Cabazitaxel lyophilized powder and precursors, reconstituting agents, methods of preparation and uses thereof

Abstract

The application discloses a kind of cabazitaxel freeze-dried powder and its precursor, reconstituted agent, preparation method and application.The application provides a kind of cabazitaxel freeze-dried powder includes cabazitaxel or its pharmaceutically acceptable salt, surfactant, dispersing agent and freeze-drying protective agent, and surfactant is anionic surfactant.Cabazitaxel freeze-dried powder of the application has good anti-prostate tumor effect, and relative to commercially available cabazitaxel preparation Jevtana®, cabazitaxel freeze-dried powder of the application has improved half-life in mouse body, average residence time.

Description

Technical Field

[0001] This invention relates to a lyophilized cabazitaxel powder, its precursor, reconstituter, preparation method, and application. Background Technology

[0002] Despite rapid advancements in medicine that have improved the quality of life, cancer continues to cause immense suffering for many patients. In most countries worldwide, cancer remains a leading cause of death, with its incidence and number of patients steadily increasing. Cancer treatment remains a major and intractable challenge for medicine.

[0003] Prostate cancer is a common urogenital tumor, ranking second among male cancers, and its incidence has been rising steadily in recent years, seriously threatening men's physical and mental health. Compared with Europe and the United States, the incidence of prostate cancer in my country is relatively low, but under the influence of factors such as population aging and changes in lifestyle, the incidence of prostate cancer shows a significant upward trend. Treatment methods for prostate cancer mainly include surgery, endocrine therapy, radiotherapy, and cytotoxic chemotherapy. For patients who do not respond well to surgery and endocrine therapy, cytotoxic drugs are often used. Among the many chemotherapy drugs, taxanes are the most widely used. These drugs are anti-tumor drugs extracted or semi-synthesized from yew trees and have broad-spectrum anti-tumor effects.

[0004] Cabazitaxel (CTX) belongs to the second-generation taxane class of compounds. It is a drug obtained by dimethylating the C10 and C7 positions of docetaxel. CTX has broad-spectrum antitumor activity. Its mechanism of action is through binding to tubulin, promoting microtubule formation and inhibiting its polymerization, leading to a significant decrease in the number of free tubules. Simultaneously, it disrupts the microtubule network structure, interfering with normal microtubule function, thereby inhibiting the mitosis and proliferation of cancer cells. Currently, CTX and its combination therapies are mainly used clinically for the treatment of prostate cancer. Compared with docetaxel, CTX contains more methyl groups in its structure and has a lower affinity for P-glycoprotein, therefore it can be used in prostate cancer patients who are unresponsive to docetaxel or have poor tolerance to other taxanes. However, due to the poor water solubility of CTX, its commercially available formulation, Jevtana®, incorporates large amounts of Tween-80 and ethanol for solubilization. However, Tween-80 is hemolytic and has high viscosity, easily causing allergic reactions such as respiratory distress, angioedema, urticaria, and even shock upon intravenous injection. Therefore, pretreatment with antihistamines and nonsteroidal anti-inflammatory drugs is necessary before clinical administration, and Jevtana® requires two dilutions before use, making clinical use inconvenient. While chemotherapy drugs have prolonged the survival of some patients, severe toxic side effects and drug resistance hinder their progress in cancer treatment. Due to the non-specific distribution of cabazitaxel in the body, it can damage normal tissues and cells, causing neurological and immune system toxicity. Improving chemotherapy drugs to achieve higher efficacy and lower toxic side effects is currently an important direction for cancer treatment.

[0005] Therefore, given the shortcomings of existing CTX formulations, scholars both domestically and internationally have conducted extensive research on novel CTX formulations, primarily focusing on the design of nanoparticle formulations. Nanoparticle drug delivery systems (NDDS) can not only improve the solubility of poorly soluble drugs but also enhance drug targeting, improve bioavailability, reduce toxic side effects, and prolong the duration of drug action in vivo. Current research has attempted to develop CTX into NDDS such as liposomes and albumin nanoparticles to optimize formulations. While these nanoparticle formulations significantly improve the drug-likeness of CTX, using liposomes as drug carriers requires the use of large amounts of excipients, such as phospholipids; while using albumin as a drug carrier increases the risk of viral transmission. Therefore, there is an urgent need to find a new formulation technology to address the shortcomings of currently available CTX injections.

[0006] Therefore, developing a simple, easy-to-use, and stable carbamate formulation is of great significance. It can provide a new approach for chemotherapy of prostate cancer and also provide theoretical basis and methodological reference for the design of chemotherapy drug delivery systems for other tumors. Summary of the Invention

[0007] The purpose of this invention is to address the shortcomings of existing cabazitaxel injections by providing a lyophilized cabazitaxel powder, its precursor, reconstitution solvent, preparation method, and applications. This invention's cabazitaxel injection formulation can achieve better antitumor effects by increasing the dosage of cabazitaxel, and by not using Tween as an excipient, it reduces toxic side effects.

[0008] The present invention solves the above-mentioned technical problems through the following technical solutions:

[0009] This invention provides a lyophilized cabazitaxel powder comprising cabazitaxel or a pharmaceutically acceptable salt thereof, a surfactant, a dispersant, and a lyophilization protectant;

[0010] The surfactant is an anionic surfactant.

[0011] In this invention, the anionic surfactant is preferably selected from one or more of sodium cholesterol sulfate, sodium deoxycholate, sodium oleate, sodium stearate, sodium dodecylbenzene sulfonate, and sodium lauryl ether sulfate, and more preferably sodium cholesterol sulfate.

[0012] In this invention, the dispersant is preferably selected from one or more of PVP, polyvinyl alcohol, polyethylene glycol, hydroxypropyl methylcellulose, polyacrylic acid, hyaluronic acid and chitosan, and more preferably PVP.

[0013] The molecular weight of the PVP is preferably 2,000 to 50,000, such as PVP K12, PVP K15, PVP K25 or PVP K30, and more preferably PVP K12.

[0014] In this invention, the freeze-drying protectant can be conventional in the art, preferably selected from one or more of trehalose, sucrose, maltose, glucose, mannitol and lactose, more preferably selected from one or more of trehalose, sucrose and maltose, and even more preferably trehalose.

[0015] In this invention, the mass ratio of the cabazitaxel or its pharmaceutically acceptable salt to the surfactant is preferably 1:(0.03~1), more preferably 1:(0.05~0.3), and even more preferably 1:(0.05~0.1), for example 1:0.031, 1:0.066, 1:0.132, 1:0.26, or 1:0.5.

[0016] In this invention, the mass ratio of the cabazitaxel or its pharmaceutically acceptable salt to the dispersant is preferably 1:(0.2~3.2), more preferably 1:(0.5~3.2), and even more preferably 1:(1~2), for example 1:0.2, 1:0.4, 1:0.8, 1:1.6 or 1:3.2.

[0017] In this invention, the ratio of the mass of the cabazitaxel or its pharmaceutically acceptable salt to the lyophilization protectant is preferably 1:(10-80), more preferably 1:(20-50), and even more preferably 1:(35-45), for example 1:20, 1:40, 1:60, or 1:80.

[0018] In this invention, the preferred mass ratio of cabazitaxel or its pharmaceutically acceptable salt, the surfactant, the dispersant, and the lyophilization protectant is 1:(0.03~1):(0.2~3.2):(10~80), more preferably 1:(0.05~0.3):(0.5~3.2):(20~50), and even more preferably 1:(0.05~0.1):(1~2):(35~45), for example 1:0.066:1.6:40. 1:0.032:1.6:40, 1:0.132:1.6:40, 1:0.26:1.6:40, 1:0.5:1.6:40, 1:1:1.6:40, 1:0.066:0.2:40, 1:0.066:0.4:40, 1:0.066:0.8:40, 1:0.066:3.2:40, 1:0.066:1.6:20, 1:0.066:1.6:60, or 1:0.066:1.6:80.

