel, human albumin, and ethanol; the cabazitaxel albumin composition comprises cabazitaxel, human albumin, ethanol, and an organic acid; the cabazitaxel albumin composition comprises cabazitaxel, human albumin, ethanol, an organic acid, and a parenterally acceptable carrier.

[0024] In some embodiments, the cabazitaxel albumin composition is a solid dosage form. In some embodiments, the solid dosage form of the cabazitaxel albumin composition is reconstituted with a parenterally acceptable carrier to obtain a liquid dosage form of the cabazitaxel albumin composition.

[0025] In some embodiments, the cabazitaxel albumin composition further comprises a pH adjuster. pH adjusters include, but are not limited to, diethanolamine, triethanolamine, sodium hydroxide, hydrochloric acid, citric acid, sodium dihydrogen phosphate, or mixtures thereof. In some embodiments, the pH adjuster is citric acid. In some embodiments, the pH of the cabazitaxel albumin composition is about 4 to about 9.5. In some embodiments, the pH of the cabazitaxel albumin composition is about 5 to about 9. In some embodiments, the pH of the cabazitaxel albumin composition is about 5 to about 8. In some embodiments, the pH of the cabazitaxel albumin composition is about 6 to about 8. In some embodiments, the pH of the cabazitaxel albumin composition is about 6.5 to about 7.5. In some embodiments, the pH of the cabazitaxel albumin composition is about 4 to about 9. In some embodiments, the pH of the cabazitaxel albumin composition is about 4 to about 8. In some embodiments, the pH of the cabazitaxel albumin composition is about 5 to about 8.5. In some embodiments, the pH of the cabazitaxel albumin composition is about 6 to about 7.5.

[0026] In some embodiments, the cabazitaxel albumin composition is prepared within 24 hours prior to infusion into the patient. In some embodiments, the cabazitaxel albumin composition is prepared within 12 hours prior to infusion into the patient. In some embodiments, the cabazitaxel albumin composition is prepared within 8 hours prior to infusion into the patient. In some embodiments, the cabazitaxel albumin composition is prepared within 6 hours prior to infusion into the patient. In some embodiments, the cabazitaxel albumin composition is prepared within 4 hours prior to infusion into the patient. In some embodiments, the cabazitaxel albumin composition is prepared within 1 hour prior to infusion into the patient.

[0027] In some embodiments, at least 10% of the cabazitaxel in the liquid dosage form is free (unbound in solution) cabazitaxel. In some embodiments, at least 20% of the cabazitaxel in the liquid dosage form is free (unbound in solution) cabazitaxel. In some embodiments, at least 30% of the cabazitaxel in the liquid dosage form is free (unbound in solution) cabazitaxel. In some embodiments, at least 40% of the cabazitaxel in the liquid dosage form is free (unbound in solution) cabazitaxel. In some embodiments, at least 50% of the cabazitaxel in the liquid dosage form is free (unbound in solution) cabazitaxel. In some embodiments, about 10% to about 90% of the cabazitaxel in the liquid dosage form is free (unbound in solution) cabazitaxel. In some embodiments, about 20% to about 80% of the cabazitaxel in the liquid dosage form is free (unbound in solution) cabazitaxel. In some embodiments, about 30% to about 70% of the cabazitaxel in the liquid dosage form is free (unbound in solution) cabazitaxel. In some embodiments, about 55% to about 65% of the cabazitaxel in the liquid dosage form is free (unbound in solution) cabazitaxel. The amount of free (unbound in solution) cabazitaxel is determined by ultrafiltration through a 30-kDa membrane.

[0028] In some embodiments, cabazitaxel and human serum albumin in the cabazitaxel albumin composition are in the same system. In some embodiments, cabazitaxel and human serum albumin in the cabazitaxel albumin composition are in two different systems.

[0029] In some embodiments, the cabazitaxel albumin composition comprises: (a) a first liquid composition comprising cabazitaxel and ethanol, and (b) a human albumin solution.

[0030] In some embodiments, the cabazitaxel albumin composition comprises: (a) a first liquid composition comprising cabazitaxel and ethanol, and (b) a second aqueous composition comprising human serum albumin and a parenterally acceptable carrier.

[0031] In some embodiments, the first liquid composition is a sterile solution.

[0032] In some embodiments, the second aqueous composition is a sterile solution.

[0033] In some embodiments, the ethanol in the first liquid composition is anhydrous ethanol.

[0034] In some embodiments, prior to infusion or administration to a patient, a first liquid composition comprising cabazitaxel and ethanol is mixed with a second aqueous composition comprising human albumin to form the liquid dosage form.

[0035] In some embodiments, the volume of the first liquid composition is about 0.5 ml to about 30 ml, for example, about 1 ml to about 20 ml, about 1 ml to about 5 ml, about 2 ml, 2.5 ml, 3 ml, 4 ml, 4.5 ml, 6 ml. In some embodiments, the volume of the first liquid composition is about 3 ml.

[0036] In some embodiments, the concentration of cabazitaxel in the first liquid composition is about 1 mg / ml to about 50 mg / ml, for example, about 1 mg / ml to about 30 mg / ml, about 5 mg / ml to about 15 mg / ml, about 8 mg / ml, 10 mg / ml, 12 mg / ml, 15 mg / ml. In some embodiments, the concentration of cabazitaxel in the first liquid composition is about 10 mg / ml.

[0037] In some embodiments, the weight ratio of cabazitaxel to ethanol in the first liquid composition is about 1:25 to about 1:500, for example, about 1:25 to about 1:400, about 1:25 to about 1:300, about 1:25 to about 1:200, about 1:30 to about 1:200, about 1:40 to about 1:100, about 1:50 to about 1:80, about 1:60 to about 1:70, about 1:60 to about 1:65, about 1:62, about 1:63, about 1:64. In some embodiments, the weight ratio of cabazitaxel to ethanol in the first liquid composition is about 1:60 to about 1:65.

[0038] In some embodiments, the first liquid composition further comprises an organic acid (such as citric acid).

[0039] In some embodiments, the first liquid composition is an injectable pharmaceutical composition.

[0040] In some embodiments, the pH of the first liquid composition is about 3 to about 7. In some embodiments, the pH of the first liquid composition is about 3 to about 6.5. In some embodiments, the pH of the first liquid composition is about 3.5 to about 6.5. In some embodiments, the pH of the first liquid composition is about 3.5 to about 6. In some embodiments, the pH of the first liquid composition is about 3.5 to about 6. In some embodiments, the pH of the first liquid composition is about 3.5 to about 5.5. In some embodiments, the pH of the first liquid composition is about 4 to about 6. To determine the pH of the first liquid composition, the injectable pharmaceutical composition is mixed with water in a ratio of 3:2 (v / v) to obtain an aqueous solution, and the pH of the aqueous solution is then determined.

[0041] In some embodiments, the first liquid composition further comprises polyethylene glycol (eg, polyethylene glycol 300, polyethylene glycol 400).

[0042] In some embodiments, the weight ratio of cabazitaxel to polyethylene glycol in the first liquid composition is about 1:10 to about 1:100, for example, about 1:10 to about 1:90, about 1:10 to about 1:80, about 1:10 to about 1:70, about 1:10 to about 1:60, about 1:10 to about 1:50, about 1:10 to about 1:40, about 1:15 to about 1:30, about 1:20 to about 1:25, about 1:20, about 1:21, about 1:22, about 1:23. In some embodiments, the weight ratio of cabazitaxel to polyethylene glycol in the first liquid composition is about 1:20 to about 1:25.

[0043] In some embodiments, the volume of the second aqueous composition is from about 100 ml to about 1 L, for example, about 100 ml, about 125 ml, about 150 ml, about 200 ml, about 225 ml, about 250 ml, about 275 ml, about 300 ml, about 325 ml, about 350 ml, about 375 ml, about 400 ml, about 450 ml, about 500 ml, about 550 ml, about 600 ml, about 700 ml, about 800 ml, about 900 ml, about 1000 ml. In some embodiments, the volume of the second aqueous composition is about 375 ml.

[0044] In some embodiments, the second aqueous composition further comprises a parenterally acceptable carrier; further, the parenterally acceptable carrier comprises physiological saline and / or glucose solution. In some embodiments, the parenterally acceptable carrier is physiological saline (such as 0.9% sodium chloride solution).

[0045] In some embodiments, the mass concentration (g / ml) of human serum albumin in the second aqueous composition is about 0.1% to about 20%, for example, about 0.1% to about 10%, about 0.1% to about 2%, about 0.2% to about 5%, about 0.3% to about 2%, about 0.3% to about 1.5%, about 0.5% to about 2%, about 0.5% to about 1.5%, about 1.0% to about 1.3%, about 1.1% to about 1.3%, about 1.15% to about 1.25%. In some embodiments, the mass concentration (g / ml) of human serum albumin in the second aqueous composition is about 1.15% to about 1.25%.

[0046] In some embodiments, the first liquid composition is added to the second aqueous composition.

[0047] In some embodiments, the second aqueous composition is in an infusion bag or an infusion bottle.

[0048] In some embodiments, the first liquid composition is injected into an infusion bag or bottle of the second aqueous composition.

[0049] In some embodiments, each administration cycle of the cabazitaxel albumin composition is at least 14-35 days, for example, 14 days, 18 days, 21 days, 24 days, 28 days, or 35 days. In some embodiments, the cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle (21 days) every 3 weeks.

[0050] In some embodiments, after a single administration of the cabazitaxel albumin composition, the cabazitaxel AUC 0-48h The range is about 200-550 h*ng / mL, for example, about 300-550 h*ng / mL, about 400-450 h*ng / mL. In some embodiments, after a single administration of the cabazitaxel albumin composition, the cabazitaxel AUC 0-48h The range is about 400-450 h*ng / mL.

[0051] In some embodiments, after a single administration of the cabazitaxel albumin composition, the cabazitaxel AUC 0-49h In some embodiments, after a single administration of the cabazitaxel albumin composition, the cabazitaxel AUC is about 400-750 h*ng / mL, for example, about 400-700 h*ng / mL, about 500-700 h*ng / mL, about 550-700 h*ng / mL, about 550-600 h*ng / mL. 0-49h The range is about 550-600h*ng / mL.

[0052] In some embodiments, after a single administration of the cabazitaxel albumin composition, the cabazitaxel AUC 0-217h In some embodiments, after a single administration of the cabazitaxel albumin composition, the cabazitaxel AUC is about 700-1500 h*ng / mL, for example, about 700-1200 h*ng / mL, about 700-1100 h*ng / mL, about 800-1400 h*ng / mL, about 800-1200 h*ng / mL, about 800-1100 h*ng / mL, about 900-1200 h*ng / mL, about 900-1100 h*ng / mL, about 1000-1100 h*ng / mL. 0-217h The range is about 1000-1100h*ng / mL.

[0053] In some embodiments, after a single administration of the cabazitaxel albumin composition, the cabazitaxel AUC 0-∞The range of about 900-1700 h*ng / mL, for example, about 1000-1600 h*ng / mL, about 1000-1500 h*ng / mL, about 1000-1350 h*ng / mL, about 1150-1500 h*ng / mL, about 1150-1350 h*ng / mL, about 1250-1500 h*ng / mL, about 1250-1350 h*ng / mL. In some embodiments, after a single administration of the cabazitaxel albumin composition, the cabazitaxel AUC 0-∞ The range is about 1250-1350h*ng / mL.

[0054] In some embodiments, after a single administration of the cabazitaxel albumin composition, the cabazitaxel C max In some embodiments, after a single administration of the cabazitaxel albumin composition, the cabazitaxel C max The range is about 200-300ng / mL.

[0055] In some embodiments, after a single administration of the cabazitaxel albumin composition, cabazitaxel T max The range of about 0.5-1h, for example, about 0.6-1h, about 0.7-1h, about 0.7-0.9h, about 0.72-0.95h, about 0.72-0.92h. In some embodiments, after a single administration of the cabazitaxel albumin composition, cabazitaxel T max The range is about 0.72-0.92h.

[0056] In some embodiments, after a single administration of the cabazitaxel albumin composition, cabazitaxel T 1 / 2 The range of about 50-150h, for example, about 50-150h, about 60-140h, about 70-130h, about 75-110h, about 75-100h, about 75-95h. In some embodiments, after a single administration of the cabazitaxel albumin composition, cabazitaxel T 1 / 2 The range is about 75-95h.

[0057] In some embodiments, the cabazitaxel albumin composition is used in combination with a corticosteroid to treat a cancer patient.

[0058] In some embodiments, the corticosteroid is a glucocorticoid or a mineralocorticoid. In some embodiments, the glucocorticoid is cortisol (Cortisol), prednisone (Prednisone), dexamethasone (Dexamethasone), methylprednisolone (Methylprednisolone) or prednisolone (Prednisolone). In some embodiments, the glucocorticoid is prednisone or prednisolone. In some embodiments, the glucocorticoid is prednisone acetate. In some embodiments, the glucocorticoid is prednisone. In some embodiments, prednisone or prednisolone are administered at a dosage of 10mg / day. In some embodiments, prednisone is administered at a dosage of 10mg / day.

[0059] In some embodiments, the cabazitaxel albumin composition reduces adverse reactions of the cancer and / or improves disease control rate.

[0060] In some embodiments, the cancer described herein is an advanced cancer. In some embodiments, the cancer is advanced prostate cancer. In some embodiments, the cancer is metastatic castration-resistant prostate cancer. In some embodiments, the cancer is prostate cancer that has failed docetaxel treatment.

[0061] In some embodiments, the patient with prostate cancer is a patient with castration-resistant prostate cancer. In some embodiments, the patient with prostate cancer is a patient with metastatic prostate cancer. In some embodiments, the patient with prostate cancer is a patient with metastatic castration-resistant prostate cancer who has failed docetaxel treatment.

[0062] In some embodiments, a cabazitaxel albumin composition is provided, comprising cabazitaxel and human serum albumin, and containing no surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with a corticosteroid; the cabazitaxel albumin composition is administered by infusion for treating cancer patients, and the cabazitaxel dose infused into the patient is about 10 to 40 mg / m 2 .

[0063] In some embodiments, a cabazitaxel albumin composition is provided, comprising cabazitaxel and human serum albumin, and containing no surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 or about 25 mg / m2 .

[0064] In some embodiments, a cabazitaxel albumin composition is provided, comprising cabazitaxel and human serum albumin, and containing no surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating patients with advanced prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 or about 25 mg / m 2 .

[0065] In some embodiments, a cabazitaxel albumin composition is provided, comprising cabazitaxel and human serum albumin, and containing no surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 to 25 mg / m 2 (e.g. about 20 mg / m 2 , about 25 mg / m 2 ), the cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks.

