Use of mitoxantrone hydrochloride liposomes

Abstract

The present invention provides use of mitoxantrone hydrochloride liposomes in the manufacture of a medicament for treating ovarian cancer, gastric cancer or head and neck squamous cell carcinoma, a method for treating ovarian cancer, gastric cancer or head and neck squamous cell carcinoma using a mitoxantrone hydrochloride liposome formulation, and a mitoxantrone hydrochloride liposome formulation for treating ovarian cancer, gastric cancer or head and neck squamous cell carcinoma.

Description

[Technical field]

[0001] This application claims priority to Chinese Patent Application No. 202011477966.6.6, filed on December 15, 2020, the entire contents of which are incorporated herein by reference in their entirety and for all purposes.

[0002] The present invention relates generally to the medical field, and more particularly to the use of mitoxantrone hydrochloride liposomes in the treatment of ovarian cancer, gastric cancer or head and neck squamous cell carcinoma. [Background technology]

[0003] Ovarian cancer is one of the most common malignant tumors in women, and due to the lack of typical symptoms and signs, once detected, most are in the mid- to late-stage and have a very short survival time. There are many types of ovarian cancer, the most common of which is epithelial ovarian cancer, which accounts for 70% of ovarian cancer cases, followed by malignant germ cell tumors and sex cord stromal tumors.

[0004] The overall prognosis of ovarian epithelial cancer is relatively poor, due to the difficulty of early diagnosis and the lack of effective treatment for drug-resistant recurrent ovarian epithelial cancer. Surgery and chemotherapy are the main treatments for ovarian malignancies, and chemotherapy plays an important role in adjuvant and recurrent treatment. Platinum-based combination chemotherapy plans are the main recommended method of chemotherapy after surgery for advanced ovarian cancer. Even if advanced stage patients achieve complete response after receiving the above treatment, 70% to 80% of them will relapse. Currently, the standard chemotherapy plan for the initial treatment of advanced epithelial ovarian cancer is mainly a combination of platinum drugs and chemotherapy, and when selecting a specific plan (also called a regimen), it is necessary to comprehensively consider the characteristics of each patient. Other recommended plans include a combination of carboplatin and doxorubicin liposomal, an anthracycline drug. Doxorubicin liposomal is also recommended for use as a single agent or in combination with bevacizumab to treat recurrent resistant ovarian cancer. However, among the current single-agent treatments for platinum-resistant recurrent tumors, no drug is superior in terms of safety or efficacy to the others.

[0005] Gastric cancer is the fifth most common cancer worldwide. For patients who have no chance of a cure by surgery or for patients with metastatic gastric cancer, the adoption of comprehensive treatment mainly based on systemic drug therapy is currently permitted. Commonly used systemic chemotherapy drugs include 5-fluorouracil (5-FU), capecitabine, TS-1 (S-1: tegafur, gimeracil, oteracil potassium), cisplatin, oxaliplatin, paclitaxel, docetaxel, Abraxane (generic name: paclitaxel-albumin suspension), irinotecan, epirubicin, etc., and targeted therapeutic drugs include trastuzumab and apatinib. Treatment of advanced recurrent (end-stage recurrent) / metastatic gastric cancer is difficult, especially in the second-line and third-line treatments, where the therapeutic effects are poor, and the options are limited.

[0006] Head and neck tumors rank sixth worldwide in incidence, including primary tumors in the nasal cavity, paranasal sinuses and nasopharynx (nasopharynx), oropharynx (middle pharynx), larynopharynx (hypopharynx), cervical esophagus, thyroid, salivary glands, oral cavity, larynx, and ear. 90% of head and neck tumors are squamous cell carcinoma of the head and neck (SCCHN), with an annual incidence of more than 550,000 cases and more than 300,000 deaths worldwide. The majority of patients are incurable due to local recurrence and metastasis, with a 5-year survival rate of less than 50%, and surgery and radiochemotherapy cannot achieve satisfactory therapeutic effects.

[0007] In patients with recurrent head and neck tumors, only a small proportion may undergo definitive local treatment such as surgery or radiation therapy again, while the majority, like metastatic patients, must undergo palliative systemic therapy (PS 0-1) or best supportive care (PS ≥ 2). Cisplatin in combination with 5-FU (PF regimen) or paclitaxel-based regimens are the commonly used first-line chemotherapy regimen choices, and if a patient is not suitable to receive cisplatin, carboplatin can be substituted, and all of the above regimens can be combined with cetuximab.