[0019] In this invention, the lyophilized cabazitaxel powder is preferably composed of the cabazitaxel or a pharmaceutically acceptable salt thereof, the surfactant, the dispersant, and the lyophilization protectant.

[0020] The present invention also provides a resolvent for cabazitaxel lyophilized powder, which is prepared by resolventizing the aforementioned cabazitaxel lyophilized powder.

[0021] In this invention, the solvent used for reconstitution can be conventional in the art, such as water for injection or glucose injection, wherein the glucose injection is preferably 5% glucose injection.

[0022] The amount of solvent added is based on the concentration of cabazitaxel in the reconstituted solvent of the cabazitaxel lyophilized powder before lyophilization. Preferably, the concentration of cabazitaxel or its pharmaceutically acceptable salt in the reconstituted solvent is preferably 0.1~10 mg / mL, more preferably 1~6 mg / mL, for example 5 mg / mL, where mg / mL refers to the ratio of the mass of cabazitaxel to the volume of the reconstituted solvent of the cabazitaxel lyophilized powder.

[0023] In this invention, the average particle size of the reconstituted solvent for the lyophilized cabazitaxel powder is preferably less than 300 nm, more preferably 120~265 nm. nm, for example 125nm, 128nm, 129nm, 130nm, 131nm, 132nm, 133nm, 134nm, 135nm, 136nm, 137nm, 140nm, 150nm, 151nm, 152nm, 153nm, 154nm, 160nm, 161nm, 165nm, 166nm, 167nm, 171nm, 172nm, 173nm, 176nm, 177nm, 180nm, 181nm, 186nm, 187nm, 188nm, 195nm, 196nm, 214nm, 215nm, 216nm, 243nm, 244nm, 245nm, 246nm, 250nm, 251nm, 252nm, 253nm, 260nm, or 261nm.

[0024] In this invention, the PDI of the reconstituted solvent for the cabazitaxel lyophilized powder is preferably less than 0.45, more preferably 0.09~0.3, for example 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41 or 0.42.

[0025] In this invention, the encapsulation efficiency of the cabazitaxel lyophilized powder reconstitution solvent is preferably 65.0% to 99.5%, more preferably 95.0% to 99.5%, for example 95.0%, 96.0%, 97.0%, 98.0%, 99.0%, 95.1%, 99.2% or 99.3%.

[0026] The present invention also provides a cabazitaxel lyophilized powder precursor, comprising cabazitaxel or a pharmaceutically acceptable salt thereof, a surfactant, a dispersant, a lyophilization protectant, and a solvent;

[0027] The surfactant is an anionic surfactant.

[0028] In this invention, the anionic surfactant, the dispersant, and the lyophilization protectant are preferably the anionic surfactant, dispersant, and lyophilization protectant described in the aforementioned cabazitaxel lyophilized powder.

[0029] In this invention, preferably, the mass ratio of cabazitaxel or its pharmaceutically acceptable salt to the surfactant, the mass ratio of cabazitaxel or its pharmaceutically acceptable salt to the dispersant, and the mass ratio of cabazitaxel or its pharmaceutically acceptable salt to the lyophilization protectant, based on cabazitaxel, are all the mass ratios of cabazitaxel or its pharmaceutically acceptable salt to the surfactant, the mass ratio of cabazitaxel or its pharmaceutically acceptable salt to the dispersant, and the mass ratio of cabazitaxel or its pharmaceutically acceptable salt to the lyophilization protectant as described in the aforementioned cabazitaxel lyophilized powder.

[0030] In this invention, the mass ratio of the cabazitaxel or its pharmaceutically acceptable salt to the solvent is preferably 1:(4~18), more preferably 1:(8~12), for example 1:9.6 or 1:18.

[0031] In this invention, the preferred mass ratio of cabazitaxel or its pharmaceutically acceptable salt, the surfactant, the dispersant, the lyophilization protectant, and the solvent is 1:(0.03~1):(0.2~3.2):(10~80):(4~18), more preferably 1:(0.05~0.3):(0.5~3.2):(20~50):(8~12), and even more preferably 1:(0.05~0.1):(1~2):(35~45):(8~10), for example 1:0.066:1.6:40:9.6, 1:0.066:1.6:40:18, 1:0.032:1.6:40:9.6, 1:0.132:1.6:40:9.6, 1:0.26:1.6:40: 9.6, 1:0.5:1.6:40:9.6, 1:1:1.6:40:9.6, 1:0.066:0.2:40:9.6, 1:0.066:0.4:40:9.6, 1:0.066:0.8:40:9.6, 1:0.066:3.2:40:9.6, 1:0.066:1.6:20:9.6, 1:0.066:1.6:60:9.6 or 1:0.066:1.6:80:9.6.

[0032] In this invention, the concentration of the cabazitaxel or its pharmaceutically acceptable salt, calculated as cabazitaxel, is a conventional concentration in the art, preferably 0.1 to 10 mg / mL, more preferably 1 to 6 mg / mL, for example 5 mg / mL, where mg / mL refers to the ratio of the mass of cabazitaxel to the volume of the lyophilized cabazitaxel precursor.

[0033] In this invention, the concentration of the surfactant is preferably 0.15~5 mg / mL, more preferably 0.16~0.5 mg / mL, for example 0.16 mg / mL, 0.33 mg / mL, 0.66 mg / mL, 1.3 mg / mL, 2.5 mg / mL or 5 mg / mL, where mg / mL refers to the ratio of the mass of the surfactant to the volume of the cabazitaxel lyophilized powder precursor.

[0034] In this invention, the concentration of the dispersant is preferably 0.1~32 mg / mL, more preferably 2~16 mg / mL, for example 1 mg / mL, 2 mg / mL, 4 mg / mL, 8 mg / mL or 16 mg / mL, where mg / mL refers to the ratio of the mass of the dispersant to the volume of the cabazitaxel lyophilized powder precursor.

[0035] In this invention, the concentration of the lyophilization protectant is preferably 0.05~0.4 g / mL, more preferably 0.1~0.2 g / mL, for example 0.1 g / mL, 0.2 g / mL, 0.3 g / mL or 0.4 g / mL, where g / mL refers to the ratio of the mass of the lyophilization protectant to the volume of the cabazitaxel lyophilized powder precursor.

[0036] In this invention, the solvent can be a conventional solvent used in injectable preparations, such as an alcohol solvent.

[0037] The alcohol solvent is preferably selected from one or more of ethanol, ethylene glycol, propylene glycol and tert-butanol, and more preferably ethanol.

[0038] The concentration of the alcohol solvent is preferably 20-90 mg / mL, more preferably 40-60 mg / mL, for example 48 mg / mL or 90 mg / mL, where mg / mL refers to the ratio of the mass of the alcohol solvent to the volume of the cabazitaxel lyophilized powder precursor.

[0039] The solvent may also include water for injection.

[0040] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel or a pharmaceutically acceptable salt thereof, 0.16–5 mg / mL surfactant, 0.1–0.4 g / mL lyophilization protectant, 1–16 mg / mL dispersant, and solvent.

[0041] In this invention, the cabazitaxel lyophilized powder precursor is composed of the cabazitaxel or a pharmaceutically acceptable salt thereof, the surfactant, the dispersant, the lyophilization protectant, and the solvent.