[0066] In some embodiments, a cabazitaxel albumin composition is provided, comprising cabazitaxel and human serum albumin, and containing no surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 to 25 mg / m 2 (e.g. about 20 mg / m 2 , about 25 mg / m 2 ), the cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0067] In some embodiments, a cabazitaxel albumin composition is provided, comprising cabazitaxel and human albumin at a weight ratio of about 150:1, and containing no surfactant; the cabazitaxel albumin composition is a clear aqueous infusion solution, wherein the concentration of cabazitaxel in the cabazitaxel albumin composition is about 0.08 mg / mL, and the content of human albumin is about 1.2% (w / v); the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20-25 mg / m 2 (e.g. about 20 mg / m 2 , about 25 mg / m 2 ), the cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0068] In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the cabazitaxel dose is about 25 mg / m 2 In some embodiments, the cabazitaxel albumin composition is administered to the patient repeatedly in a new cycle every 3 weeks. In some embodiments, the prednisone is administered at a dose of 10 mg / day.

[0069] In some embodiments, the cabazitaxel dose is about 20 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks. In some embodiments, the cabazitaxel dose is about 25 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks. In some embodiments, the cabazitaxel dose is about 20 mg / m 2 , the prednisone is administered at a dose of 10 mg / day. In some embodiments, the cabazitaxel dose is about 25 mg / m 2 In some embodiments, the cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day. In some embodiments, the cabazitaxel dose is about 20 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day. In some embodiments, the cabazitaxel dose is about 25 mg / m 2The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0070] Another aspect of the present invention provides the use of the above-mentioned cabazitaxel albumin composition in the preparation of a drug for treating cancer, wherein the cabazitaxel dose is about 10-40 mg / m 2 , for example, about 20 mg / m 2 Up to 25 mg / m 2 , about 20 mg / m 2 , about 25 mg / m 2 .

[0071] Another aspect of the present invention provides the use of a corticosteroid in combination with the above-mentioned cabazitaxel albumin composition in the preparation of a drug for treating cancer, wherein the cabazitaxel dose is about 10-40 mg / m 2 , for example, about 20 mg / m 2 Up to 25 mg / m 2 , about 20 mg / m 2 , about 25 mg / m 2 .

[0072] Another aspect of the present invention provides the use of the above-mentioned cabazitaxel albumin composition administered in combination with a corticosteroid in the preparation of a medicament for treating cancer, wherein the cabazitaxel dose is about 20 mg / m 2 or about 25 mg / m 2 .

[0073] Another aspect of the present invention provides a method for reducing adverse reactions caused by cabazitaxel and / or improving disease control rate, comprising formulating cabazitaxel into the above-mentioned cabazitaxel albumin composition.

[0074] Another aspect of the present invention provides a method for treating a cancer patient, comprising administering to the patient cabazitaxel at a dose of about 10-40 mg / m 2 (e.g. about 20 mg / m 2 Up to 25 mg / m 2 , about 20 mg / m 2 , about 25 mg / m 2 ) of the above-mentioned cabazitaxel albumin composition.

[0075] Another aspect of the present invention provides a method for treating a cancer patient, comprising administering to the patient a corticosteroid and cabazitaxel at a dose of about 10-40 mg / m 2 (e.g. about 20 mg / m 2 Up to 25 mg / m 2 , about 20 mg / m2 , about 25 mg / m 2 ) of the above-mentioned cabazitaxel albumin composition.

[0076] In some embodiments, the cabazitaxel dose is about 20 mg / m 2 or 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the cabazitaxel dose is about 25 mg / m 2 .

[0077] In some embodiments, the patient is a human. In some embodiments, the patient is of Asian population.

[0078] In some embodiments, the composition can reduce adverse reactions and / or disease control rate.

[0079] In some embodiments, the adverse reactions include: decreased neutrophil count, febrile neutropenia, decreased white blood cell count, and anemia.

[0080] In some embodiments, the adverse reactions include: decreased neutrophil count, febrile neutropenia.

[0081] In some embodiments, a use of a cabazitaxel albumin composition administered in combination with prednisone in the preparation of a medicament for treating metastatic castration-resistant prostate cancer is provided, wherein the cabazitaxel albumin composition comprises cabazitaxel and human serum albumin and does not contain a surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 or 25 mg / m 2 .

[0082] In some embodiments, a use of a cabazitaxel albumin composition administered in combination with prednisone in the preparation of a medicament for treating advanced prostate cancer is provided, wherein the cabazitaxel albumin composition comprises cabazitaxel and human serum albumin and does not contain a surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered by infusion for treating patients with advanced prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 or 25 mg / m 2 .

[0083] In some embodiments, a use of a cabazitaxel albumin composition administered in combination with prednisone in the preparation of a medicament for treating metastatic castration-resistant prostate cancer is provided, wherein the cabazitaxel albumin composition comprises cabazitaxel and human serum albumin and does not contain a surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 or 25 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks.

[0084] In some embodiments, a use of a cabazitaxel albumin composition administered in combination with prednisone in the preparation of a medicament for treating metastatic castration-resistant prostate cancer is provided, wherein the cabazitaxel albumin composition comprises cabazitaxel and human serum albumin and does not contain a surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 or 25 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0085] In some embodiments, a use of a cabazitaxel albumin composition administered in combination with prednisone in the preparation of a medicament for treating metastatic castration-resistant prostate cancer is provided, wherein the cabazitaxel albumin composition comprises cabazitaxel and human albumin at a weight ratio of about 150:1 and does not contain a surfactant; the cabazitaxel albumin composition is a clear aqueous infusion solution, wherein the concentration of cabazitaxel in the cabazitaxel albumin composition is about 0.08 mg / mL and the content of human albumin is about 1.2% (w / v); the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 or 25 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0086] In some embodiments, the prednisone is free prednisone.

[0087] In some embodiments, a method for treating metastatic castration-resistant prostate cancer is provided, comprising administering a cabazitaxel albumin composition to a patient, wherein the cabazitaxel albumin composition comprises cabazitaxel and human serum albumin and does not contain a surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with prednisolone; the cabazitaxel albumin composition is administered by infusion for treating a patient with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 or 25 mg / m 2 .

[0088] In some embodiments, a method for treating advanced prostate cancer is provided, comprising administering a cabazitaxel albumin composition to a patient, wherein the cabazitaxel albumin composition comprises cabazitaxel and human albumin and does not contain a surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with prednisolone; the cabazitaxel albumin composition is administered by infusion for treating a patient with advanced prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 or 25 mg / m 2 .

[0089] In some embodiments, a method for treating metastatic castration-resistant prostate cancer is provided, comprising administering a cabazitaxel albumin composition to a patient, wherein the cabazitaxel albumin composition comprises cabazitaxel and human serum albumin and does not contain a surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating a patient with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 or 25 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks.

[0090] In some embodiments, a method for treating metastatic castration-resistant prostate cancer is provided, comprising administering a cabazitaxel albumin composition to a patient, wherein the cabazitaxel albumin composition comprises cabazitaxel and human serum albumin and does not contain a surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating a patient with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 or 25 mg / m 2The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0091] In some embodiments, a method for treating metastatic castration-resistant prostate cancer is provided, comprising administering a cabazitaxel albumin composition to a patient, wherein the cabazitaxel albumin composition comprises cabazitaxel and human albumin at a weight ratio of about 150:1 and does not contain a surfactant; the cabazitaxel albumin composition is a clear aqueous infusion solution, wherein the concentration of cabazitaxel in the cabazitaxel albumin composition is about 0.08 mg / mL and the content of human albumin is about 1.2% (w / v); the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating a patient with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 or 25 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0092] In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the cabazitaxel dose is about 25 mg / m 2 In some embodiments, the cabazitaxel albumin composition is administered to the patient repeatedly in a new cycle every 3 weeks. In some embodiments, the prednisone is administered at a dose of 10 mg / day.

[0093] In some embodiments, the cabazitaxel albumin composition contains about 25-40 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 30 mg of cabazitaxel.

[0094] In some embodiments, the cabazitaxel dose is about 20 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks. In some embodiments, the cabazitaxel dose is about 25 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks. In some embodiments, the cabazitaxel dose is about 20 mg / m 2 , the prednisone is administered at a dose of 10 mg / day. In some embodiments, the cabazitaxel dose is about 25 mg / m 2In some embodiments, the cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day. In some embodiments, the cabazitaxel dose is about 20 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day. In some embodiments, the cabazitaxel dose is about 25 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day. In some embodiments, the cabazitaxel dose is about 20 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks, the prednisone is administered at a dose of 10 mg / day, and the cabazitaxel albumin composition contains about 30 mg of cabazitaxel. In some embodiments, the cabazitaxel dose is about 25 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, the prednisone is administered at a dose of 10 mg / day, and the cabazitaxel albumin composition contains about 30 mg of cabazitaxel. Beneficial effects:

[0095] The cabazitaxel albumin composition of the present invention has advantages such as safety and higher tolerability in treating solid tumors (such as prostate cancer). DETAILED DESCRIPTION

[0096] The following will clearly and completely describe the concept and technical effects of the present invention in conjunction with the embodiments to fully understand the purpose, features and effects of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work are all within the scope of protection of the present invention.

[0097] Pharmaceutical compositions and pharmaceutical preparations

[0098] In one aspect, the present invention provides a cabazitaxel albumin composition, comprising cabazitaxel and human serum albumin, and containing no surfactant; the cabazitaxel albumin composition is a clear solution in liquid state, and the cabazitaxel albumin composition is administered by infusion for treating cancer patients, wherein the cabazitaxel dose infused into the patient is about 10-40 mg / m 2 .

[0099] In some embodiments, the cabazitaxel albumin composition contains about 5-40 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 5-35 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 10-40 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 10-35 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 15-40 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 15-35 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 20-40 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 20-35 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 25-40 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 25-35 mg of cabazitaxel. In some embodiments, the cabazitaxel albumin composition contains about 30 mg of cabazitaxel.

[0100] In some embodiments, the human albumin is natural human albumin and / or recombinant human albumin; it is substantially free of fatty acids. In some embodiments, the human albumin comes from freeze-dried human albumin powder or human albumin solution. In some embodiments, the human albumin comes from a human albumin solution. In some embodiments, the human albumin solution is a human albumin solution for infusion, which can be obtained commercially or homemade. In some embodiments of the present invention, the human albumin solution is an aqueous solution prepared by diluting commercially available human albumin for infusion. In some embodiments, the human albumin solution can be prepared by diluting a commercially available human albumin solution for infusion with an acceptable carrier for parenteral administration. Alternatively, human albumin can be prepared by mixing human albumin powder dissolved in water with other pharmaceutically acceptable stabilizers contained in commercially available albumin products.In some embodiments, the mass concentration (g / ml) of the human serum albumin solution described herein may be 0.01% to 60%, including but not limited to: 0.01% to 60%, 0.01% to 50%, 0.01% to 40%, 0.01% to 30%, 0.01% to 25%, 0.01% to 20%, 0.01% to 15%, 0.01% to 10%, 0.01% to 5%, 0.01% to 2%, 0.01% to 1%, 0.01% to 0.1%, 0.1% to 60%, 0.1% to 50%, 0.1% to 40%, 0.1% to 30%, 0.1% to 25 %, 0.1%-20%, 0.1%-15%, 0.1%-10%, 0.1%-5%, 0.1%-2%, 0.1%-1%, 0.5%-60%, 0.5%-50%, 0.5%-40%, 0.5%-30%, 0.5%-25%, 0.5%-20%, 0.5%-15%, 0.5%-10%, 0.5%-5%, 0.5%-2%, 0.5%-1%, 1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-25%, 1%-20%, 1%-15%, 1%-10%, 1%-5%, 1 %~2%, 2%~60%, 2%~50%, 2%~40%, 2%~30%, 2%~25%, 2%~20%, 2%~15%, 2%~10%, 2%~5%, 5%~60%, 5%~50%, 5%~40%, 5%~30%, 5%~25%, 5%~20%, 5%~15%, 5%~10%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10%~25%, 10%~20%, 10%~15%, 15%~60%, 15%~50%, 15%~40%, 15%~30%, 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 60%, 0.01%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 60%. In some embodiments, the mass concentration (g / ml) of the human albumin solution is 5%, 10%, 20% or 25%. In some embodiments, the mass concentration (g / ml) of the human serum albumin solution is 20%. In some embodiments, the mass concentration (g / ml) of the human serum albumin solution is 25%.

[0101] In some embodiments, the surfactant comprises polysorbate 80.

[0102] In some embodiments, the cabazitaxel albumin composition further comprises ethanol.

[0103] In some embodiments, the cabazitaxel albumin composition further comprises a parenterally acceptable carrier. In some embodiments, the parenterally acceptable carrier comprises a physiological saline solution and / or a glucose solution. In some embodiments, the parenterally acceptable carrier is a physiological saline solution.

[0104] In some embodiments, the cabazitaxel albumin composition further comprises an amino acid. In some preferred embodiments of the present invention, the amino acid may be arginine.

[0105] In some embodiments, the cabazitaxel albumin composition further comprises an organic acid. In some embodiments, the organic acid is selected from one or more of 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. In some embodiments, the organic acid is citric acid.

[0106] In some embodiments, the cabazitaxel albumin composition further comprises a pH adjuster. pH adjusters include, but are not limited to, diethanolamine, triethanolamine, sodium hydroxide, hydrochloric acid, citric acid, sodium dihydrogen phosphate, or mixtures thereof. In some embodiments, the pH adjuster is citric acid. In some embodiments, the pH of the cabazitaxel albumin composition is about 4 to about 9.5. In some embodiments, the pH of the cabazitaxel albumin composition is about 5 to about 9. In some embodiments, the pH of the cabazitaxel albumin composition is about 5 to about 8. In some embodiments, the pH of the cabazitaxel albumin composition is about 6 to about 8. In some embodiments, the pH of the cabazitaxel albumin composition is about 6.5 to about 7.5. In some embodiments, the pH of the cabazitaxel albumin composition is about 4 to about 9. In some embodiments, the pH of the cabazitaxel albumin composition is about 4 to about 8. In some embodiments, the pH of the cabazitaxel albumin composition is about 5 to about 8.5. In some embodiments, the pH of the cabazitaxel albumin composition is about 6 to about 7.5.

[0107] In some embodiments, the cabazitaxel albumin composition comprises (a) a first composition comprising cabazitaxel, and (b) a second composition comprising human albumin; and does not contain a surfactant.