[0042] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0043] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.16 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0044] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.66 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0045] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 1.3 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0046] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 2.5 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0047] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 5 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0048] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 1 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0049] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 2 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0050] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 4 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0051] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 16 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0052] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.1 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0053] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.3 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0054] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.4 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0055] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL sucrose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0056] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL maltose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0057] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL mannitol, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0058] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL lactose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection.

[0059] In some embodiments of the present invention, the cabazitaxel lyophilized powder precursor preferably comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 90 mg / mL ethanol, and water for injection.

[0060] The present invention also discloses a method for preparing cabazitaxel lyophilized powder, which includes the following steps: the mixture is lyophilized to obtain cabazitaxel lyophilized powder;

[0061] The mixture comprises cabazitaxel or a pharmaceutically acceptable salt thereof, a surfactant, a dispersant, a lyophilization protectant, and a solvent, wherein the surfactant is an anionic surfactant.

[0062] In this invention, the cabazitaxel or its pharmaceutically acceptable salt, the surfactant, the dispersant, the lyophilization protectant, and the solvent are preferably the cabazitaxel or its pharmaceutically acceptable salt, surfactant, dispersant, lyophilization protectant, and solvent described in the aforementioned cabazitaxel lyophilized powder precursor.

[0063] In this invention, the preparation method of the mixture preferably includes the following steps: mixing the cabazitaxel or its pharmaceutically acceptable salt, the surfactant, the dispersant and the solvent, heating at 25~65°C to obtain a preliminary mixture, and mixing the preliminary mixture with the lyophilization protectant to obtain the mixture.

[0064] The heating temperature is preferably 45°C.

[0065] The heating time is generally set to stop when the mixture dissolves.

[0066] The initial mixture and the lyophilization protectant are preferably mixed using either method one or method two:

[0067] The first method includes the following steps: mixing the initial mixture, the freeze-drying protectant, and water for injection to obtain a dispersion, followed by stirring;

[0068] Method 2 includes the following steps: the initial mixture is mixed and stirred with water for injection to obtain a dispersion, and then the dispersion is mixed with the lyophilization protectant.

[0069] In both Method 1 and Method 2, the stirring speed is preferably 100~1300 rpm, for example, 100 rpm, 500 rpm, 900 rpm or 1300 rpm. The stirring time is preferably 1~10 min, for example, 1 min, 2 min, 5 min or 10 min.

[0070] In some preferred embodiments of the present invention, the stirring speed is 500 rpm and the stirring time is 2 min.

[0071] In some preferred embodiments of the present invention, the stirring speed is 500 rpm and the stirring time is 1 min.

[0072] In some preferred embodiments of the present invention, the stirring speed is 500 rpm and the stirring time is 5 min.

[0073] In some preferred embodiments of the present invention, the stirring speed is 500 rpm and the stirring time is 10 min.

[0074] In some preferred embodiments of the present invention, the stirring speed is 100 rpm and the stirring time is 2 min.

[0075] In some preferred embodiments of the present invention, the stirring speed is 900 rpm and the stirring time is 2 min.

[0076] In some preferred embodiments of the present invention, the stirring speed is 1300 rpm and the stirring time is 2 min.

[0077] In this invention, the freeze-drying process can be conventional in the art. Preferably, the freeze-drying includes the following steps: holding at -50 to -30°C for 100 to 200 min, raising the temperature to -40 to -20°C and holding for 3000 to 5000 min, and then raising the temperature to 10 to 30°C and holding for 120 to 360 min. For example, pre-freezing at -50°C for 150 min, raising the temperature to -30°C and holding for 4000 min, and then raising the temperature to 20°C and holding for 240 min.

[0078] In this invention, before freeze-drying, the mixture may be filtered and / or dispensed according to conventional procedures in the art.

[0079] The filtration method can be a conventional filtration method in the art, preferably using a 0.22 μm sterile filter membrane, which can filter out bacteria and other impurities.

[0080] The present invention also discloses a method for preparing the aforementioned lyophilized cabazitaxel powder.

[0081] This invention also discloses the application of the aforementioned lyophilized cabazitaxel powder, or lyophilized cabazitaxel powder reconstituter, or lyophilized cabazitaxel powder precursor, or the aforementioned method for preparing lyophilized cabazitaxel powder, in the preparation of drugs for treating cancer, preferably prostate cancer.

[0082] In this invention, the preferred dosage of the lyophilized carbamate powder or the reconstituted carbamate lyophilized powder is 5-14 mg / kg, for example, 6 mg / kg or 12 mg / kg, based on a single dose of carbamate.

[0083] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0084] The positive and progressive effects of this invention are as follows:

[0085] The lyophilized cabazitaxel powder of the present invention has a good anti-tumor (prostate tumor) effect; and compared with the commercially available cabazitaxel preparation Jevtana®, the lyophilized cabazitaxel powder of the present invention has an improved half-life and average retention time in mice. Attached Figure Description

[0086] Figure 1 The images show the morphology of solid tumors in each group of mice.

[0087] Figure 2 This is a blood drug concentration-time curve. Detailed Implementation

[0088] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0089] Raw material sources: Cabazitaxel was purchased from Wuhan Xinxinjiali Biotechnology Co., Ltd.; PVP K12 was purchased from BASF; and anhydrous ethanol was purchased from Yonghua Chemical Co., Ltd.

[0090] In the following examples, the particle size and PDI were measured using a Malvern laser particle size analyzer, the encapsulation efficiency was determined using a microporous membrane filtration method (membrane pore size of 0.22 μm), and the content was detected and calculated using Waters high performance liquid chromatography. The particle size in the following examples refers to the average particle size.

[0091] Example 1: Preparation of carbamate lyophilized powder injection with different surfactant dosages

[0092] (1) In this embodiment, different amounts of sodium cholesterol sulfate were used to prepare lyophilized carbamate powder for injection with carbamate, PVP K12, anhydrous ethanol, trehalose and water for injection as raw materials, as shown in prescriptions 1-6 in Table 1.

[0093] Table 1

[0094]

[0095] (2) Cabazitaxel nanodispersions were prepared using the raw materials in the above formulation. The preparation steps included:

[0096] Weigh out the prescribed amounts of cabazitaxel, sodium cholesterol sulfate, and PVP K12, mix them, add ethanol, and heat at 45°C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing the prescribed amount of trehalose, and stir at 500 rpm for 2 min to obtain cabazitaxel nanodispersions. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by passing through a 0.22 μm filter membrane, dispense, freeze-dry, seal, and cap to obtain the freeze-dried cabazitaxel nanodispersion powder for injection.

[0097] The freeze-drying process is as follows: pre-freeze at -50℃ for 150 min, raise the temperature to -30℃ and hold for 4000 min, then raise the temperature to 20℃ and hold for 240 min.

[0098] (3) Experimental results

[0099] Reconstitution: Slowly inject the reconstituted cabazitaxel solution along the inner wall of the vial using water for injection or 5% glucose injection (the concentration of cabazitaxel after reconstitution is the same as before lyophilization). Gently shake or slowly invert the drug for at least 1 minute to ensure complete dispersion and dissolution of the lyophilized powder, avoiding the formation of air bubbles, to obtain the reconstituted cabazitaxel nanodispersion. Table 2 shows the appearance, particle size distribution, and encapsulation efficiency of the reconstituted cabazitaxel nanodispersions for each formulation.

[0100] Table 2

[0101]

[0102] It can be seen that different amounts of surfactant have different effects on the dispersibility of the reconstituted carbamate nanodispersions. Within the above dosage range, the reconstituted carbamate nanodispersions of Formulation 2 have smaller particle size and more uniform distribution, and higher encapsulation efficiency.

[0103] Example 2: Preparation of carbatataxel lyophilized powder for injection with different dispersant dosages

[0104] (1) In this embodiment, cabazitaxel lyophilized powder injections were prepared with different amounts of PVP K12. The raw materials are shown in Formulation 1-Formulation 4 in Table 3.

[0105] Table 3

[0106]

[0107] (2) Cabazitaxel nanodispersions were prepared using the raw materials in the above formulation. The preparation steps included:

[0108] Weigh out the prescribed amounts of cabazitaxel, sodium cholesterol sulfate, and PVP K12, mix them, add ethanol, and heat at 45°C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing the prescribed amount of trehalose, and stir at 500 rpm for 2 min to obtain cabazitaxel nanodispersions. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by passing through a 0.22 μm filter membrane, dispense, freeze-dry, seal, and cap to obtain the freeze-dried cabazitaxel nanodispersion powder for injection.

[0109] The freeze-drying process is as follows: pre-freeze at -50℃ for 150 min, raise the temperature to -30℃ and hold for 4000 min, then raise the temperature to 20℃ and hold for 240 min.

[0110] Comparative Example 1

[0111] The raw material composition of this comparative example is basically the same as that of Formula 1 in Example 2, except that PVPK12 is not added in this comparative example, and the preparation process and steps are the same as those in Example 2.

[0112] The lyophilized cabazitaxel nanodispersions of Example 2 and Comparative Example 1 were reconstituted using the process described in Example 1 to obtain reconstituted cabazitaxel nanodispersions. Table 4 shows the appearance, particle size distribution, and encapsulation efficiency of each formulation of Example 2 and the reconstituted cabazitaxel nanodispersions of Comparative Example 1.

[0113] Table 4

[0114]

[0115] It can be seen that without the addition of dispersant, the particle size and distribution of the cabazitaxel nanodispersion increased significantly after reconstitution, and the encapsulation efficiency decreased. From the formulations of Example 2, different amounts of dispersant have different effects on the dispersibility of the nanodispersion. Within the above dosage range, the cabazitaxel nanodispersion of formulation 3 has a smaller particle size and more uniform distribution, and a higher encapsulation efficiency.

[0116] Example 3: Preparation of carbatataxel lyophilized powder injection with different types of lyophilization protectants

[0117] (1) In this embodiment, cabazitaxel nanodispersions were prepared using different types of freeze-drying protectants. The raw materials are shown in Formulations 1-6 in Table 5.

[0118] Table 5

[0119]

[0120] (2) Cabazitaxel nanodispersions were prepared using the raw materials in the above formulation. The preparation steps included:

[0121] Weigh out the prescribed amounts of cabazitaxel, sodium cholesterol sulfate, and PVP K12, mix them, add ethanol, and heat at 45°C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing 2 g of different lyophilization protectants, and stir at 500 rpm for 2 min to obtain cabazitaxel nanodispersions. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by passing through a 0.22 μm filter membrane, dispense, lyophilize, seal, and cap to obtain the lyophilized cabazitaxel nanodispersion powder for injection.

[0122] (3) Experimental results

[0123] The lyophilized cabazitaxel nanodispersion for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersion. Table 6 shows the appearance of the lyophilized cabazitaxel nanodispersion for injection of each formulation, as well as the appearance, particle size distribution, and encapsulation efficiency of the reconstituted cabazitaxel nanodispersion.

[0124] Table 6

[0125]

[0126] It can be seen that different types of freeze-drying protectants have different effects on the particle size, dispersibility and encapsulation efficiency of cabazitaxel nanodispersions. Among them, the freeze-dried powder of formulation 1 has a smooth and full appearance, and the nanodispersions after reconstitution have smaller particle size, narrower distribution and higher encapsulation efficiency.

[0127] Example 4: Preparation of carbatataxel lyophilized powder injection with different amounts of lyophilizing protectant

[0128] (1) In this embodiment, cabazitaxel lyophilized powder injection was prepared with different amounts of freeze-drying protectant. The raw materials are shown in Formulation 1-Formulation 4 in Table 7.

[0129] Table 7

[0130]

[0131] (2) Cabazitaxel nanodispersions were prepared using the raw materials in the above formulation. The preparation steps included:

[0132] Weigh out the prescribed amounts of cabazitaxel, sodium cholesterol sulfate, and PVP K12, mix them, add ethanol, and heat at 45°C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing the prescribed amount of trehalose, and stir at 500 rpm for 2 min to obtain cabazitaxel nanodispersions. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by passing through a 0.22 μm filter membrane, dispense, freeze-dry, seal, and cap to obtain the freeze-dried cabazitaxel nanodispersion powder for injection.

[0133] (3) Experimental results

[0134] The lyophilized cabazitaxel nanodispersible powder for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersible. Table 8 shows the appearance, particle size distribution, and encapsulation efficiency of the cabazitaxel nanodispersible before lyophilization and after reconstitution for each formulation.

[0135] Table 8

[0136]

[0137] It can be seen that different amounts of freeze-drying protectant have different effects on the dispersibility of nano-dispersions. When the amount of protectant in Formula 3 is reached, the encapsulation efficiency of the freeze-dried and reconstituted nano-dispersions gradually decreases with the increase of the amount of freeze-drying protectant. The changes in particle size, distribution, and encapsulation efficiency of the nano-dispersions in Formulas 1 and 2 before and after freeze-drying are relatively small.

[0138] Example 5

[0139] Weigh out 50 mg of cabazitaxel, 3.3 mg of sodium cholesterol sulfate, and 80 mg of PVP K12, mix them, add 480 mg of ethanol, and heat at 45 °C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing 2 g of trehalose, and stir at 500 rpm for 2 min to obtain a cabazitaxel nanodispersion. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by filtering through a 0.22 μm filter membrane, dispense, lyophilize (pre-freeze at -50 °C for 150 min, raise the temperature to -30 °C and hold for 4000 min, then raise the temperature to 20 °C and hold for 240 min), seal, and cap to obtain a lyophilized cabazitaxel nanodispersion powder for injection.

[0140] The lyophilized cabazitaxel nanodispersion for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersion. The particle size of the reconstituted cabazitaxel nanodispersion was determined to be 128.0 nm, the PDI was 0.1217, and the drug encapsulation efficiency was 98.86%.

[0141] Example 6

[0142] Weigh out 50 mg of cabazitaxel, 3.3 mg of sodium cholesterol sulfate, and 80 mg of PVP K12, mix them, add 900 mg of ethanol, and heat at 45 °C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing 2 g of trehalose, and stir at 500 rpm for 2 min to obtain a cabazitaxel nanodispersion. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by filtering through a 0.22 μm filter membrane, dispense, lyophilize (pre-freeze at -50 °C for 150 min, raise the temperature to -30 °C and hold for 4000 min, then raise the temperature to 20 °C and hold for 240 min), seal, and cap to obtain a lyophilized cabazitaxel nanodispersion powder for injection.

[0143] The lyophilized cabazitaxel nanodispersion for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersion. The particle size of the reconstituted cabazitaxel nanodispersion was determined to be 245.2 nm, the PDI was 0.1342, and the drug encapsulation efficiency was 90.95%.

[0144] Example 7

[0145] Weigh out 50 mg of cabazitaxel, 3.3 mg of sodium cholesterol sulfate, and 80 mg of PVP K12, mix them, add 480 mg of ethanol, and heat at 45 °C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing 2 g of trehalose, and stir at 100 rpm for 2 min to obtain cabazitaxel nanodispersion. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by filtering through a 0.22 μm filter membrane, dispense, lyophilize (pre-freeze at -50 °C for 150 min, raise the temperature to -30 °C and hold for 4000 min, then raise the temperature to 20 °C and hold for 240 min), seal, and cap to obtain lyophilized cabazitaxel nanodispersion powder for injection.