[0108] In some embodiments, the mass of cabazitaxel in the first composition is about 5 mg to about 100 mg, such as about 5 mg to about 90 mg, about 10 mg to about 80 mg, about 15 mg to about 70 mg, about 20 mg to about 60 mg, about 25 mg to about 50 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg.

[0109] In some embodiments, the mass of human albumin in the second composition is about 1 g to about 10 g, about 10 g to about 20 g, about 20 g to about 30 g, about 30 g to about 40 g, about 40 g to about 50 g, about 5 g, about 10 g, about 15 g, about 20 g, about 25 g.

[0110] In some embodiments, the weight ratio of cabazitaxel in the first composition to human albumin in the second composition is about 1:10 to about 1:2000, for example, about 1:10 to about 1:1500, about 1:10 to about 1:1200, about 1:10 to about 1:1000, about 1:20 to about 1:800, about 1:30 to about 1:700, about 1:40 to about 1:600, about 1:50 To about 1:500, about 1:60 to about 1:450, about 1:70 to about 1:400, about 1:80 to about 1:350, about 1:90 to about 1:300 about 1:100 to about 1:250, about 1:120 to about 1:200, about 1:120 to about 1:160 about 1:130 to about 1:160, about 130, about 140, about 150, about 155, about 160.

[0111] In some embodiments, the first composition further comprises an organic acid. In some embodiments, the organic acid is citric acid.

[0112] In some embodiments, the weight ratio of cabazitaxel to citric acid in the first composition is from about 5000:1 to about 1:1, including but not limited to: about 2000:1 to about 1:1, about 1000:1 to about 1:1, about 500:1 to about 1:1, about 5000:1 to about 10:1, about 2000:1 to about 10:1, about 1000:1 to about 10:1, about 1000:1 to about 100:1, about 600:1 to about 200:1, about 500:1 to about 10:1, about 700:1 to about 200:1, about 250:1, about 5000:1, about 2000:1, 5000:1.

[0113] In some embodiments, the cabazitaxel albumin composition comprises (a) a first liquid composition comprising cabazitaxel and ethanol, and (b) a human albumin solution; and does not contain a surfactant.

[0114] In some embodiments, the cabazitaxel albumin composition comprises: (a) a first liquid composition comprising cabazitaxel and ethanol, and (b) a second aqueous composition comprising human serum albumin and a parenterally acceptable carrier.

[0115] In some embodiments, the cabazitaxel albumin composition is in a liquid dosage form. Further, the liquid dosage form is an infusion solution; in some embodiments, the infusion solution is a sterile infusion solution.

[0116] In some embodiments, the cabazitaxel albumin composition is a clear aqueous infusion solution.

[0117] In some embodiments, the infusion solution is an aqueous infusion solution. Further, the aqueous infusion solution is a clear aqueous infusion solution.

[0118] In some embodiments, the cabazitaxel albumin composition is a solid dosage form, and the solid dosage form of the cabazitaxel albumin composition is reconstituted with a parenterally acceptable carrier to obtain a liquid dosage form of the cabazitaxel albumin composition.

[0119] In some preferred embodiments of the present invention, the liquid dosage form of the cabazitaxel albumin composition is for parenteral infusion, comprising cabazitaxel, human serum albumin, and ethanol, and does not contain a surfactant (e.g., polysorbate 80); further, 1 ml of the liquid dosage form contains no more than 10, no more than 20, no more than 30, no more than 50, no more than 100, no more than 150, or no more than 2000 particles larger than 10 μm. Or; further, 1 ml of the liquid dosage form contains no more than 5, no more than 10 particles larger than 25 μm; further, 1 ml of the liquid dosage form contains no more than 5 particles larger than 15 μm; further, 1 ml of the liquid dosage form contains no more than 20 particles larger than 25 μm.

[0120] In some embodiments, the liquid dosage form does not include lipids (eg, soybean oil).

[0121] In some embodiments, the mass concentration of cabazitaxel in the liquid dosage form is about 0.01 mg / ml to about 1 mg / ml, about 0.01 mg / ml to about 0.5 mg / ml, about 0.01 mg / ml to about 0.3 mg / ml, about 0.01 mg / ml to about 0.2 mg / ml, about 0.02 mg / ml to about 0.25 mg / ml, about 0.02 mg / ml to about 0.2 mg / ml, about 0.03 mg / ml to about 1 mg / ml, about 0.03 mg / ml to about 0.5 mg / ml l, about 0.03 mg / ml to about 0.3 mg / ml, about 0.03 mg / ml to about 0.2 mg / ml, about 0.03 mg / ml to about 0.15 mg / ml, about 0.03 mg / ml to about 0.1 mg / ml, about 0.05 mg / ml to about 0.15 mg / ml, about 0.08 mg / ml to about 0.1 mg / ml, 0.05 mg / ml to about 1 mg / ml, about 0.05 mg / ml to about 0.5 mg / ml, about 0.05 mg / ml to about 0.3 mg / ml, about 0.05 mg / ml to about 0.2 mg / ml, about 0.07 mg / ml to about 1 mg / ml, about 0.07 mg / ml to about 0.5 mg / ml, about 0.07 mg / ml to about 0.3 mg / ml, about 0.07 mg / ml to about 0.2 mg / ml, about 0.1 mg / ml to about 1 mg / ml, about 0.1 mg / ml to about 0.5 mg / ml, about 0.1 mg / ml to about 0.3 mg / ml, about 0.1 mg / ml to about 0.2 mg / ml, about 0.05 mg / ml ml, about 0.06 mg / ml, about 0.07 mg / ml, about 0.08 mg / ml, about 0.09 mg / ml, about 0.10 mg / ml, about 0.11 mg / ml, about 0.12 mg / ml, about 0.13 mg / ml, about 0.14 mg / ml, about 0.15 mg / ml, about 0.16 mg / ml, about 0.17 mg / ml, about 0.18 mg / ml, about 0.19 mg / ml, about 0.20 mg / ml, about 0.25 mg / ml or about 0.30 mg / ml.

[0122] In some embodiments, the mass concentration (g / ml) of human serum albumin in the liquid dosage form is 0.1% to about 25%, about 0.1% to about 20%, about 0.2% to about 20%, 0.5% to about 20%, about 0.5% to about 15%, about 0.5% to about 10%, about 0.25% to about 10%, about 1% to about 10%, about 0.3% to about 8%, about 0.3% to about 5%, about 0.5% to about 5%, about 0.3% to about 2.5%, about 0.3% to about 1.5% , about 0.5% to about 1.2%, about 0.5% to about 1%, 0.2% to about 1.5%, about 0.1% to about 5%, about 0.2% to about 5%, about 5% to about 10%, about 1% to about 10%, about 1% to about 5%, about 0.3% to about 3%, about 2% to about 6%, about 0.5% to about 4%, 0.5% to about 5%, about 5% to about 10%, about 1% to about 5%, about 0.5% to about 3%, about 0.3% to about 3%, about 0.2% to about 6%, about 2% to about 6%.

[0123] In some embodiments, the weight ratio of human serum albumin to cabazitaxel in the liquid dosage form is about 10:1 to about 2000:1, about 10:1 to about 500:1, about 20:1 to about 200:1, about 50:1 to about 150:1, about 150:1, about 120:1, about 100:1, about 80:1, about 60:1, or about 50:1, 50:1 to about 2000:1, about 50:1 to about 150:1, about 150:1, about 120:1, about 100:1, about 80:1, about 60:1, or about 50:1, 50:1 to about 2000:1, about 5 0:1 to about 1000:1, about 50:1 to about 600:1, about 100:1 to about 2000:1, about 100:1 to about 1000:1, about 100:1 to about 600:1, about 50:1 to about 300:1, about 100:1 to about 200:1, about 100:1 to about 300:1, about 200:1 to about 600:1, about 300:1 to about 800:1.

[0124] In some embodiments, the volume concentration of ethanol in the liquid dosage form is no more than 15% (v / v), no more than 10% (v / v), no more than 5% (v / v), no more than 3% (v / v), no more than 2% (v / v), no more than 1.5% (v / v), no more than 1% (v / v), no more than 0.8% (v / v), no more than 0.7% (v / v), about 0.1% to about 15% (v / v), about 0.2% to about 10% (v / v), about 0.1% to about 10% (v / v), about 0.5% to about 3% (v / v), about 0 %. 0.1% to about 3% (v / v), about 1% to about 5% (v / v), about 0.1% to about 5% (v / v), about 0.5% to about 5% (v / v), about 0.5% to about 10% (v / v), about 0.5% to about 3% (v / v), about 2% to about 8% (v / v), about 0.2% to about 4% by volume, about 0.1% to about 3% by volume, about 0.5% to about 2% by volume, or about 0.7% to about 1.5% by volume, about 0.5%, about 0.7% by volume, about 0.8% by volume, about 1% by volume, or about 2% by volume.

[0125] In some embodiments, the volume of ethanol in the liquid dosage form is no more than 30 ml, no more than 15 ml, no more than 10 ml, no more than 5 ml, or no more than 2.5 ml.

[0126] In some embodiments, the liquid dosage form has a pH of about 4 to about 9.5, about 5 to about 9, about 5 to about 8, about 6 to about 8, about 6.5 to about 7.5, about 4 to about 9, about 4 to about 8, about 5 to about 8.5, about 6 to about 7.5.

[0127] In some embodiments, the liquid dosage form remains clear and free of precipitation for at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, at least 8 hours. In some embodiments, when the liquid dosage form is maintained at about 20-25° C., the liquid dosage form remains clear and free of precipitation for at least 1 hour, 2 hours, 3 hours, 4 hours, or 6 hours. In some embodiments, when the liquid dosage form is maintained at about 2-8° C., the liquid dosage form remains clear and free of precipitation for at least 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, or 24 hours.

[0128] In some embodiments, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, about 10% to about 90%, about 20% to about 80%, about 30% to about 70% of the cabazitaxel in the liquid dosage form is free (unbound in solution) cabazitaxel. The mass concentration of free (unbound in solution) cabazitaxel in the liquid dosage form is about 0.001 mg / ml to about 0.2 mg / ml, about 0.005 mg / ml to about 0.2 mg / ml, about 0.01 mg / ml to about 0.2 mg / ml, about 0.02 mg / ml to about 0.2 mg / ml, about 0.002 mg / ml to about 0.15 mg / ml, about 0.005 mg / ml to about 0.15 mg / ml, about 0.01 mg / ml to about 0.15 mg / ml, about 0.02 mg / ml to about 0.15 mg / ml, about 0.005 mg / ml to about 0.12 mg / ml, about 0.01 mg / ml to about 0.12 mg / ml, about 0.02 mg / ml to about 0.12 mg / ml, about 0.002 mg / ml to about 0.10 mg / ml, about 0.005 mg / ml to about 0.10 mg / ml l, about 0.01 mg / ml to about 0.10 mg / ml, about 0.02 mg / ml to about 0.10 mg / ml, about 0.02 mg / ml to about 0.08 mg / ml, about 0.03 mg / ml to about 0.08 mg / ml, about 0.03 mg / ml to about 0.06 mg / ml, about 0.020 mg / ml, about 0.025 mg / ml, about 0.030 mg / ml, about 0.035 mg / ml The amount of free (unbound in solution) cabazitaxel was determined by ultrafiltration through a 30-kDa membrane.

[0129] In some embodiments, prior to infusion or administration to a patient, a first liquid composition comprising cabazitaxel and ethanol is mixed with a second aqueous composition comprising human albumin to form the liquid dosage form.

[0130] In some embodiments, the volume of the first liquid composition is about 0.5 ml to about 30 ml, about 1 ml to about 20 ml, about 1 ml to about 10 ml, about 1 ml to about 5 ml, about 1 ml, 1.5 ml, 2 ml, 2.5 ml, 3 ml, 3.5 ml, 4 ml, 4.5 ml, 5 ml, 5.5 ml, 6 ml, 9 ml, 12 ml, 15 ml, 18 ml, 21 ml, 24 ml, 27 ml, 30 ml.

[0131] In some embodiments, the volume of the second aqueous composition is about 100 ml to about 1 L, about 100 ml to about 600 ml, about 150 ml to about 500 ml, about 150 ml to about 450 ml, about 250 ml to about 500 ml, about 250 ml to about 450 ml.

[0132] In some embodiments, the first liquid composition is a sterile solution.

[0133] In some embodiments, the second aqueous composition is a sterile solution.

[0134] In some embodiments, the mass of cabazitaxel in the first liquid composition is about 5 mg to about 100 mg, such as about 5 mg to about 90 mg, about 10 mg to about 80 mg, about 15 mg to about 70 mg, about 20 mg to about 60 mg, about 25 mg to about 50 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg.

[0135] In some embodiments, the mass concentration of cabazitaxel in the first liquid composition is about 1 mg / ml to about 50 mg / ml, about 2 mg / ml to about 45 mg / ml, about 2 mg / ml to about 40 mg / ml, about 3 mg / ml to about 35 mg / ml, about 4 mg / ml to about 30 mg / ml, about 5 mg / ml to about 25 mg / ml, about 5 mg / ml to about 20 mg / ml, about 10 mg / ml, or about 5 mg / ml.

[0136] In some embodiments, the first liquid composition further comprises an organic acid. In some embodiments, the organic acid is citric acid.

[0137] In some embodiments, the weight ratio of cabazitaxel to citric acid in the first liquid composition is about 5000:1 to about 1:1, including but not limited to about 2000:1 to about 1:1, about 1000:1 to about 1:1, about 500:1 to about 1:1, about 5000:1 to about 10:1, about 2000:1 to about 10:1, about 1000:1 to about 10:1, about 1000:1 to about 100:1, about 600:1 to about 200:1, about 500:1 to about 10:1, and about 700:1 to about 200:1.

[0138] In some embodiments, the weight ratio of cabazitaxel in the first liquid composition to human albumin in the second aqueous composition is about 1:10 to about 1:2000, for example, about 1:10 to about 1:1500, about 1:10 to about 1:1200, about 1:10 to about 1:1000, about 1:20 to about 1:800, about 1:30 to about 1:700, about 1:40 to about 1:600, about 1: 1:50 to about 1:500, about 1:60 to about 1:450, about 1:70 to about 1:400, about 1:80 to about 1:350, about 1:90 to about 1:300 about 1:100 to about 1:250, about 1:120 to about 1:200, about 1:120 to about 1:160 about 1:130 to about 1:160, about 130, about 140, about 150, about 155, about 160.

[0139] In some embodiments, the first liquid composition further comprises other organic solvents (e.g., propylene glycol, polyethylene glycol (hereinafter referred to as "PEG"), etc.). Preferably, the molecular weight of PEG is about 300 (i.e., PEG 300) or about 400 (i.e., PEG 400). If desired, PEG of other molecular weights known to those skilled in the art may be included in alternative embodiments.

[0140] In some embodiments, the weight ratio of cabazitaxel to polyethylene glycol in the first liquid composition is from about 1:10 to about 1:100, e.g., from about 1:10 to about 1:90, from about 1:10 to about 1:95, from about 1:10 to about 1:85, from about 1:10 to about 1:80, from about 1:10 to about 1:75, from about 1:10 to about 1:70, from about 1:10 to about 1:65, from about 1:10 to about 1:60, from about 1:10 to about 1:55, from about 1:10 to about 1:50, from about 1:10 to about 1:45, from about 1:10 to about 1:40, from about 1:15 to about 1:40, from about 1:15 to about 1:30, from about 1:20 to about 1:30, from about 1:20 to about 1:25, from about 1:20, from about 1:21, from about 1:22, from about 1:23. In some embodiments, the weight ratio of cabazitaxel to polyethylene glycol in the first liquid composition is about 1:20 to about 1:25.

[0141] In some embodiments, the first liquid composition comprises cabazitaxel, ethanol, and propylene glycol. In some embodiments, the first liquid composition comprises cabazitaxel, ethanol, and PEG (polyethylene glycol). In some embodiments, the first liquid composition comprises cabazitaxel, ethanol, and PEG 300. In some embodiments, the first liquid composition comprises cabazitaxel, ethanol, and PEG 400. In some embodiments, the first liquid composition comprises cabazitaxel, ethanol, and citric acid. In some embodiments, the first liquid composition comprises cabazitaxel, ethanol, propylene glycol, and citric acid. In some embodiments, the first liquid composition comprises cabazitaxel, ethanol, and citric acid. In some embodiments, the first liquid composition comprises cabazitaxel, ethanol, PEG (e.g., PEG 300, PEG 400), and citric acid.

[0142] In some embodiments, the second aqueous composition further comprises a parenterally acceptable carrier. Further, the parenterally acceptable carrier comprises physiological saline and / or glucose solution.

[0143] In some embodiments, the second aqueous composition is prepared by adding a human albumin solution to a parenterally acceptable carrier. In some embodiments, the second aqueous composition is prepared by adding a human albumin solution to an infusion bag or bottle containing a parenterally acceptable carrier. In some embodiments, the second aqueous composition is prepared by adding a human albumin infusion solution to a parenterally acceptable carrier. In some embodiments, the second aqueous composition is prepared by adding a human albumin infusion solution to an infusion bag or bottle containing a parenterally acceptable carrier.

[0144] In some embodiments, the mass concentration (g / ml) of human serum albumin in the second aqueous composition is about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 10%, about 0.1% to about 8%, about 0.1% to about 6%, about 0.1% to about 4%, about 0.1% to about 2%, about 0.2% to about 5%, about 0.3% to about 2%, about 0.3% to about 1.5%, about 0.5% to about 2%, about 0.5% to about 1.5%, about 1.0% to about 1.3%, about 1.1% to about 1.3%, about 1.15% to about 1.25%.

[0145] In some embodiments, the second aqueous composition comprises about 0.1 g to about 20 g, about 0.5 g to about 15 g, about 0.5 g to about 10 g, about 1 g to about 10 g, about 1 g to about 5 g, about 2 g to about 8 g, about 3 g to about 8 g, about 4 g to about 8 g, about 5 g to about 8 g of human albumin.

[0146] In some embodiments, the mixing is performed in an infusion bag or an infusion bottle.

[0147] In some embodiments, the first liquid composition is injected into an infusion bag or bottle of the second aqueous composition.

[0148] In some embodiments, the injection time is no more than 60 seconds, no more than 30 seconds, no more than 15 seconds, no more than 10 seconds, or no more than 5 seconds.

[0149] In some embodiments, during the process of injecting the first liquid composition into the infusion bag or infusion bottle containing the second aqueous composition, stirring or agitation is not required. After the first liquid composition is injected into the infusion bag or infusion bottle, the first liquid composition and the second aqueous composition are thoroughly mixed (for example, by gently turning the bag containing the composition upside down by hand) to obtain a clear infusion solution without precipitation. In some embodiments, the infusion bag or infusion bottle containing the second aqueous composition remains stationary during the injection process. In some embodiments, the first liquid composition is injected below the liquid surface of the second aqueous composition during the injection process. In some embodiments, after the injection is completed, the infusion bag or infusion bottle is repeatedly and gently turned upside down to thoroughly mix the first liquid composition and the second aqueous composition. In some embodiments, after the injection is completed, the infusion bag or infusion bottle is gently turned upside down until a clear solution without precipitation is obtained. In some embodiments, after the injection is completed, the infusion bag or infusion bottle is gently turned upside down for about 5 seconds to about 10 minutes. In some embodiments, after the injection is completed, the infusion bag or infusion bottle is gently turned upside down for about 10 seconds to about 5 minutes. In some embodiments, after the injection is completed, the infusion bag or infusion bottle is gently inverted upside down for about 0.5 minutes to about 3 minutes. In some embodiments, after the injection is completed, the first liquid composition and the second aqueous composition are fully mixed until a clear infusion solution without precipitation is obtained.

[0150] In some embodiments, the first liquid composition and the second aqueous composition are mixed within less than or equal to about 24 hours, less than or equal to about 8 hours, less than or equal to about 6 hours, less than or equal to about 2 hours, or less than or equal to about 1 hour prior to infusion or administration to a patient.

[0151] In some embodiments, the liquid dosage form of the cabazitaxel albumin composition comprises two compositions that are mixed in an infusion bag or bottle prior to infusion or administration to a patient, the two compositions comprising: (a) a first liquid composition comprising cabazitaxel and ethanol, and (b) a second aqueous composition comprising human serum albumin and a parenterally acceptable carrier, wherein the liquid dosage form does not contain a surfactant (e.g., polysorbate 80).

[0152] In some embodiments, a liquid dosage form of a cabazitaxel albumin composition comprises two compositions that are mixed prior to infusion or administration to a patient, the two compositions comprising: (a) a first liquid composition comprising about 5 mg to about 60 mg of cabazitaxel and about 0.5 ml to about 15 ml of ethanol, and (b) a second aqueous composition comprising about 0.5 g to about 20 g of human albumin in a parenterally acceptable vehicle. In some preferred embodiments of the present invention, a cabazitaxel pharmaceutical formulation comprises two compositions that are mixed prior to infusion or administration to a patient, the two compositions comprising: (a) a first liquid composition comprising citric acid, about 5 mg to about 60 mg of cabazitaxel and ethanol, and (b) a second aqueous composition comprising about 0.5 g to about 20 g of human albumin in a parenterally acceptable vehicle. In some preferred embodiments of the present invention, the cabazitaxel pharmaceutical formulation comprises two compositions that are mixed prior to infusion or administration to a patient, the two compositions comprising: (a) a first liquid composition comprising about 10 mg to about 50 mg of cabazitaxel, citric acid, and ethanol, and (b) a second aqueous composition comprising about 1 g to about 10 g of human albumin in a parenterally acceptable carrier. In some embodiments, the first liquid composition comprises about 15 mg to about 40 mg of cabazitaxel, citric acid, and ethanol. In some embodiments, the second aqueous composition comprises about 1.5 g to about 10 g of human albumin. In some embodiments, the first liquid composition comprises about 15 mg to about 40 mg of cabazitaxel, citric acid, ethanol, and polyethylene glycol 300. In some embodiments, the second aqueous composition comprises about 2 g to about 5 g of human albumin.

[0153] In some embodiments, the cabazitaxel is free cabazitaxel.

[0154] In some embodiments, the liquid dosage forms of the present invention are described in WO2022 / 056396 and other family patent applications / patents, the entire contents of which (including term definitions) are incorporated herein for all purposes.

[0155] In some embodiments, the cabazitaxel albumin composition is administered to a patient in need thereof by a parenteral route, for example, the cabazitaxel albumin composition is administered to a patient in need thereof by infusion (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular administration, including drip). In some embodiments, the cabazitaxel albumin composition is administered to a patient in need thereof by intravenous drip.

[0156] In some embodiments of the present invention, the infusion time is about 30-120 min, about 30-100 min, about 30-90 min, about 30-80 min, about 30-70 min, about 30-60 min, about 40-120 min, about 40-100 min, about 40-90 min, about 40-80 min, about 40-70 min, about 40-60 min, about 50-120 min, about 50-100 min, about 50-90 min, about 50-80 min, about 50-70 min, about 50-60 min, about 30 min, about 40 min, about 45 min, about 50 min, about 60 min. The specific infusion time can be determined and / or adjusted according to the actual clinical situation.

[0157] In some embodiments, the cabazitaxel albumin composition is used in combination with a corticosteroid to treat a cancer patient.

[0158] In some embodiments, the corticosteroid is a glucocorticoid or a mineralocorticoid. In some embodiments, the glucocorticoid is cortisol (Cortisol), prednisone (Prednisone), dexamethasone (Dexamethasone), methylprednisolone (Methylprednisolone) or prednisolone (Prednisolone). In some embodiments, the glucocorticoid is prednisone or prednisolone. In some embodiments, the glucocorticoid is prednisone acetate. In some embodiments, the glucocorticoid is prednisone. In some embodiments, prednisone or prednisolone are administered at a dosage of 10mg / day. In some embodiments, prednisone is administered at a dosage of 10mg / day.

[0159] In some embodiments, the patient is a patient with a solid tumor. In some embodiments, the patient is a patient with advanced cancer. In some embodiments, the patient is a patient with advanced solid tumors. In some embodiments, the patient is a patient with prostate cancer. In some embodiments, the patient is a patient with advanced prostate cancer. In some embodiments, the patient with prostate cancer is a patient with castration-resistant prostate cancer. In some embodiments, the prostate patient is a patient with metastatic prostate cancer. In some embodiments, the prostate patient is a patient with prostate cancer who has failed docetaxel treatment. In some embodiments, the prostate patient is an Asian patient. In some embodiments, the patient with prostate cancer is a patient with metastatic castration-resistant prostate cancer. In some embodiments, the patient with prostate cancer is a patient with metastatic castration-resistant prostate cancer who has failed docetaxel treatment. In some embodiments, the patient with prostate cancer is an Asian patient with metastatic castration-resistant prostate cancer who has failed docetaxel treatment. In some embodiments, the patient with prostate cancer is a patient with advanced prostate cancer.

[0160] The dosage can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the patient's age and health status. In some embodiments of the present invention, the dosage of cabazitaxel administered includes, but is not limited to, about 10 to 40 mg / m2 based on the patient's BSA (body surface area). 2 , about 10-35 mg / m 2 , about 10-30 mg / m 2 , about 10-25 mg / m 2 , about 10-20 mg / m 2 , about 20-40 mg / m 2 , about 20-35 mg / m 2 , about 20-30 mg / m 2 , about 20-25 mg / m 2 , about 10mg / m 2 , about 12 mg / m 2 , about 15mg / m 2 , about 18mg / m 2 , about 20mg / m 2 , about 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 .

[0161] Each administration cycle of the cabazitaxel albumin composition of the present invention is at least 14-35 days, for example, 14 days, 18 days, 21 days, 24 days, 28 days, or 35 days. The cabazitaxel albumin composition of the present invention can be administered until disease progression, death, or intolerable toxic reactions (whichever occurs earlier). In some embodiments, the treatment cycle is 1-24 cycles, for example, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, 5-6, 1, 2, 3, 4, 5, 6 treatment cycles. In some embodiments, the cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle (21 days) every 3 weeks.

[0162] In some embodiments, a cabazitaxel albumin composition is provided, comprising cabazitaxel and human serum albumin, and containing no surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0163] In some embodiments, a cabazitaxel albumin composition is provided, comprising cabazitaxel and human serum albumin, and containing no surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 25 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0164] In some embodiments, a cabazitaxel albumin composition is provided, comprising cabazitaxel and human albumin at a weight ratio of about 150:1, and containing no surfactant; the cabazitaxel albumin composition is a clear aqueous infusion solution, wherein the concentration of cabazitaxel in the cabazitaxel albumin composition is about 0.08 mg / mL, and the content of human albumin is about 1.2% (w / v); the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0165] In some embodiments, a cabazitaxel albumin composition is provided, comprising cabazitaxel and human albumin at a weight ratio of about 150:1, and containing no surfactant; the cabazitaxel albumin composition is a clear aqueous infusion solution, wherein the concentration of cabazitaxel in the cabazitaxel albumin composition is about 0.08 mg / mL, and the content of human albumin is about 1.2% (w / v); the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 25 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0166] In some embodiments, the cabazitaxel albumin composition can reduce adverse reactions and / or improve disease control rate.

[0167] In some embodiments, the liquid dosage form of the present invention has reduced adverse reactions compared to the original cabazitaxel injection (JEVTANA) and / or improved disease control rate in patients with advanced solid tumors compared to the original cabazitaxel injection (JEVTANA).

[0168] Kits / Test Kits

[0169] In one aspect, the present invention provides a kit for preparing the cabazitaxel albumin composition described in the present invention, comprising: a first container containing a composition comprising docetaxel; and a second container containing a composition comprising human albumin.

[0170] In some embodiments, the cabazitaxel albumin composition is in liquid dosage form.

[0171] In another aspect, the present invention provides a kit for preparing the liquid dosage form described herein, comprising: a first container comprising a liquid composition comprising docetaxel; and a second container comprising a liquid composition comprising human albumin.

[0172] In some embodiments, the kit includes a first container containing a liquid composition comprising docetaxel and ethanol and a second container containing a liquid composition comprising human albumin. In some embodiments, 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 albumin. In some embodiments, the kit includes a first container containing a liquid composition comprising docetaxel, citric acid and anhydrous ethanol and a second container containing a liquid composition comprising human albumin. In some embodiments, 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 albumin. In some embodiments, the kit includes a first container containing a liquid composition comprising docetaxel, citric acid and ethanol and a second container containing a human albumin solution (e.g., 20%, 25% or 5% (w / v)). In some embodiments, the liquid compositions in the first container and the second container are both sterile solutions.

[0173] In some embodiments, if necessary, the kit may further include the amino acid described in the present invention (eg, arginine).

[0174] In some embodiments, the kit is for infusion.

[0175] In some embodiments, the kits of the present invention are described in WO2022 / 056396 and other family members of patent applications / patents, the entire contents of which, including term definitions, are incorporated herein for all purposes.

[0176] Preparation method

[0177] In one aspect, the present invention provides a method for preparing the liquid dosage form of the present invention, comprising mixing the first liquid composition and the second liquid composition to obtain an infusion composition comprising cabazitaxel, human serum albumin, and ethanol; the first liquid composition is as described above, and the second liquid composition is as described above.