[0146] The lyophilized cabazitaxel nanodispersion for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersion. The particle size of the reconstituted cabazitaxel nanodispersion was determined to be 167.3 nm, the PDI was 0.1737, and the drug encapsulation efficiency was 93.38%.

[0147] Example 8

[0148] Weigh out 50 mg of cabazitaxel, 3.3 mg of sodium cholesterol sulfate, and 80 mg of PVP K12, mix them, add 480 mg of ethanol, and heat at 45 °C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing 2 g of trehalose, and stir at 900 rpm for 2 min to obtain cabazitaxel nanodispersion. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by filtering through a 0.22 μm filter membrane, dispense, lyophilize (pre-freeze at -50 °C for 150 min, raise the temperature to -30 °C and hold for 4000 min, then raise the temperature to 20 °C and hold for 240 min), seal, and cap to obtain lyophilized cabazitaxel nanodispersion powder for injection.

[0149] The lyophilized cabazitaxel nanodispersion for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersion. The particle size of the reconstituted cabazitaxel nanodispersion was determined to be 214.4 nm, the PDI was 0.1639, and the drug encapsulation efficiency was 92.76%.

[0150] Example 9

[0151] Weigh out 50 mg of cabazitaxel, 3.3 mg of sodium cholesterol sulfate, and 80 mg of PVP K12, mix them, add 480 mg of ethanol, and heat at 45 °C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing 2 g of trehalose, and stir at 1300 rpm for 2 min to obtain cabazitaxel nanodispersion. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by filtering through a 0.22 μm filter membrane, dispense, lyophilize (pre-freeze at -50 °C for 150 min, raise the temperature to -30 °C and hold for 4000 min, then raise the temperature to 20 °C and hold for 240 min), seal, and cap to obtain lyophilized cabazitaxel nanodispersion powder for injection.

[0152] The lyophilized cabazitaxel nanodispersion for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersion. The particle size of the reconstituted cabazitaxel nanodispersion was determined to be 250.7 nm, the PDI was 0.2116, and the drug encapsulation efficiency was 90.72%.

[0153] Example 10

[0154] Weigh out 50 mg of cabazitaxel, 3.3 mg of sodium cholesterol sulfate, and 80 mg of PVP K12, mix them, add 480 mg of ethanol, and heat at 45 °C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing 2 g of trehalose, and stir at 500 rpm for 1 min to obtain cabazitaxel nanodispersion. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by filtering through a 0.22 μm filter membrane, dispense, lyophilize (pre-freeze at -50 °C for 150 min, raise the temperature to -30 °C and hold for 4000 min, then raise the temperature to 20 °C and hold for 240 min), seal, and cap to obtain lyophilized cabazitaxel nanodispersion powder for injection.

[0155] The lyophilized cabazitaxel nanodispersion for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersion. The particle size of the reconstituted cabazitaxel nanodispersion was determined to be 128.1 nm, the PDI was 0.1335, and the drug encapsulation efficiency was 96.65%.

[0156] Example 11

[0157] Weigh out 50 mg of cabazitaxel, 3.3 mg of sodium cholesterol sulfate, and 80 mg of PVP K12, mix them, add 480 mg of ethanol, and heat at 45 °C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing 2 g of trehalose, and stir at 500 rpm for 5 min to obtain cabazitaxel nanodispersion. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by filtering through a 0.22 μm filter membrane, dispense, lyophilize (pre-freeze at -50 °C for 150 min, raise the temperature to -30 °C and hold for 4000 min, then raise the temperature to 20 °C and hold for 240 min), seal, and cap to obtain lyophilized cabazitaxel nanodispersion powder for injection.

[0158] The lyophilized cabazitaxel nanodispersion for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersion. The particle size of the reconstituted cabazitaxel nanodispersion was determined to be 134.8 nm, the PDI was 0.1893, and the drug encapsulation efficiency was 98.78%.

[0159] Example 12

[0160] Weigh out 50 mg of cabazitaxel, 3.3 mg of sodium cholesterol sulfate, and 80 mg of PVP K12, mix them, add 480 mg of ethanol, and heat at 45 °C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing 2 g of trehalose, and stir at 500 rpm for 10 min to obtain cabazitaxel nanodispersion. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by filtering through a 0.22 μm filter membrane, dispense, lyophilize (pre-freeze at -50 °C for 150 min, raise the temperature to -30 °C and hold for 4000 min, then raise the temperature to 20 °C and hold for 240 min), seal, and cap to obtain lyophilized cabazitaxel nanodispersion powder for injection.

[0161] The lyophilized cabazitaxel nanodispersion for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersion. The particle size of the reconstituted cabazitaxel nanodispersion was determined to be 152.1 nm, the PDI was 0.2785, and the drug encapsulation efficiency was 96.26%.

[0162] Example 13

[0163] Weigh out 50 mg of cabazitaxel, 3.3 mg of sodium cholesterol sulfate, and 80 mg of PVP K12, mix them, add 480 mg of ethanol, and heat at 25 °C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing 2 g of trehalose, and stir at 500 rpm for 2 min to obtain a cabazitaxel nanodispersion. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by filtering through a 0.22 μm filter membrane, dispense, lyophilize (pre-freeze at -50 °C for 150 min, raise the temperature to -30 °C and hold for 4000 min, then raise the temperature to 20 °C and hold for 240 min), seal, and cap to obtain a lyophilized cabazitaxel nanodispersion powder for injection.

[0164] The lyophilized cabazitaxel nanodispersion for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersion. The particle size of the reconstituted cabazitaxel nanodispersion was determined to be 131.1 nm, the PDI was 0.1347, and the drug encapsulation efficiency was 97.50%.

[0165] Example 14

[0166] Weigh out 50 mg of cabazitaxel, 3.3 mg of sodium cholesterol sulfate, and 80 mg of PVP K12, mix them, add 480 mg of ethanol, and heat at 65 °C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into 10 mL of water for injection containing 2 g of trehalose, and stir at 500 rpm for 2 min to obtain cabazitaxel nanodispersion. After removing ethanol by ultrafiltration or rotary evaporation, sterilize by filtering through a 0.22 μm filter membrane, dispense, lyophilize (pre-freeze at -50 °C for 150 min, raise the temperature to -30 °C and hold for 4000 min, then raise the temperature to 20 °C and hold for 240 min), seal, and cap to obtain lyophilized cabazitaxel nanodispersion powder for injection.

[0167] The lyophilized cabazitaxel nanodispersion for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersion. The particle size of the reconstituted cabazitaxel nanodispersion was determined to be 132.2 nm, the PDI was 0.1218, and the drug encapsulation efficiency was 97.67%.

[0168] Example 15

[0169] Weigh out 50 mg of cabazitaxel, 3.3 mg of sodium cholesterol sulfate, and 80 mg of PVP K12, mix them, add 480 mg of ethanol, and heat at 45 °C to dissolve, obtaining a concentrated cabazitaxel solution. Inject the concentrated solution into a quantitative amount of water for injection, and stir at 500 rpm for 2 min to obtain cabazitaxel nanodispersion. After removing ethanol by ultrafiltration or rotary evaporation, add 2 g of trehalose, stir to dissolve, and bring the volume to 10 ml with water for injection. Sterilize by filtering through a 0.22 μm filter membrane, dispense, lyophilize (pre-freeze at -50 °C for 150 min, raise the temperature to -30 °C and hold for 4000 min, then raise the temperature to 20 °C and hold for 240 min), seal, and cap to obtain lyophilized cabazitaxel nanodispersion powder for injection.

[0170] The lyophilized cabazitaxel nanodispersion for injection was reconstituted using the process described in Example 1 to obtain the reconstituted cabazitaxel nanodispersion. The particle size of the reconstituted cabazitaxel nanodispersion was determined to be 129.4 nm, the PDI was 0.1426, and the drug encapsulation efficiency was 98.32%.

[0171] Effect Example

[0172] 1. Stability Study

[0173] The stability of the lyophilized powder injection prepared in Example 5 was studied.

[0174] The lyophilized cabazitaxel nanodispersion powder of Example 5 was reconstituted using the reconstitution process of Example 1 to obtain the reconstituted cabazitaxel nanodispersion.

[0175] The stability results under accelerated conditions (25℃ ± 2℃, 60% ± 5%RH) are shown in Table 9, and the stability results under long-term conditions (5℃ ± 3℃) are shown in Table 10.

[0176] Table 9. Accelerated stability results under conditions of 25℃ ± 2℃ and 60% ± 5%RH.

[0177]

[0178] Table 10. Long-term stability results at 5℃ ± 3℃

[0179]

[0180] As can be seen, the lyophilized carbamate nanodispersion powder prepared in Example 5 showed no significant changes in appearance, particle size and distribution, and encapsulation efficiency after being placed under accelerated conditions (25℃ ± 2℃, 60% ± 5%RH) for 6 months and under long-term conditions (5℃ ± 3℃) for 12 months, respectively, demonstrating good stability.

[0181] 2. Maximum tolerated dose study of cabazitaxel nanodispersions

[0182] (1) Experimental methods

[0183] The dosage and safety of animals during the pharmacodynamic experiment were determined by measuring the maximum tolerated dose of the carbamate-tween injection group (i.e., the commercially available Jevtana®) and the carbamate nanodispersion (the reconstituted carbamate nanodispersion lyophilized powder for injection in Example 5).

[0184] Thirty-six SPF-grade male C57BL / 6 mice (weighing 18–22 g, purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd.) were randomly divided into two groups: a cabazitaxel-tween injection group and a cabazitaxel nanodispersion group. The dosages of the cabazitaxel-tween injection group were 6, 8, and 10 mg / kg (calculated as cabazitaxel), respectively; the dosages of the cabazitaxel nanodispersion group were 12, 14, and 16 mg / kg (calculated as cabazitaxel), respectively. Animals in each group were injected via tail vein on days 0, 2, 4, and 6. The mean daily tolerance (MTD) of both groups was determined by changes in body weight, general indicators, and mortality. Symptoms in mice after administration were observed, and the number of deaths was recorded. If a mouse's body weight decreased by no more than 20% and no mice died during the administration period, this dose was considered the maximum tolerated dose for subsequent experiments.

[0185] ;

[0186] RW represents weight change, W0 and W tThe values ​​represent the mouse's body weight before administration and its body weight after the last administration, respectively.

[0187] (2) Experimental results

[0188] The results of the maximum tolerated dose are shown in Table 11.

[0189] Table 11

[0190]

[0191] The results showed that, compared to cabazitaxel-tween injection, cabazitaxel nanodispersion was well-tolerated in animals. At a dose of only 10 mg / kg, cabazitaxel-tween injection resulted in a 24.89% decrease in body weight in mice; while at 16 mg / kg, cabazitaxel nanodispersion resulted in a comparable decrease in body weight. The maximum tolerated dose is typically defined as a weight loss of no more than 20%, and the maximum tolerated dose of cabazitaxel nanodispersion is approximately 14 mg / kg, significantly higher than that of cabazitaxel-tween injection.

[0192] 3. Pharmacodynamic study of cabazitaxel nanodispersions

[0193] (1) Experimental methods

[0194] RM-1 cells in logarithmic growth phase (purchased from Shanghai Cell Bank, Chinese Academy of Sciences) were resuspended in PBS and the cell density was adjusted to 1×10⁻⁶. 7 Cells were injected at a rate of 0.2 mL / mL into the right axilla of SPF-grade C57BL / 6 male mice (weighing 18-22 g, purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd.). After 14 days, the mice were randomly divided into the following groups according to tumor volume: ① 5% glucose injection group (Control); ② Cabazitaxel-Twyn injection group (CTX-TW-6 mg / kg); ③ Low-dose cabazitaxel nanodispersion group (CTX-NP-3 mg / kg); ④ Medium-dose cabazitaxel nanodispersion group (CTX-NP-6 mg / kg); ⑤ High-dose cabazitaxel nanodispersion group (CTX-NP-12 mg / kg). The cabazitaxel-Twyn injection group used commercially available Jevtana®, and the cabazitaxel nanodispersion referred to the reconstituted lyophilized powder of the cabazitaxel nanodispersion in Example 5. Six mice were administered the drug via tail vein injection every two days for a total of four administrations. The mice were sacrificed the day after drug withdrawal, and the tumors were removed, weighed, and the tumor inhibition rate was calculated.

[0195] ;

[0196] ;

[0197] ;

[0198] ;

[0199] In the formula, W and L are the short and long diameters of the mouse tumor, respectively; TIR is the tumor inhibition rate, W control and W treat These represent the average tumor weight in the Control and Treatment groups, respectively; RTV represents the relative tumor volume, V0 and V... t The values ​​represent the tumor volume at the time of grouping and at each measurement, respectively, and R represents the relative tumor proliferation rate.

[0200] (2) Experimental results

[0201] The changes in tumor weight in each group of mice are shown in Table 12.

[0202] Table 12

[0203]

[0204] Note: Compared with the CTX-NP-6mg / kg group: * P < 0.05; compared with the CTX-TW-6mg / kg group: # P < 0.05.

[0205] Table 13 shows the changes in tumor volume and mouse weight over time in each group of mice.

[0206] Table 13

[0207]

[0208] Figure 1 The image shows the morphology of solid tumors in each group of mice.

[0209] The results showed that 12 mg / kg cabazitaxel nanodispersion exhibited the best tumor-suppressive effect. At the same dose (6 mg / kg, based on cabazitaxel), compared to cabazitaxel-Tween injection, the cabazitaxel nanodispersion demonstrated stronger antitumor activity and less weight loss in mice, indicating better drug safety. These results suggest that, while ensuring drug safety, cabazitaxel nanodispersion can achieve a more significant antitumor effect by increasing the dosage of cabazitaxel.

[0210] 4. Pharmacokinetic Study of Cabazitaxel Nanodispersions

[0211] (1) Experimental methods

[0212] Twelve male SPF-grade SD rats (180-220g, purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd.) were randomly divided into two groups of six each. Rats were fasted for 24 hours before the experiment, but water was allowed. The following administrations were administered via tail vein: ① 5 mg / kg carbamate-tween injection (CTX-TW); ② 5 mg / kg carbamate nanodispersion (CTX-NP). The carbamate-tween injection was commercially available Jevtana®, and the carbamate nanodispersion was obtained by reconstitution of the lyophilized carbamate nanodispersion powder from Example 5. 0.5 mL of blood was collected from the orbital sinus at 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, and 5 h after administration.

[0213] Sample processing and analysis: Plasma samples were centrifuged at 5000 rpm / min for 10 min. 100 μL of the supernatant was collected, and 10 μL of carbamazepine internal standard solution (0.05 mg / mL) was added. After vortexing for 30 s, 1 mL of acetonitrile was added for extraction, followed by vortexing for 3 min and centrifugation at 10000 rpm for 10 min. The supernatant was collected, and the organic phase was evaporated to dryness using a vacuum concentrator. 200 μL of acetonitrile was added to reconstitute the sample, followed by vortexing for 3 min and centrifugation at 10000 rpm for 5 min. The supernatant was collected, and the drug content was determined by HLPC. The blood drug concentration was calculated, and pharmacokinetic fitting was performed using DAS 2.0 software.