[0178] In some embodiments, the mixing is performed in an infusion bag or bottle. In some embodiments, the first liquid composition is injected into the infusion bag or bottle containing the second aqueous composition. In some embodiments, stirring or agitation is not required during the injection of the first liquid composition into the infusion bag or bottle containing the second aqueous composition. After the first liquid composition is injected into the infusion bag or bottle, the first liquid composition and the second aqueous composition are thoroughly mixed (e.g., by gently turning the bag containing the compositions upside down by hand) to obtain a clear infusion solution without precipitation.

[0179] In another aspect, the present invention provides a method for preparing the liquid dosage form of the present invention, comprising the following steps:

[0180] (i) obtaining a first liquid composition comprising cabazitaxel and ethanol;

[0181] (ii) obtaining a second liquid composition comprising human serum albumin in a parenterally acceptable carrier;

[0182] (iii) mixing the first liquid composition and the second liquid composition to obtain an infusion composition comprising cabazitaxel, human serum albumin, and ethanol.

[0183] In some embodiments, the method for preparing the liquid dosage form comprises the following steps:

[0184] (i) obtaining a first liquid composition comprising cabazitaxel and ethanol;

[0185] (ii) obtaining a second liquid composition in an infusion bag or an infusion bottle, wherein the second liquid composition comprises human serum albumin in a parenterally acceptable carrier;

[0186] (iii) mixing the first liquid composition and the second liquid composition to obtain an infusion composition comprising cabazitaxel, human serum albumin and ethanol in an infusion bag or an infusion bottle.

[0187] In some embodiments, the cabazitaxel albumin composition is prepared by reconstituted lyophilized powder of cabazitaxel and human serum albumin in a pharmaceutically acceptable carrier.

[0188] In some embodiments, the preparation of the lyophilized powder of cabazitaxel and human albumin comprises the following steps: (i) obtaining an organic solution of cabazitaxel in a polar water-miscible organic solvent; (ii) obtaining a first aqueous solution of human albumin; (iii) mixing the organic solution of cabazitaxel with the first aqueous solution of human albumin to obtain a second aqueous solution; and (iv) removing the solvent to obtain the lyophilized powder of cabazitaxel and human albumin.

[0189] In some embodiments, the preparation method of the cabazitaxel albumin composition and liquid dosage form thereof of the present invention is described in WO2017123760A1, WO2019204738A1, WO2022 / 056396 and other patent applications / patents of the same family, and the entire contents of the patents or patent applications (including term definitions) are incorporated herein for all purposes.

[0190] Methods and uses

[0191] In one aspect, the present invention provides a use of the above-mentioned cabazitaxel albumin composition in the preparation of a medicament for treating cancer, wherein the cabazitaxel dose is about 10-40 mg / m 2 In some embodiments, the dose of cabazitaxel is about 20-25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0192] In another aspect, the present invention provides a use of the above-mentioned cabazitaxel albumin composition in the preparation of a medicament for treating solid tumors, wherein the cabazitaxel dose is about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0193] In another aspect, the present invention provides a use of the above-mentioned cabazitaxel albumin composition in the preparation of a medicament for treating advanced cancer, wherein the cabazitaxel dose is about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0194] In another aspect, the present invention provides a use of the above-mentioned cabazitaxel albumin composition in the preparation of a medicament for treating advanced solid tumors, wherein the cabazitaxel dose is about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0195] In another aspect, the present invention provides a use of the above-mentioned cabazitaxel albumin composition in the preparation of a medicament for treating advanced prostate cancer, wherein the cabazitaxel dose is about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0196] In another aspect, the present invention provides a use of the above-mentioned cabazitaxel albumin composition in the preparation of a medicament for treating castration-resistant prostate cancer, wherein the cabazitaxel dose is about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0197] In another aspect, the present invention provides a use of the above-mentioned cabazitaxel albumin composition in the preparation of a medicament for treating metastatic prostate cancer, wherein the cabazitaxel dose is about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0198] In another aspect, the present invention provides a use of the above-mentioned cabazitaxel albumin composition in the preparation of a medicament for treating metastatic castration-resistant prostate cancer, wherein the cabazitaxel dose is about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0199] In another aspect, the present invention provides a use of the above-mentioned cabazitaxel albumin composition in the preparation of a medicament for treating prostate cancer that has failed docetaxel treatment, wherein the cabazitaxel dose is about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0200] In another aspect, the present invention provides a use of the above-mentioned cabazitaxel albumin composition in the preparation of a medicament for treating metastatic castration-resistant prostate cancer that has failed docetaxel treatment, wherein the cabazitaxel dose is about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0201] In some embodiments, the cabazitaxel albumin composition is used in combination with a corticosteroid, as defined above.

[0202] In some embodiments, the cabazitaxel albumin composition can reduce adverse reactions and / or disease control rate.

[0203] In another aspect, the present invention provides a method for reducing adverse reactions caused by cabazitaxel and / or improving disease control rate, comprising formulating cabazitaxel into the above-mentioned cabazitaxel albumin composition, wherein the cabazitaxel dose is about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0204] In another aspect, the present invention provides a method for treating solid tumors comprising administering to a patient cabazitaxel at a dose of about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0205] In another aspect, the present invention provides a method for treating advanced cancer comprising administering to a patient cabazitaxel at a dose of about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0206] In another aspect, the present invention provides a method for treating advanced solid tumors comprising administering to a patient cabazitaxel at a dose of about 20 mg / m2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0207] In another aspect, the present invention provides a method for treating advanced prostate cancer comprising administering to a patient cabazitaxel at a dose of about 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0208] In another aspect, the present invention provides a method for treating castration-resistant prostate cancer, comprising administering to a patient cabazitaxel at a dose of 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0209] In another aspect, the present invention provides a method for treating metastatic prostate cancer, comprising administering to a patient cabazitaxel at a dose of 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0210] In another aspect, the present invention provides a method for treating metastatic castration-resistant prostate cancer, comprising administering to a patient cabazitaxel at a dose of 20 mg / m 2 or about 25 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0211] In another aspect, the present invention provides a method for treating prostate cancer that has failed docetaxel treatment, comprising administering to a patient cabazitaxel at a dose of about 10-40 mg / m2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0212] In another aspect, the present invention provides a method for treating metastatic castration-resistant prostate cancer that has failed docetaxel treatment, comprising administering to the patient cabazitaxel at a dose of about 10-40 mg / m 2 In some embodiments, the cabazitaxel dose is about 20 mg / m 2 In some embodiments, the dose of cabazitaxel is about 25 mg / m 2 .

[0213] In some embodiments, the cabazitaxel albumin composition is used in combination with a corticosteroid, as defined above.

[0214] In some embodiments, the present invention provides a method of treating cancer in a subject, the method comprising:

[0215] i) mixing a first liquid composition described herein and a second aqueous composition described herein to obtain an infusion solution comprising cabazitaxel; and

[0216] ii) Cabazitaxel dose as needed (e.g., approximately 20 mg / m2 depending on the patient's BSA) 2 or about 25 mg / m 2 The preparation obtained in step (i) is administered by infusion to a subject in need thereof (amount of cabazitaxel in the dose).

[0217] In some embodiments, the present invention provides a method of treating cancer in a subject, the method comprising:

[0218] i) mixing a first liquid composition described herein and a second aqueous composition described herein to obtain a solution comprising the desired cabazitaxel dose (e.g., about 20 mg / m2 based on the patient's BSA). 2 or about 25 mg / m 2 infusion of cabazitaxel at a dose of 1 mg / kg; and

[0219] ii) administering the desired dose of cabazitaxel to a subject in need thereof by infusion using the preparation obtained in step (i).

[0220] In some embodiments, the desired docetaxel dose (e.g., about 20 mg / m2 based on the patient's BSA) is included. 2 or about 25 mg / m 2The infusion solution of cabazitaxel (amount of cabazitaxel dose) can be prepared in one or more infusion bags or bottles (e.g., in 2 infusion bags or bottles).

[0221] In some embodiments, a use of a cabazitaxel albumin composition administered in combination with prednisone in the preparation of a medicament for treating metastatic castration-resistant prostate cancer is provided, wherein the cabazitaxel albumin composition comprises cabazitaxel and human albumin at a weight ratio of about 150:1 and does not contain a surfactant; the cabazitaxel albumin composition is a clear aqueous infusion solution, wherein the concentration of cabazitaxel in the cabazitaxel albumin composition is about 0.08 mg / mL and the content of human albumin is about 1.2% (w / v); the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0222] In some embodiments, a use of a cabazitaxel albumin composition administered in combination with prednisone in the preparation of a medicament for treating metastatic castration-resistant prostate cancer is provided, wherein the cabazitaxel albumin composition comprises cabazitaxel and human albumin at a weight ratio of about 150:1 and does not contain a surfactant; the cabazitaxel albumin composition is a clear aqueous infusion solution, wherein the concentration of cabazitaxel in the cabazitaxel albumin composition is about 0.08 mg / mL and the content of human albumin is about 1.2% (w / v); the cabazitaxel albumin composition is administered by infusion for treating patients with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 25 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0223] In some embodiments, a method for treating metastatic castration-resistant prostate cancer is provided, comprising administering a cabazitaxel albumin composition to a patient, wherein the cabazitaxel albumin composition comprises cabazitaxel and human serum albumin and does not contain a surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating a patient with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 20 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0224] In some embodiments, a method for treating metastatic castration-resistant prostate cancer is provided, comprising administering a cabazitaxel albumin composition to a patient, wherein the cabazitaxel albumin composition comprises cabazitaxel and human albumin and does not contain a surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered in combination with prednisone; the cabazitaxel albumin composition is administered by infusion for treating a patient with metastatic castration-resistant prostate cancer, and the cabazitaxel dose infused into the patient is about 25 mg / m 2 The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day.

[0225] In some embodiments, the cabazitaxel dose is about 20 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks. In some embodiments, the cabazitaxel dose is about 25 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks. In some embodiments, the cabazitaxel dose is about 20 mg / m 2 , the prednisone is administered at a dose of 10 mg / day. In some embodiments, the cabazitaxel dose is about 25 mg / m 2 In some embodiments, the cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day. In some embodiments, the cabazitaxel dose is about 20 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day. In some embodiments, the cabazitaxel dose is about 25 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks, and the prednisone is administered at a dose of 10 mg / day. In some embodiments, the cabazitaxel dose is about 20 mg / m 2 The cabazitaxel albumin composition is administered to the patient in a new cycle every 3 weeks, the prednisone is administered at a dose of 10 mg / day, and the cabazitaxel albumin composition contains about 30 mg of cabazitaxel. In some embodiments, the cabazitaxel dose is about 25 mg / m 2The cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks, the prednisone is administered at a dose of 10 mg / day, and the cabazitaxel albumin composition contains about 30 mg of cabazitaxel.

[0226] In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is an advanced solid tumor. In some embodiments, the cancer is advanced prostate cancer. In some embodiments, the cancer is castration-resistant prostate cancer. In some embodiments, the cancer is metastatic castration-resistant prostate cancer. In some embodiments, the cancer is prostate cancer that has failed docetaxel treatment.

[0227] In some embodiments, the patient is of Asian population.

[0228] In some embodiments, the cabazitaxel albumin composition can reduce adverse reactions and / or disease control rate.

[0229] In some embodiments, the adverse reactions include but are not limited to: decreased neutrophil count, febrile neutropenia, decreased white blood cell count, and anemia. In some embodiments, the incidence of grade 3 / 4 severe decreased neutrophil count and febrile decreased neutrophil count caused by the liquid dosage form of the cabazitaxel albumin composition of the present invention is significantly lower than that of the original cabazitaxel injection. In some embodiments, the incidence of grade 3 / 4 severe neutropenia and febrile neutropenia caused by the liquid dosage form of the cabazitaxel albumin composition of the present invention in Asian populations is significantly lower than that of the original cabazitaxel injection.

[0230] In some embodiments, the solid tumor is an advanced solid tumor, such as an advanced solid tumor that cannot be surgically removed or metastatic (confirmed by histology or cytology). Refers to a disease characterized by rapid and uncontrolled growth of abnormal cell proliferation, examples of which include but are not limited to esophageal cancer, bile duct cancer, gallbladder cancer, hepatocellular carcinoma, ovarian cancer, endometrial cancer, lung cancer (e.g., non-small cell lung cancer), thymic cancer, renal cancer, melanoma, head and neck squamous cell carcinoma, bladder cancer, prostate cancer, breast cancer, gastrointestinal tumors (e.g., gastric cancer, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, colon cancer, colorectal cancer, colorectal adenocarcinoma), brain cancer, bone cancer, liposarcoma. Preferred are prostate cancer, gastric cancer, non-small cell lung cancer, breast cancer, esophageal cancer, head and neck squamous cell carcinoma, ovarian cancer, and liposarcoma.

[0231] In some embodiments, the TNM stage of the advanced solid tumor is Tx or T4, and the N stage is N1 or Nx.

[0232] In some embodiments, the advanced solid tumor is an advanced solid tumor for which previous systemic treatment has failed or has intolerable toxicity. In some embodiments, the previous systemic treatment includes at least one of the following treatment regimens for the patient: endocrine therapy, targeted drug therapy, radiotherapy, chemotherapy, and immunotherapy; further, the treatment regimen includes chemotherapy. In some embodiments, the previous systemic treatment includes the following regimens: endocrine therapy alone, targeted drug therapy alone, radiotherapy alone, chemotherapy alone, immunotherapy alone, chemotherapy combined with endocrine therapy, chemotherapy combined with targeted drug therapy, chemotherapy combined with radiotherapy, chemotherapy combined with immunotherapy, chemotherapy combined with targeted therapy combined with endocrine therapy, and endocrine therapy combined with chemotherapy and radiotherapy. In some embodiments, the drugs used in the endocrine therapy include but are not limited to: goserelin acetate, leuprorelin, bicalutamide, triptorelin acetate, apalutamide, flutamide, flutamide, abiraterone, enzalutamide, etc.; the drugs used in the targeted drug therapy include but are not limited to: olaparib, fluzoparib, niraparib, pamiparib, apatinib; the drugs used in the chemotherapy include but are not limited to paclitaxel and docetaxel; the drugs used in the immunotherapy include but are not limited to pembrolizumab. In some embodiments, the drugs used in the previous systemic treatment are selected from the following combinations: (1) goserelin acetate, bicalutamide, LAE001, abiraterone acetate, SHR3680, docetaxel, and amiparib; (2) triptorelin acetate, goserelin acetate, abiraterone, olaparib, and apalutamide; (3) bicalutamide, zoledronic acid, abiraterone, bee therapy, anti-tumor Chinese medicine, abiraterone, SHR3680 tablets, docetaxel, prednisone, fluzoparib, and apatinib; (4) Flutamide, goserelin acetate, bicalutamide, abiraterone, prednisone acetate, pembrolizumab, docetaxel, apalutamide; (5) flutamide, bicalutamide, goserelin, leuprolide, prostate pelvic lymph node DT 50Gy, abiraterone, prednisone, docetaxel, apalutamide; (6) abiraterone, prednisone, goserelin, zoledronic acid, docetaxel; (7) leuprolide, bicalutamide, abiraterone, prednisone, docetaxel, radiotherapy, enzalutamide, leuprolide, apalutamide, pamiparib. In some embodiments, the drugs used in the previous systemic treatment include at least docetaxel.

[0233] Prostate cancer is sensitive to androgens, so androgen deprivation therapy (ADT) is the primary treatment for prostate cancer. While this treatment is reasonably effective in the early stages, after approximately 14 to 36 months of treatment, most patients gradually progress to castration-resistant prostate cancer (CRPC) (prostate cancer that progresses despite continued ADT), and endocrine therapy has minimal efficacy. Chemotherapy with cytotoxic drugs is one of the main treatment options for patients at this stage, with taxanes being the most common cytotoxic chemotherapies. Cabazitaxel, a semisynthetic taxane derivative, is a new treatment option for patients with metastatic castration-resistant prostate cancer that is resistant to docetaxel.

[0234] The present invention formulates cabazitaxel into the above-mentioned cabazitaxel albumin composition (e.g., its liquid dosage form). Surprisingly, it is found that the liquid dosage form can reduce adverse reactions and toxic reactions during the treatment of CRPC, enhance its clinical treatment safety and tolerability, and achieve a high-efficiency and low-toxicity treatment effect.

[0235] In some embodiments, the castration-resistant prostate cancer includes metastatic castration-resistant prostate cancer and non-metastatic castration-resistant prostate cancer. In some embodiments, the castration-resistant prostate cancer is metastatic castration-resistant prostate cancer. In some embodiments, the castration-resistant prostate cancer is non-metastatic castration-resistant prostate cancer.

[0236] The cabazitaxel albumin composition described herein is as defined above: comprising cabazitaxel and human albumin, without a surfactant; and being a clear solution in a liquid state; wherein the cabazitaxel albumin composition is administered to a patient in need thereof by infusion, wherein the cabazitaxel dose infused to the patient in need thereof is about 10 to 40 mg / m 2 .

[0237] The cabazitaxel albumin composition described herein includes a liquid dosage form or a solid dosage form thereof. In some embodiments, the cabazitaxel albumin composition is a liquid dosage form. In some embodiments, the cabazitaxel albumin composition is a solid dosage form.

[0238] In some embodiments, the liquid dosage form of the present invention can be administered by a suitable route, for example, preferably by injection (eg, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular administration, including drip); more preferably, by intravenous drip.

[0239] In some embodiments of the present invention, the injection time is about 30-120 min, about 30-100 min, about 30-90 min, about 30-80 min, about 30-70 min, about 30-60 min, about 40-120 min, about 40-100 min, about 40-90 min, about 40-80 min, about 40-70 min, about 40-60 min, about 50-120 min, about 50-100 min, about 50-90 min, about 50-80 min, about 50-70 min, about 50-60 min, about 30 min, about 40 min, about 45 min, about 50 min, about 60 min. The specific injection time can be determined and / or adjusted according to the desired infusion time.

[0240] In some embodiments, since the liquid dosage form of the cabazitaxel albumin composition of the present invention does not contain a surfactant (Tween 80), there is no need for prophylactic use of antihistamines (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent), corticosteroids (dexamethasone 8 mg or equivalent steroid), and H2 antagonists (ranitidine 50 mg or equivalent H2 antagonists) before each injection of the liquid dosage form.

[0241] The amount of the liquid dosage form administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. In some embodiments of the present invention, the dosage of the liquid dosage form administered includes, but is not limited to, about 10 to 40 mg / m2 based on the patient's BSA (body surface area). 2 , about 10-35 mg / m 2 , about 10-30 mg / m 2 , about 10-25 mg / m 2 , about 10-20 mg / m 2 , about 20-40 mg / m 2 , about 20-35 mg / m 2 , about 20-30 mg / m 2 , about 20-25 mg / m 2 , about 10mg / m 2 , about 12 mg / m 2 , about 15mg / m 2 , about 18mg / m 2 , about 20mg / m 2 , about 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 .

[0242] Each administration cycle of the liquid dosage form of the present invention is at least 14-35 days, for example, 14 days, 18 days, 21 days, 24 days, 28 days, 35 days. The liquid dosage form of the present invention can be administered until disease progression, death, or intolerable toxic reactions (whichever occurs earlier). In some embodiments, the treatment cycle is 1-24 cycles, for example, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, 5-6, 1, 2, 3, 4, 5, 6 treatment cycles.

[0243] In some embodiments, the uses and methods of the present invention further comprise administering the cabazitaxel albumin composition (e.g., liquid dosage form) in combination with another anticancer therapeutic. Suitable examples of another anticancer therapeutic include prednisone acetate, doxorubicin, cyclophosphamide, cisplatin, prednisone, and fluorouracil or a combination thereof. These other anticancer therapeutics can be administered sequentially (before or after) or simultaneously with the cabazitaxel albumin composition (or its liquid formulation) of the present claims. In some embodiments, the other anticancer therapeutic can be administered at about 5 mg / m2 based on the patient's exact diagnosis and the advice of the treating physician. 2 Up to 50 mg / m 2 Dosage administration.

[0244] In some embodiments, 10 mg of prednisone acetate tablets are orally administered daily throughout the administration of the cabazitaxel albumin composition (eg, liquid dosage form thereof).

[0245] definition

[0246] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs; however, in case of conflict, the definitions in this specification shall prevail.

[0247] As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0248] All numerical values ​​or expressions used in the specification and claims referring to amounts of ingredients, process conditions, and the like are to be understood as modified in all instances by the word "about." The term "about," when referring to an amount or a range of values, means that the amount or range of values ​​indicated is an approximation within the experimental variability (or within the statistical experimental error), and thus the amount or range of values ​​may vary, for example, by ±5% of the stated amount or range of values.

[0249] All ranges relating to the same component or property include the endpoints, which are independently combinable. Since these ranges are continuous, they include every value between the minimum and maximum values. It should also be understood that any numerical range cited herein is intended to include all subranges within that range.

[0250] When the invention is defined in terms of ranges for physical properties, such as molecular weight, or for chemical properties, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included, and the term "comprising" (and related terms such as "containing" or "including" or "having" or "including") includes embodiments such as, for example, any combination of substances, compositions, methods or processes, etc., which "consist of" or "consist essentially of the described features."

[0251] It should be understood that in any method claimed herein that includes more than one step or act, the order of the method steps and acts is not necessarily limited to the order of the method steps and acts recited unless explicitly indicated to the contrary.

[0252] The term "cabazitaxel" as used herein refers to CAS No. 183133-96-2 and the compound having the following chemical structure:

[0253] or a pharmaceutically acceptable salt thereof.

[0254] Cabazitaxel is lipophilic, practically insoluble in water, and soluble in alcohol.

[0255] In addition, cabazitaxel, a microtubule inhibitor, is used in combination with prednisone to treat men with hormone-refractory metastatic prostate cancer who have previously received docetaxel.

[0256] The term "cabazitaxel" as used herein also includes pharmaceutically acceptable salts, solvates, and hydrates of cabazitaxel.

[0257] As used herein, the term "pharmaceutically acceptable" or "pharmaceutically acceptable" refers to a substance that is not biologically or otherwise substantially undesirable, i.e., the substance can be administered to a subject without causing any undesirable biological effect or interacting in a deleterious manner with any other components of the composition in which it is contained.

[0258] As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the desired biological activity of a compound (e.g., cabazitaxel, arginine) and minimize undesirable toxic side effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

[0259] In some embodiments, pharmaceutically acceptable salts may be preferred over the respective free bases or free acids because the salts impart greater stability or solubility to the molecule, thereby facilitating formulation. Basic compounds can generally be formed into pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, glycolate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, propionate, lauryl sulfate, mesylate, ), esylate, 2-hydroxyethanesulfonate, besylate, p-aminobenzenesulfonate, p-toluenesulfonate (tosylate), naphthalene-2-sulfonate, edisylate, hydrogen sulfide, bitartrate, gluconate, glucuronate, p-bromobenzenesulfonate, carbonate, pyrosulfate, sulfite, bisulfite, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, decanoate, octanoate, caprate, propiolate, suberate, sebacate, butyne-1,4-dioate, hexyne-1,6-dioate, terephthalate, sulfonate, xylenesulfonate, phenylpropionate, phenylbutyrate, beta-hydroxybutyrate, glycolate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and 2,5-dihydroxybenzoate. Suitable bases include pharmaceutically acceptable inorganic bases and pharmaceutically acceptable organic bases.Representative pharmaceutically acceptable base addition salts include alkali metal hydroxides (including sodium, potassium and lithium); alkaline earth metal hydroxides (such as calcium and magnesium); hydroxides of other metals (such as aluminum and zinc); ammonia, organic amines, such as unsubstituted or hydroxy-substituted mono-, di- or trialkylamines, dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, di- or tri-(2-OH-(C1-C6)-alkylamines), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids, such as arginine, lysine, and the like.

[0260] In some embodiments, cabazitaxel may be a cabazitaxel having a one-equivalent acetone solvate. In some embodiments, cabazitaxel or a salt thereof may be crystalline or amorphous. In some embodiments, cabazitaxel or a salt thereof may be in the form of a hydrate. In some embodiments, cabazitaxel can be, for example, U.S. Patent Application Publication No. 20150315164, U.S. Patent Application Publication No. 20160257663, U.S. Patent Application Publication No. 20160340327, U.S. Patent Application Publication No. 20160244420, U.S. Patent Application Publication No. 20150141673, U.S. Patent No. 9012665, U.S. Patent No. 9353076, U.S. Patent No. 9394266, U.S. Patent No. 9309210, U.S. Patent No. 9199953, U.S. Patent No. 8735611, U.S. Patent No. 8735611, U.S. Patent No. 8901322, PCT Publication No. WO2014115168, PCT Publication No. WO Any of the solvates, hydrates and / or crystalline forms of cabazitaxel disclosed in PCT Publication No. WO2015087228, PCT Publication No. WO2014067207, PCT Publication No. WO2014128728 or PCT Publication No. WO 2015058960, the disclosure of each of which is incorporated herein by reference in its entirety.

[0261] Human serum albumin (HSA) is a highly soluble globular protein with a relative molecular weight (Mr) of 65K and is composed of 585 amino acids. HSA is the most abundant protein in plasma, accounting for 70-80% of the colloid osmotic pressure of human plasma. The amino acid sequence of HSA contains a total of 17 disulfide bridges, a free sulfhydryl group (Cys34) and a single tryptophan (Trp214). Intravenous use of HSA solution has been shown to be useful for the prevention and treatment of hypovolemic shock (see, for example, Tullis, JAMA, 237, 355-360, 460-463, (1977) and Houser et al., Surgery, Gynecology and Obstetrics, 150, 811-816 (1980)), and in combination with exchange transfusion therapy for the treatment of neonatal hyperbilirubinemia (see, for example, Finlayson, Seminars in Thrombosis and Hemostasis, 6, 85-120, (1980)).

[0262] As used herein, the term "human albumin" refers to both natural human albumin and recombinant human albumin. In some embodiments, the human albumin is natural human albumin. In some embodiments, the human albumin is recombinant human albumin. "Native human albumin" and other plasma proteins herein can be precipitated from human plasma by altering the pH and adding ethanol, a process known as the Cohn fractionation process (Cohn EJ et al., J. Am. Chem. Soc. 1946; 68: 459-475). By controlling the pH and ethanol content, semi-purified plasma protein fractions can be produced. In the Cohn process, one of the last proteins to precipitate is natural human albumin. After precipitation, a wet paste of crude natural human albumin is obtained. Subsequent bioprocessing steps (purification, filtration, pasteurization, etc.) can be used to produce a purified, stabilized form of natural human albumin for commercial use (Lin JJ et al., Pharmaceutical Research 2000; 17: 391-6). Recombinant human albumin is a highly purified, animal component-free, virus-free, and prion-free product that serves as a replacement for natural human albumin, with the two being structurally identical (Bosse D et al., J. Clin. Pharmacol. 2005; 45: 57-67). Recombinant human albumin is produced by various prokaryotic and eukaryotic hosts (Chen Z et al., Biochimica et Biophysica Acta 2013; 1830: 5515-5525).

[0263] In some embodiments, "human albumin" refers to a human albumin solution. In some embodiments, "human albumin" refers to a commercially available human albumin infusion solution (e.g., 20%, 5%, 25% (w / v, unit: g / ml)). Suitable human albumin solutions include, but are not limited to, commercially available human albumin infusion solutions. Commercially available human albumin infusion solutions contain pharmaceutically acceptable excipients, such as sodium N-acetyltryptophan, sodium octanoate, sodium chloride, sodium bicarbonate, sodium hydroxide, or sodium acetate, or mixtures thereof. In some embodiments, the human albumin solution is prepared by diluting a commercially available human albumin infusion solution with a parenterally acceptable carrier.

[0264] Unless otherwise specified, human albumin concentration is expressed as mass concentration, expressed in g / ml. g / ml represents the mass of solute per milliliter of solution. For example, 0.01% (w / v) represents a mass concentration of 0.001 g / ml. 20% (w / v) represents a mass concentration of 0.2 g / ml. Unless otherwise specified, human albumin content refers to its concentration.

[0265] Alternatively, human albumin solution can be prepared by mixing human albumin powder with other pharmaceutically acceptable excipients that may be provided in commercially available albumin products in water.

[0266] In some embodiments, the human albumin solution is a commercially available human albumin USP infusion solution. In some embodiments, the human albumin infusion solution is a commercially available human albumin USP infusion solution. In some embodiments, the human albumin solution comprises a commercially available human albumin USP infusion solution. In some embodiments, a commercially available human albumin USP infusion solution is used as a source of the human albumin solution. In some embodiments, the human albumin solution is a 5% (w / v) human albumin USP infusion solution. In some embodiments, the human albumin solution is a 20% (w / v) human albumin USP infusion solution. In some embodiments, the human albumin solution is a 25% (w / v) human albumin USP infusion solution. In some embodiments, the human albumin solution is an aqueous solution prepared by diluting a commercially available human albumin infusion solution.