[0214] (2) Experimental results

[0215] The plasma concentration-time curves of SD rats injected with CTX-TW and CTX-NP are shown below. Figure 2 As shown.

[0216] The main pharmacokinetic parameters are shown in Table 14.

[0217] Table 14

[0218]

[0219] Note: Compared with the cabazitaxel injection group: *P < 0.05, **P < 0.01, ***P < 0.001.

[0220] In the table above, T 1 / 2 MRT(0-t) represents the half-life, MRT(0-t) represents the average residence time from 0 to t, and MRT(0-∞) represents the average residence time from 0 to ∞. max The peak plasma concentration is represented by AUC; the area under the curve during drug administration is represented by CLz; and the clearance rate is represented by CLz.

[0221] The results showed that, compared with the CTX-TW group, the in vivo half-life T of CTX-NP was longer. 1 / 2The mean residence time (MRT) was prolonged, approximately 4.1 times and 2.8 times that of the CTX-TW group, respectively. The AUC was significantly increased, approximately 2.6 times that of the CTX-TW group, which is beneficial for drug accumulation at the tumor site, thus resulting in a better anti-tumor effect.

Claims

1. A lyophilized carbamate powder, characterized in that, It includes cabazitaxel or its pharmaceutically acceptable salts, surfactants, dispersants, and lyophilization protectants; The surfactant is an anionic surfactant.

2. The lyophilized cabazitaxel powder as described in claim 1, characterized in that, The lyophilized cabazitaxel powder satisfies one or more of the following conditions (a) to (g): (a) The anionic surfactant is selected from one or more of sodium cholesterol sulfate, sodium deoxycholate, sodium oleate, sodium stearate, sodium dodecylbenzene sulfonate and sodium lauryl ether sulfate, preferably sodium cholesterol sulfate; (b) The dispersant is selected from one or more of PVP, polyvinyl alcohol, polyethylene glycol, hydroxypropyl methylcellulose, polyacrylic acid, hyaluronic acid and chitosan, preferably PVP; the molecular weight of the PVP is preferably 2,000 to 50,000, such as PVP K12, PVP K15, PVP K25 or PVP K30, more preferably PVP K12; (c) The freeze-drying protectant is selected from one or more of trehalose, sucrose, maltose, glucose, mannitol and lactose, preferably from one or more of trehalose, sucrose and maltose, and more preferably trehalose; (d) The mass ratio of the cabazitaxel or its pharmaceutically acceptable salt to the surfactant is 1:(0.03~1), preferably 1:(0.05~0.3), more preferably 1:(0.05~0.1), for example 1:0.031, 1:0.066, 1:0.132, 1:0.26 or 1:0.5; (e) The mass ratio of the cabazitaxel or its pharmaceutically acceptable salt to the dispersant is 1:(0.2 to 3.2), preferably 1:(0.5 to 3.2), more preferably 1:(1 to 2), for example 1:0.2, 1:0.4, 1:0.8, 1:1.6 or 1:3.2; (f) The mass ratio of the cabazitaxel or its pharmaceutically acceptable salt to the lyophilization protectant is 1:(10-80), preferably 1:(20-50), more preferably 1:(35-45), for example 1:20, 1:40, 1:60 or 1:80, based on cabazitaxel. Preferably, the mass ratio of the cabazitaxel or its pharmaceutically acceptable salt, the surfactant, the dispersant, and the lyophilization protectant is 1:(0.03~1):(0.2~3.2):(10~80), more preferably 1:(0.05~0.3):(0.5~3.2):(20~50), and even more preferably 1:(0.05~0.1):(1~2):(35~45), for example 1:0.066:1.6:40, 1:0 .032:1.6:40, 1:0.132:1.6:40, 1:0.26:1.6:40, 1:0.5:1.6:40, 1:1:1.6:40, 1:0.066:0.2:40, 1:0.066:0.4:40, 1:0.066:0.8:40, 1:0.066:3.2:40, 1:0.066:1.6:20, 1:0.066:1.6:60 or 1:0.066:1.6:80; And, (g) the lyophilized cabazitaxel powder consists of the cabazitaxel or a pharmaceutically acceptable salt thereof, the surfactant, the dispersant and the lyophilization protectant.

3. A lyophilized precursor for cabazitaxel, characterized in that, It includes cabazitaxel or its pharmaceutically acceptable salts, surfactants, dispersants, lyophilization protectants, and solvents; The surfactant is an anionic surfactant.

4. The cabazitaxel lyophilized powder precursor as described in claim 3, characterized in that, The cabazitaxel lyophilized powder precursor satisfies one or more of the following conditions (a) to (i): (a) The anionic surfactant, the dispersant and the lyophilization protectant are the anionic surfactant, dispersant and lyophilization protectant described in the cabazitaxel lyophilized powder of claim 2; (b) The mass ratio of the cabazitaxel or its pharmaceutically acceptable salt to the surfactant, the mass ratio of the cabazitaxel or its pharmaceutically acceptable salt to the dispersant, and the mass ratio of the cabazitaxel or its pharmaceutically acceptable salt to the lyophilization protectant are the same as those described in the cabazitaxel lyophilized powder of claim 2. (c) The mass ratio of the cabazitaxel or its pharmaceutically acceptable salt to the solvent is 1:(4-18), preferably 1:(8-12), for example 1:9.6 or 1:18; Preferably, based on cabazitaxel, the mass ratio of the cabazitaxel or its pharmaceutically acceptable salt, the surfactant, the dispersant, the lyophilization protectant, and the solvent is 1:(0.03~1):(0.2~3.2):(10~80):(4~18), more preferably 1:(0.05~0.3):(0.5~3.2):(20~50):(8~12), and even more preferably 1:(0.05~0.1):(1~2):(35~45):(8~10), for example 1:0.066:1.6:40:9.6, 1:0.066:1.6:40:18, 1:0.032:1.6:40:9.6, 1:0.132:1.6:40:9.6, 1:0.26:1.6:40: 9.6, 1:0.5:1.6:40:9.6, 1:1:1.6:40:9.6, 1:0.066:0.2:40:9.6, 1:0.066:0.4:40:9.6, 1:0.066:0.8:40:9.6, 1:0.066:3.2:40:9.6, 1:0.066:1.6:20:9.6, 1:0.066:1.6:60:9.6 or 1:0.066:1.6:80:9.6; (d) The concentration of the cabazitaxel or its pharmaceutically acceptable salt, calculated as cabazitaxel, is 0.1 to 10 mg / mL, preferably 1 to 6 mg / mL, for example 5 mg / mL, where mg / mL refers to the ratio of the mass of the cabazitaxel to the volume of the lyophilized cabazitaxel precursor. (e) The concentration of the surfactant is 0.15 to 5 mg / mL, preferably 0.16 to 0.5 mg / mL, for example 0.16 mg / mL, 0.33 mg / mL, 0.66 mg / mL, 1.3 mg / mL, 2.5 mg / mL or 5 mg / mL, where mg / mL refers to the ratio of the mass of the surfactant to the volume of the cabazitaxel lyophilized powder precursor; (f) The concentration of the dispersant is 0.1~32 mg / mL, preferably 2~16 mg / mL, for example 1 mg / mL, 2 mg / mL, 4 mg / mL, 8 mg / mL or 16 mg / mL, where mg / mL refers to the ratio of the mass of the dispersant to the volume of the cabazitaxel lyophilized powder precursor; (g) The concentration of the lyophilization protectant is 0.05~0.4 g / mL, preferably 0.1~0.2 g / mL, for example 0.1 g / mL, 0.2 g / mL, 0.3 g / mL or 0.4 g / mL, where g / mL refers to the ratio of the mass of the lyophilization protectant to the volume of the cabazitaxel lyophilized powder precursor; (h) The solvent is an alcohol solvent, preferably selected from one or more of ethanol, ethylene glycol, propylene glycol, and tert-butanol, more preferably ethanol; the concentration of the alcohol solvent is preferably 20-90 mg / mL, more preferably 40-60 mg / mL, for example 48 mg / mL or 90 mg / mL, where mg / mL refers to the ratio of the mass of the alcohol solvent to the volume of the cabazitaxel lyophilized powder precursor; the solvent preferably also includes water for injection; And, (i) the cabazitaxel lyophilized powder precursor consists of the cabazitaxel or a pharmaceutically acceptable salt thereof, the surfactant, the dispersant, the lyophilization protectant and the solvent.