[0267] The term "cabazitaxel albumin composition" as used herein means that cabazitaxel and human albumin can be in the same system or in two different systems. For example, "the cabazitaxel albumin composition comprises: (a) a first liquid composition comprising cabazitaxel and ethanol, and (b) a human albumin solution" means that cabazitaxel and human albumin are in two different systems.

[0268] As used herein, "cabazitaxel albumin composition in a liquid state" means that cabazitaxel and human serum albumin in the composition are in the same solution system.

[0269] As used herein, "solid dosage form" refers to a solid state, such as a powder.

[0270] As used herein, "liquid dosage form" refers to a solution.

[0271] As used herein, the term "clear solution" or "clear" is transparent upon visual observation and substantially free of visible particles or precipitates of undissolved cabazitaxel, excluding turbidity or milky white.

[0272] The terms "individual", "patient" or "subject" in the present invention refer to humans (e.g., patients) and animals (e.g., mice, rats, dogs, cats, rabbits, chickens, monkeys, etc.). When the subject is a human patient (usually calculated based on a body weight of 60 kg), unless otherwise specified, the dosage described in the present invention can be obtained by converting the dosage using the conversion factor of experimental animals (e.g., human dosage = mouse dosage / 12.3) (Kin Tam. "Estimating the "First in human" dose-a revisit with special evidence on the oncology drug, ADMET & DMPK 1 (4) (2013) 63-75). A person of ordinary skill in the art can reasonably adjust the dosage based on common sense, according to factors such as the weight of the subject, the type and severity of the disease, and the like, and these adjusted technical solutions are all within the scope of the technical solutions required by the present invention.

[0273] As used herein, the term "dose" is the amount of a drug that elicits a therapeutic effect. Unless otherwise indicated, the dose is relative to the amount of the drug in free form. If the drug is in the form of a pharmaceutically acceptable salt, the amount of the drug is proportionally increased compared to the amount of the drug in free form. For example, the dose will be stated on the product packaging or product information sheet.

[0274] As used herein, "cabazitaxel dose" refers to the dose of free cabazitaxel.

[0275] As used herein, the term "free form" refers to a compound in its single, pure form, rather than as part of a drug complex, solvent, or salt. For example, free cabazitaxel refers to a cabazitaxel molecule that is not bound to other substances (e.g., salts, solvents), i.e., cabazitaxel alone, excluding cabazitaxel salts and other forms.

[0276] As used herein, "aqueous infusion solution" or "aqueous solution" or "aqueous composition" means that the solvent includes water, and the concentration of the organic solvent is no more than 15% (v / v), no more than 10% (v / v), no more than 8% (v / v), no more than 7% (v / v), no more than 6% (v / v), no more than 5% (v / v), no more than 4% (v / v), no more than 3% (v / v), no more than 2% (v / v), and no more than 1% (v / v).

[0277] As used herein, the terms "treat," "treat," and "treat" are intended to mean delaying the development of a disease, preventing the development of a disease, and / or reducing the severity of symptoms that will develop or are expected to develop. Thus, these terms include ameliorating existing disease symptoms, preventing additional symptoms, ameliorating or preventing potential metabolic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, alleviating the disorder or disease, causing the disorder or disease to regress, alleviating symptoms caused by the disease or disorder, or halting symptoms of the disease or disorder.

[0278] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of an agent sufficient to provide a desired biological outcome. This outcome can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use refers to the amount of a composition comprising a compound as the active ingredient of the invention required to achieve a clinically significant reduction in disease. In any individual case, an appropriate "effective" amount can be determined by one of ordinary skill in the art using routine experimentation. Thus, the expression "effective amount" generally refers to the amount of an active substance that has a therapeutic effect.

[0279] The term "parenteral" as used herein refers to a route selected from subcutaneous (SC), intravenous (IV), intramuscular (IM), intradermal (ID), intraperitoneal (IP), and the like.

[0280] As used herein, the term "infusion" refers to parenteral infusion.

[0281] The term "prednisone" used herein also includes pharmaceutically acceptable salts, solvates, and hydrates of prednisone, such as prednisone acetate.

[0282] The cabazitaxel albumin composition of the present invention is used to be administered to humans and animals in unit dosage form, and the cabazitaxel albumin composition having a pharmaceutical therapeutic effect is formulated and administered in unit dosage form. As used in the present invention, the unit dosage form refers to a physically independent unit suitable for human and animal subjects and is independently packaged, as known in the art. Each unit dose contains a predetermined amount of therapeutically active compound sufficient to produce the desired therapeutic effect. Examples of unit dosage forms include ampoules and syringes, as well as individually packaged tablets or capsules. The unit dosage form can be administered in portions or in multiples thereof. In the present invention, the cabazitaxel albumin composition contains a unit dose of cabazitaxel of about 5-40 mg.

[0283] The terms "combination", "combined use", or "combination therapy" as used herein refer to the administration of the cabazitaxel albumin composition of the present invention and other pharmacological ingredients so that they work together to provide a beneficial effect. The beneficial effects of the above combination include, but are not limited to, the pharmacokinetic or pharmacodynamic synergy produced by the combination of the above ingredients. The combined administration of these ingredients is usually completed within a specified time period (usually minutes, hours, days or weeks). "Combination therapy" is intended to include the administration of these ingredients in a sequential manner, that is, each of the ingredients is administered at a different time, and also includes the administration of these ingredients in a substantially simultaneous manner, or the administration of at least two of these ingredients.

[0284] The term "reconstitution" as used herein refers to the process of restoring a solid dosage form (such as lyophilized powder) to a liquid form by adding an appropriate amount of solvent (such as sterile water, a dedicated diluent, physiological saline, glucose solution, etc.).

[0285] The term "disease progression with intolerable toxicity" as used herein means: disease progression refers to worsening of the disease state, such as a relative increase of at least 20% in the sum of the diameters of all target lesions measured during the entire experimental study (if the baseline measurement value is the smallest, the baseline value is used as a reference); in addition, an absolute increase of at least 5 mm in the sum of the diameters must be met (the appearance of one or more new lesions is also considered disease progression).

[0286] The term "intolerable toxic reaction" as used in this article refers to a serious adverse reaction caused by a drug or treatment that is so severe that the patient cannot tolerate it and must stop or change the treatment plan.

[0287] The term "original cabazitaxel injection" used in this article Developed by Sanofi-Aventis, it was approved by the U.S. Food and Drug Administration (USFDA) on June 17, 2010, for the treatment of hormone-refractory prostate cancer as a new treatment option for patients with metastatic castration-resistant prostate cancer that is resistant to docetaxel. Cabazitaxel (JEVTANA) is supplied in the form of a kit comprising (a) cabazitaxel injection containing 60 mg of cabazitaxel dissolved in 1.5 mL of polysorbate 80; and (b) a diluent containing approximately 5.7 mL of 13% (W / W) ethanol.

[0288] As used herein, the term "adverse reaction" is any unfavorable and generally unexpected or unwanted sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment. For example, an adverse reaction may be associated with activation of the immune system in response to the treatment or expansion of immune system cells (e.g., T cells) in response to the treatment. A medical treatment may have one or more associated reactions, and each reaction may have the same or varying levels of severity.

[0289] The term "disease control rate (DCR)" used in this article refers to the percentage of cases that achieved remission and lesion stability after treatment among the evaluable cases, based on the latest disease progression when the patient was discharged from the group.

[0290] As used herein, the term "body surface area" or "BSA" 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 weight. The table below shows the body surface area for typical height and weight. Calculations are made using the DuBois & DuBois formula: (Weight (kg)) 0.425 ×(Height (cm)) 0.725 × 0.007184. Weight is on the horizontal axis, first in pounds, then in kilograms. Height is on the vertical axis, first in inches, then in centimeters. The result is body surface area in square meters. A typical BSA is provided in the figure below.

[0291] As used herein, the term "mass concentration" in the unit of g / ml refers to the mass of the solute per milliliter of solution, such as 0.01% means the mass concentration is 0.001 g / ml.

[0292] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The methods and materials described herein are used in this application; in addition, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In the event of conflict, the present specification, including definitions, will control.

[0293] Example

[0294] The composition and preparation steps of Cabazitaxel Albumin Injection are as follows: Cabazitaxel Albumin Injection was developed as a novel polysorbate 80 (Tween 80)-free cabazitaxel injection formulation. Cabazitaxel Albumin is prepared as a sterile injectable product (10 mg / mL cabazitaxel solution in ethanol). The Cabazitaxel Albumin package contains a 30 mg / mL vial of Cabazitaxel Albumin (Cabazitaxel Injection) and a 50 mL vial of 10 grams of commercially available 20% human albumin solution for infusion. Each 3 mL of Cabazitaxel Albumin (Cabazitaxel Injection) contains 30 mg cabazitaxel, 1894 mg anhydrous ethanol, and 675 mg polyethylene glycol 300. Anhydrous citric acid is used to adjust the pH. In this clinical study, each patient received an intravenous infusion of 0.08 mg / ml cabazitaxel solution, and the dose of the test drug was 20 mg / m 2 and 25 mg / m 2 In the preparation of the final infusion solution of the experimental drug, the volume ratio of cabazitaxel albumin drug (cabazitaxel injection), 20% human albumin solution for infusion, and 0.9% sodium chloride injection was 1:7.5:116.5 (v / v). 2 The dosage is 20 mg / m 2 Taking patients as an example, the preparation method of the final infusion solution of the trial drug is as follows:

[0295] ●For BSA: 2m 2 For cancer patients, the dose of cabazitaxel in the infusion bag is 40 mg. To prepare an infusion solution containing 0.08 mg / ml of cabazitaxel, 4 ml of cabazitaxel albumin (10 mg cabazitaxel / ml), 30 ml of 20% human albumin solution for infusion, and 466 ml of 0.9% sodium chloride injection are required. (In the present invention, the mass concentration of cabazitaxel in the cabazitaxel infusion solution is calculated by dividing the total mass by the total volume, where the total volume is obtained by simply adding the volumes of the component solutions.)

[0296] Use a sterile, disposable syringe to inject 30 ml of 20% human albumin solution for infusion along the bottle wall into the infusion bag / bottle containing 466 ml of 0.9% sodium chloride injection. Gently swirl manually approximately 10 times to thoroughly mix, resulting in the albumin-saline infusion solution for the final dilution of cabazitaxel albumin injection.

[0297] ●Using only a gauge 8 (0.8 mm) needle and a graduated syringe, aseptically draw up 4 mL of cabazitaxel albumin injection. Inject rapidly into the prepared albumin-saline infusion solution at a single injection below the liquid level. Immediately, gently swirl the solution manually approximately 20 times (approximately 1 minute total) to thoroughly mix the infusion solution to a final concentration of 0.08 mg / mL.

[0298] The prepared cabazitaxel albumin infusion (in albumin-saline infusion) should be used immediately. If it cannot be used immediately and needs to be stored, it should be used within 3 hours after preparation at room temperature.

[0299] Cabazitaxel concentrations in patient plasma were measured using validated analytical methods, as described below.

[0300] A method for determining the concentration of cabazitaxel in human plasma using liquid chromatography-mass spectrometry (HPLC-MS / MS).

[0301] Cabazitaxel concentrations in human plasma were determined using liquid chromatography-mass spectrometry (HPLC-MS / MS) with EDTA-K2 as the anticoagulant. Human plasma samples were extracted by liquid-liquid extraction. After vortex centrifugation, the supernatant was concentrated with nitrogen sparge, dried, and reconstituted. Liquid chromatography-mass spectrometry analysis was performed using cabazitaxel-d9 as the isotopic internal standard. The quantitation range of cabazitaxel was 1.00 to 1000 ng / mL, and the volume of human plasma sample used was 100 μL.

[0302] Example 1

[0303] This example is a Phase I clinical trial of the safety, tolerability, and pharmacokinetics of cabazitaxel albumin injection in patients with advanced solid tumors. The doses of cabazitaxel albumin injection were 15, 20, 25, 30, and 35 mg / m 2 , to evaluate the safety, tolerability, pharmacokinetic characteristics and preliminary antitumor activity of cabazitaxel albumin injection in Chinese patients with advanced solid tumors.

[0304] 1.1 Patient selection criteria

[0305] 1.1.1 Selection criteria

[0306] Age ≥ 18 years, regardless of gender; patients with a confirmed histological or cytological diagnosis of advanced solid tumors (preferably prostate cancer, gastric cancer, non-small cell lung cancer, breast cancer, esophageal cancer, head and neck squamous cell carcinoma, ovarian cancer, liposarcoma, etc.), disease progression after standard treatment or no standard treatment, and, except for prostate cancer, with measurable lesions on CT / MRI; ECOG score 0-2 points, expected survival ≥ 3 months; with adequate hematological and organ function, and based on laboratory test results within 7 days before the first dose, meeting the following conditions: no blood transfusion, blood products or blood cytokine treatment such as granulocyte colony-stimulating factor (G-CSF) within 14 days of the first dose, blood routine: neutrophil count ≥ 2.0×109 / L, platelet count ≥ 10 9 / L, white blood cell count ≥4.0×10 9 / L, hemoglobin concentration ≥8.0 g / dL; blood biochemistry: liver function: aspartate aminotransferase and alanine aminotransferase ≤1.5 times the upper limit of normal (ULN), total bilirubin ≤ULN; renal function: creatinine ≤1.5×ULN; baseline left ventricular ejection fraction ≥50% as determined by echocardiography, normal or clinically insignificant abnormality in the 12-lead electrocardiogram, QTc interval <450 ms (male) or <470 ms (female), no symptoms or signs of heart failure; and generally normal function of major organs (heart, lung, liver, kidney, bone marrow, gastrointestinal tract). Normal or abnormal symptoms are of no clinical significance, and the acute toxicity caused by previous treatment has been alleviated to a level of ≤1 (excluding alopecia); the interval between the first dose of surgery, chemotherapy, immunotherapy, biological therapy, targeted therapy, anti-tumor Chinese medicine, or small molecule targeted drug treatment is 4 weeks or 5 half-lives or more (whichever is shorter); if the chemotherapy drug is mitomycin or nitrosourea, it needs to be discontinued for more than 6 weeks; the first dose is more than 6 weeks after the last radiotherapy (excluding palliative radiotherapy for local pain control), and no whole pelvic radiotherapy (radiotherapy ≤30% of the bone marrow area) has been performed in the past.

[0307] 1.1.2 Exclusion criteria

[0308] Patients who have received cabazitaxel treatment before; patients with severe allergies to cabazitaxel, human albumin, or alcohol; patients currently receiving other anti-tumor treatments; patients who have received systemic treatment with glucocorticoids (>10mg / d prednisone or equivalent dose of hormones) or other immunosuppressants within 14 days before the first dose. In the absence of active autoimmune diseases, inhaled or topical glucocorticoids can be used, and hormone replacement therapy doses ≤10 mg / d prednisone equivalents are allowed; patients who need to use strong inhibitors or inducers of CYP3A4 within 14 days of the first dose and during the study; patients with clinically significant mental or central nervous system diseases; patients with active brain metastases; patients with two or more malignant tumors (except cured non-melanoma skin cancer, cervical cancer, thyroid cancer and gastrointestinal mucosal cancer); patients who have received more than two doses of mitomycin or nitrosourea treatment, or have received intensive treatment with autologous stem cell transplantation; patients with severe internal medicine diseases; patients with known HIV, HBV, HCV and Treponema pallidum infection (patients with positive hepatitis B surface antigen (HBsAg) and HBV-DNA higher than 1000 IU / mL are not eligible for inclusion; patients with positive HCV-Ab and HCV Patients with RNA copy numbers above the upper limit of normal are not eligible for inclusion); patients with a history of drug abuse; pregnant or lactating women; female patients of childbearing potential with a positive pregnancy test within 7 days before the first dose; any male and female patients of childbearing potential who do not agree to use medically approved effective contraceptive methods throughout the trial and within 3 months after the last study medication; patients who have participated in clinical trials of other drugs within 28 days before the first dose; patients who have been vaccinated within 30 days before the first dose or who have been vaccinated during the entire study (except inactivated vaccines).

[0309] 1.2 Study Design

[0310] This study is a multicenter, open-label phase I clinical study to evaluate the safety, tolerability, and PK characteristics of cabazitaxel albumin injection in patients with advanced solid tumors and to preliminarily assess its anti-tumor activity.

[0311] The study used the traditional "3+3" dose escalation design to determine the MTD (i.e., maximum tolerated dose). 3 to 6 patients were enrolled in each of the 2 to 4 dose groups, with the doses ranging from low to high being 15 mg / m 2 , 20mg / m 2 , 25mg / m 2 , 30mg / m 2 , 35mg / m 2A total of 12 to 24 patients with advanced solid tumors were enrolled. Patients received cabazitaxel albumin injection via intravenous infusion over a 1-hour (±5-minute) infusion period every 3 weeks (21 days) for up to 6 cycles or until disease progression, death, or intolerable toxicity (whichever occurred first). For patients with metastatic castration-resistant prostate cancer, cabazitaxel albumin injection was administered in combination with prednisone acetate tablets. Prednisone acetate tablets (10 mg) were taken orally daily throughout cabazitaxel treatment.

[0312] Cabazitaxel albumin injection does not contain Tween 80. Prophylactic use of antihistamines (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent), corticosteroids (dexamethasone 8 mg or equivalent steroid), and H2 antagonists (ranitidine 50 mg or equivalent H2 antagonist) is not required before each injection of cabazitaxel albumin injection.

[0313] The dosage will be 20 mg / m 2 The dose group was started, and the dose was further increased to 25 mg / m based on the safety and tolerability results. 2 dose group or reduce to the previous dose group 15mg / m 2 According to the “3+3” dose escalation design method, determine whether to increase the dose to 30mg / m 2 , 35mg / m 2 Dosage group.

[0314] During the first dosing cycle of each dose group, 4.0 mL of blood samples were collected from patients for pharmacokinetic analysis. Blood samples were collected within 1 hour before dosing, 30 minutes (±2 minutes) after the start of the infusion, 45 minutes (±2 minutes) after the start of the infusion, 5 minutes before the end of the infusion, and 5 minutes (±2 minutes), 15 minutes (±2 minutes), 30 minutes (±2 minutes), 1 hour (±5 minutes), 3 hours (±5 minutes), 5 hours (±5 minutes), 8 hours (±5 minutes), 24 hours (±5 minutes), 48 hours (±30 minutes), 72 hours (±30 minutes), 120 hours (±30 minutes), 168 hours (±30 minutes), and 216 hours (±30 minutes) after the end of the infusion. Cabazitaxel plasma concentrations were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method, and pharmacokinetic parameters such as Cmax, AUC, t1 / 2, CL, and Vss were evaluated. Efficacy evaluation was performed every 9 weeks (±7 days) after the first administration.

[0315] 1.3 Research Results

[0316] A total of 12 patients (20 mg / m 2 Six patients were enrolled in the group; 25 mg / m 2All 12 patients were prostate cancer patients (including metastatic castration-resistant prostate cancer and non-metastatic castration-resistant prostate cancer), see Table 1.

[0317] Table 1 Baseline characteristics of the study disease - history of solid tumors

[0318] All 12 patients had previously received standard endocrine therapy (including goserelin acetate, leuprorelin, bicalutamide, triptorelin acetate, apalutamide, flutamide, abiraterone, enzalutamide, etc.), and / or targeted therapy (including olaparib, fluzoparib, niraparib, pamiparib, apatinib, etc.), chemotherapy (including paclitaxel, docetaxel), immunotherapy (including pembrolizumab), radiotherapy, etc. Among them, 11 patients had previously received docetaxel treatment (see Table 2).

[0319] Table 2 Baseline characteristics of the study disease - previous treatment history related to the study disease

[0320] The previous anti-tumor treatment status of the patients who could be evaluated for efficacy is shown in Table 3.

[0321] Table 3 * Previous tumor treatment history of individual patients (n=7)

[0322] *: This table shows the previous tumor treatment history of patients with evaluable efficacy data.

[0323] All 12 enrolled patients received cabazitaxel albumin injection.

[0324] The results of the study showed that patients with prostate cancer who received cabazitaxel albumin injection 20 mg / m 2 and 25 mg / m 2 The overall dose was well tolerated. The main adverse reactions were decreased neutropenia, decreased leukopenia, and anemia. The incidence of grade 3 / 4 severe neutropenia and febrile neutropenia in Asians was significantly lower than that of the original cabazitaxel injection. Better safety, see Table 4.

[0325] Table 4 Cabazitaxel albumin and original research Comparison with previous studies

[0326] Note:

[0327] a: Adverse reaction evaluation criteria refer to the Common Criteria for Adverse Events (CTCAE) Version 5.0. Adverse reaction data statistics are based on the highest level of adverse reactions experienced by patients during the study.

[0328] b: Grade 3 decreased neutrophil count: <1000~500 / mm 3 ; <1.0~0.5×10 9 / L. Grade 4 neutrophil count decreased: <500 / mm 3 ; <0.5×10 9 / L.

[0329] c: Grade 3 febrile neutropenia: ANC < 1000 / mm 3 Accompanied by a single temperature >38.3°C (101°F) or a temperature ≥38°C (100.4°F) for more than 1 hour. Grade 4 febrile neutropenia: life-threatening; urgent treatment is required.

[0330] literature [1] :Hirofumi Mukai, Shunji Takahashi, Masahiro Nozawa, et al. Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer [J]. Cancer Chemother Pharmacol, DOI: 10.1007 / s00280-014-2394-z.

[0331] literature [2] : Masahiro Nozawa, Hirofumi Mukai, Shunji Takahashi, et al. Japanese phase I study of cabazitaxel in metastatic castration-resistant prostate cancer [J]. Int J Clin Oncol, DOI: 10.1007 / s10147-015-0820-9.

[0332] 20 mg / m 2 and 25 mg / m 2 There were 4 and 3 patients in the dose group respectively who underwent efficacy evaluation after treatment, of which 25 mg / m 2In the dose group, one patient had non-metastatic castration-resistant prostate cancer (CRPC), and the rest had metastatic castration-resistant prostate cancer (mCRPC). 2 and 25 mg / m 2 All dose groups showed significant clinical efficacy, with overall efficacy reaching a stable disease state without disease progression. The disease control rates of target lesions, non-target lesions, and overall efficacy were all 100% (see Table 5), significantly higher than those of the original cabazitaxel injection. The data of clinical trials previously conducted on similar populations (83.3%) are shown in Table 6.

[0333] Table 5 Subject tumor efficacy evaluation checklist (SS)

[0334] NA: Not applicable.

[0335] Complete remission (CR): All target lesions disappear and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10mm.

[0336] Partial response (PR): The sum of the target lesion diameters decreased by at least 30% compared with the baseline level.

[0337] Disease progression (PD): The minimum value of the sum of all target lesion diameters measured during the entire experimental study is used as a reference, and the relative increase in the diameter sum is at least 20% (if the baseline measurement value is the minimum, the baseline value is used as a reference); in addition, the absolute value of the diameter sum must increase by at least 5 mm (the appearance of one or more new lesions is also considered as disease progression).

[0338] Stable disease (SD): The target lesion has neither decreased to the level of PR nor increased to the level of PD, but is somewhere in between, with the minimum sum of diameters during the study as a reference.

[0339] *: Patient E had non-metastatic castration-resistant prostate cancer (CRPC), and the other patients had metastatic castration-resistant prostate cancer (mCRPC).

[0340] a: A target lesion is a measurable lesion that has at least one accurately measurable diameter (recorded as the maximum diameter). The minimum length is as follows:

[0341] 1) CT scan 10mm (CT scan layer thickness is not more than 5mm);

[0342] 2) 10 mm for routine clinical examination instruments (tumor lesions that cannot be accurately measured with calipers should be recorded as unmeasurable);

[0343] 3) Chest X-ray 20mm;

[0344] 4) Malignant lymph nodes: Pathologically enlarged and measurable, with the short diameter of a single lymph node on CT scan ≥15 mm (CT scan slice thickness recommended not to exceed 5 mm). Only the short diameter should be measured and followed up at baseline and during follow-up.

[0345] b: Non-target lesions, also known as non-measurable lesions, refer to all other lesions, including small lesions (longest diameter <10 mm or pathological lymph node short diameter ≥10 mm to <15 mm) and lesions that cannot be measured. These lesions include meningeal disease, ascites, pleural or pericardial effusions, inflammatory breast cancer, lymphangitic carcinomatosis of the skin or lung, abdominal masses that cannot be diagnosed and followed up by imaging, and cystic lesions.

[0346] Table 6 Cabazitaxel albumin and original research Comparison with previous studies

[0347] *: The evaluable sample size refers to the sample size with efficacy evaluation data.

[0348] d: The disease control rate (DCR) is based on the latest disease progression when the patient leaves the group.

[0349] literature [3]* :Heck MM, M, Horn T, et al. Compassionate use of abiraterone and cabazitaxel: first experiences in docetaxel-pretreated castration-resistant prostate cancer patients[J].Der Urologe,2012,51:390-397.

[0350] The main pharmacokinetic parameters of the 20 mg / m2 and 25 mg / m2 dose groups after a single dose of cabazitaxel albumin injection are shown in Table 7.

[0351] Table 7 Cabazitaxel albumin single dose 20 mg / m 2 and 25 mg / m 2 The main pharmacokinetic parameters after

[0352] While the embodiments of the present invention have been described in detail above with reference to the embodiments, the present invention is not limited to the embodiments described above. Various modifications may be made within the scope of knowledge possessed by a person skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof may be combined with one another unless there is a conflict.

Claims

1. A cabazitaxel albumin composition, wherein: The cabazitaxel albumin composition comprises cabazitaxel and human serum albumin and does not contain a surfactant; the cabazitaxel albumin composition is a clear solution in a liquid state; the cabazitaxel albumin composition is administered by infusion for treating cancer patients, and the cabazitaxel dose infused into the patient is about 10-40 mg / m 2 .

2. The cabazitaxel albumin composition according to claim 1, wherein The cabazitaxel albumin composition contains about 5-40 mg of cabazitaxel; Optionally, the weight ratio of human serum albumin to cabazitaxel in the liquid dosage form is from about 10:1 to about 2000:1; Optionally, the cabazitaxel albumin composition is a clear aqueous infusion solution, the concentration of cabazitaxel in the cabazitaxel albumin composition is about 0.01 mg / mL to about 1 mg / mL, and the content of human serum albumin is about 0.1% to about 25% (w / v).

3. The cabazitaxel albumin composition according to claim 1, wherein Each administration cycle of the cabazitaxel albumin composition is at least 14-35 days, for example, 14 days, 18 days, 21 days, 24 days, 28 days, or 35 days; preferably, the cabazitaxel albumin composition is repeatedly administered to the patient in a new cycle every 3 weeks.

4. The cabazitaxel albumin composition according to claim 1, wherein After a single administration of the cabazitaxel albumin composition, cabazitaxel AUC 0-∞ The range is about 900-1700h*ng / mL; and / or, after a single administration of the cabazitaxel albumin composition, cabazitaxel C max The range is about 100-400ng / mL.

5. The cabazitaxel albumin composition according to claim 1, wherein The cabazitaxel albumin composition is used in combination with corticosteroids to treat cancer patients; Preferably, the corticosteroid is selected from the group consisting of Cortisol, Prednisone, Dexamethasone, Methylprednisolone, and Prednisolone; Preferably, the corticosteroid is prednisone or prednisolone; Optionally, prednisone or prednisolone is administered at a dose of 10 mg / day.

6. The cabazitaxel albumin composition according to claim 1, wherein The cabazitaxel albumin composition reduces adverse reactions of the cancer and / or improves the disease control rate.

7. Use of the cabazitaxel albumin composition according to any one of claims 1 to 6 in the preparation of a medicament for treating cancer, wherein the dose of cabazitaxel is about 10-40 mg / m 2 .

8. Use of a corticosteroid in combination with the cabazitaxel albumin composition according to any one of claims 1 to 6 in the preparation of a medicament for treating cancer, wherein the dose of cabazitaxel is about 10-40 mg / m 2 or, the use of the cabazitaxel albumin composition of any one of claims 1-6 in the preparation of a medicament for treating cancer, wherein the cabazitaxel dose is about 20 mg / m 2 or about 25 mg / m 2 .

9. A method of treating a cancer patient comprising administering to said patient cabazitaxel at a dose of about 10-40 mg / m 2 The cabazitaxel albumin composition according to any one of claims 1 to 6; preferably, the cabazitaxel albumin composition is used in combination with a corticosteroid; preferably, the corticosteroid is prednisone or prednisolone.

10. The cabazitaxel albumin composition according to any one of claims 1 to 6, or the use according to claim 7 or 8, or the method according to claim 9, wherein The cancer is an advanced cancer; preferably, the cancer is an advanced metastatic cancer; preferably, the cancer is an advanced prostate cancer; preferably, the cancer is castration-resistant prostate cancer; preferably, the cancer is metastatic castration-resistant prostate cancer; preferably, the cancer is prostate cancer that has failed docetaxel treatment.

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