5. The cabazitaxel lyophilized powder precursor as described in claim 3, characterized in that, The cabazitaxel lyophilized powder precursor comprises 5 mg / mL cabazitaxel or a pharmaceutically acceptable salt thereof, 0.16–5 mg / mL surfactant, 0.1–0.4 g / mL lyophilization protectant, 1–16 mg / mL dispersant, and solvent; Preferably, the cabazitaxel lyophilized powder precursor satisfies the following scheme: The lyophilized cabazitaxel precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the lyophilized cabazitaxel precursor comprises 5 mg / mL cabazitaxel, 0.16 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the cabazitaxel lyophilized powder precursor comprises 5 mg / mL cabazitaxel, 0.66 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the cabazitaxel lyophilized powder precursor comprises 5 mg / mL cabazitaxel, 1.3 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the cabazitaxel lyophilized powder precursor comprises 5 mg / mL cabazitaxel, 2.5 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the cabazitaxel lyophilized powder precursor comprises 5 mg / mL cabazitaxel, 5 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the lyophilized cabazitaxel precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 1 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the lyophilized cabazitaxel precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 2 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the lyophilized cabazitaxel precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 4 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the lyophilized cabazitaxel precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 16 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the cabazitaxel lyophilized powder precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.1 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the lyophilized cabazitaxel precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.3 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the cabazitaxel lyophilized powder precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.4 g / mL trehalose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the cabazitaxel lyophilized powder precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL sucrose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the cabazitaxel lyophilized powder precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL maltose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the cabazitaxel lyophilized powder precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL mannitol, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the cabazitaxel lyophilized powder precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL lactose, 8 mg / mL PVP K12, 48 mg / mL ethanol, and water for injection; Alternatively, the lyophilized cabazitaxel precursor comprises 5 mg / mL cabazitaxel, 0.33 mg / mL sodium cholesterol sulfate, 0.2 g / mL trehalose, 8 mg / mL PVP K12, 90 mg / mL ethanol, and water for injection.

6. A method for preparing a lyophilized cabazitaxel powder, characterized in that, It includes the following steps: the mixture is freeze-dried to obtain cabazitaxel freeze-dried powder; The mixture comprises cabazitaxel or a pharmaceutically acceptable salt thereof, a surfactant, a dispersant, a lyophilization protectant, and a solvent, wherein the surfactant is an anionic surfactant.

7. The method for preparing cabazitaxel lyophilized powder as described in claim 6, characterized in that, The cabazitaxel or its pharmaceutically acceptable salt, the surfactant, the dispersant, the lyophilization protectant, and the solvent are the cabazitaxel or its pharmaceutically acceptable salt, surfactant, dispersant, lyophilization protectant, and solvent described in the cabazitaxel lyophilized powder precursor of claim 4 or 5. And / or, the preparation method of the mixture includes the following steps: mixing the cabazitaxel or its pharmaceutically acceptable salt, the surfactant, the dispersant and the solvent, heating at 25~65°C to obtain a preliminary mixture, and mixing the preliminary mixture with the lyophilization protectant to obtain the mixture; Preferably, the heating temperature is 45°C; Preferably, the initial mixture is mixed with the lyophilization protectant using either method one or method two. The first method includes the following steps: mixing the initial mixture, the lyophilization protectant, and water for injection to obtain a dispersion, followed by stirring; The second method includes the following steps: the initial mixture is mixed and stirred with water for injection to obtain a dispersion, and then the dispersion is mixed with the lyophilization protectant; The stirring speed is preferably 100~1300 rpm, for example 100 rpm, 500 rpm, 900 rpm or 1300 rpm; the stirring time is preferably 1~10 min, for example 1 min, 2 min, 5 min or 10 min; preferably, the freeze-drying includes the following steps: holding at -50~-30℃ for 100~200 min, raising the temperature to -40~-20℃ and holding for 3000~5000 min, and then raising the temperature to 10~30℃ and holding for 120~360 min, for example, pre-freezing at -50℃ for 150 min, raising the temperature to -30℃ and holding for 4000 min, and then raising the temperature to 20℃ and holding for 240 min; Preferably, before freeze-drying, the mixture is further filtered and / or dispensed; the filtration is preferably performed using a 0.22 μm sterile filter membrane.

8. A lyophilized cabazitaxel powder prepared by the method for preparing lyophilized cabazitaxel powder as described in claim 6 or 7.

9. A reconstituter for lyophilized cabazitaxel powder, characterized in that, It is prepared by reconstituted cabazitaxel lyophilized powder according to any one of claims 1-2 and 8; Preferably, the carbamate lyophilized powder reconstituter satisfies one or more of the following conditions (a) to (e): (a) The solvent used for reconstitution is water for injection or glucose injection, preferably 5% glucose injection; (b) In the reconstituted solution of the lyophilized cabazitaxel powder, the concentration of the cabazitaxel or its pharmaceutically acceptable salt is 0.1 to 10 mg / mL, preferably 1 to 6 mg / mL, for example 5 mg / mL, based on cabazitaxel. mg / mL refers to the ratio of the mass of cabazitaxel to the volume of the reconstituted solution of the lyophilized cabazitaxel powder. (c) The average particle size of the reconstituted solvent for the lyophilized cabazitaxel powder is less than 300 nm, preferably 120~265 nm. nm, for example 125nm, 128nm, 129nm, 130nm, 131nm, 132nm, 133nm, 134nm, 135nm, 136nm, 137nm, 140nm, 150nm, 151nm, 152nm, 153nm, 154nm, 160nm, 161nm, 165nm, 166nm, 167nm, 171nm, 172nm, 173nm, 176nm, 177nm, 180nm, 181nm, 186nm, 187nm, 188nm, 195nm, 196nm, 214nm, 215nm, 216nm, 243nm, 244nm, 245nm, 246nm, 250nm, 251nm, 252nm, 253nm, 260nm or 261nm; (d) The PDI of the reconstituted solvent for the lyophilized cabazitaxel powder is less than 0.45, preferably 0.09 to 0.3, for example 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41 or 0.42; The encapsulation efficiency of the reconstituted lyophilized cabazitaxel powder, as described in (e), is 65.0% to 99.5%, preferably 95.0% to 99.5%, for example 95.0%, 96.0%, 97.0%, 98.0%, 99.0%, 95.1%, 99.2% or 99.3%.

10. The use of any one of the following in the preparation of a cancer treatment drug: the lyophilized carbazone powder as described in claim 1 or 2, the lyophilized carbazone powder precursor as described in claims 3 to 5, the lyophilized carbazone powder as described in claim 8, and the lyophilized carbazone powder reconstituter as described in claim 9; Ideally, the cancer is prostate cancer; Preferably, the dosage of the lyophilized cabazitaxel powder or the reconstituted lyophilized cabazitaxel powder is 5-14 mg / kg, for example, 6 mg / kg or 12 mg / kg, calculated based on a single dose of cabazitaxel.

Images