[0008] There is currently no standard treatment plan for recurrent metastatic head and neck squamous cell carcinoma after failure of first-line platinum-based therapy, and commonly used drugs are methotrexate, paclitaxel or docetaxel, cetuximab, and immune checkpoint inhibitors. For patients who have failed first-line platinum-based therapy, the choice of immunotherapy or other plans can be made based on the results of PD-L1 testing in second-line / salvage therapy. Therefore, better treatment tools and strategies are urgently needed for difficult-to-treat cancers such as ovarian cancer, gastric cancer, or squamous cell carcinoma of the head and neck. Summary of the Invention

[0009] According to a first aspect, the present invention provides the use of mitoxantrone liposomes hydrochloride in the manufacture of a medicament for treating ovarian cancer, gastric cancer or head and neck squamous cell carcinoma. In some embodiments, mitoxantrone hydrochloride liposomes are the only active ingredient in the medicament.

[0010] In some embodiments, the medicament or mitoxantrone hydrochloride liposome has one or more of the following properties: (i) the particle size of the mitoxantrone hydrochloride liposome is about 30 to 80 nm, for example, about 35 to 75 nm, about 40 to 70 nm, about 40 to 60 nm, or about 60 nm; (ii) the property that mitoxantrone hydrochloride forms a poorly soluble precipitate with multivalent counter ions (e.g., sulfate ions, citrate ions, or phosphate ions) in liposomes; (iii) the phospholipid bilayer in the mitoxantrone hydrochloride liposomes comprises a phospholipid having a phase transition temperature (Tm) higher than body temperature, whereby the phase transition temperature of the liposome is higher than body temperature, the phospholipid being selected from, for example, hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, lecithin dipalmitate, lecithin distearate, or any combination thereof; and (iv) the phospholipid bilayer in the mitoxantrone hydrochloride liposomes has one or more properties selected from the group consisting of properties comprising hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine (DSPE-PEG2000).

[0011] In some embodiments, the phospholipid bilayer in the mitoxantrone hydrochloride liposomes comprises hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of about 3:1:1, the mitoxantrone hydrochloride and multivalent acid ions in the liposomes form a poorly soluble precipitate, and the particle size of the mitoxantrone hydrochloride liposomes in the pharmaceutical preparation is about 60 nm.

[0012] In some embodiments, the ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer. In some embodiments, the gastric cancer is advanced gastric cancer. In some embodiments, the head and neck squamous cell carcinoma is a squamous cell carcinoma occurring in the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, larynopharynx, cervical esophagus, thyroid, salivary glands, oral cavity, larynx, and / or ear. In some embodiments, the head and neck squamous cell carcinoma is recurrent or metastatic head and neck squamous cell carcinoma that has failed first-line treatment, for example, the first-line treatment is a combination of cisplatin / carboplatin with 5-FU or paclitaxel, optionally further combined with cetuximab. In some embodiments, the medicament is in an injectable form, such as a liquid injection, an injectable powder, or an injectable tablet. In some embodiments, the medicament is a liquid injectable. In some embodiments, the content of the active ingredient in the pharmaceutical is 0.5 to 5 mg / mL, for example 1 to 2 mg / mL, or 1 mg / mL based on mitoxantrone.

[0013] According to a second aspect, the present invention provides a method of treating ovarian cancer, gastric cancer or head and neck squamous cell carcinoma in an individual comprising administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of mitoxantrone liposome hydrochloride. In some embodiments, mitoxantrone hydrochloride liposomes are the only active ingredient in the pharmaceutical composition. In some embodiments, the pharmaceutical composition or mitoxantrone hydrochloride liposomes have one or more of the following properties: (i) the particle size of the mitoxantrone hydrochloride liposome is about 30 to 80 nm, for example, about 35 to 75 nm, about 40 to 70 nm, about 40 to 60 nm, or about 60 nm; (ii) the formation of poorly soluble precipitates between mitoxantrone hydrochloride and polyvalent counterions (e.g., sulfate, citrate or phosphate) in liposomes; (iii) the phospholipid bilayer in the mitoxantrone hydrochloride liposomes comprises a phospholipid having a phase transition temperature (Tm) greater than body temperature, whereby the phase transition temperature of the liposome is greater than body temperature, and the phospholipid is selected from, for example, hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, lecithin dipalmitate, lecithin distearate, or any combination thereof; (iv) the phospholipid bilayer in the mitoxantrone hydrochloride liposomes has one or more properties selected from the group consisting of properties comprising hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine (DSPE-PEG2000).

[0014] In some embodiments, the phospholipid bilayer in the mitoxantrone hydrochloride liposomes contains hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of about 3:1:1, mitoxantrone hydrochloride and polyvalent acid ions in the liposomes form a poorly soluble precipitate, and the particle size of the mitoxantrone hydrochloride liposomes in the pharmaceutical preparation is about 60 nm. In some embodiments, the ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer. In some embodiments, the gastric cancer is advanced gastric cancer. In some embodiments, the head and neck squamous cell carcinoma is a squamous cell carcinoma occurring in the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, larynopharynx, cervical esophagus, thyroid, salivary glands, oral cavity, larynx, and / or ear. In some embodiments, the head and neck squamous cell carcinoma is recurrent or metastatic head and neck squamous cell carcinoma that has failed first-line treatment, e.g., a combination of cisplatin / carboplatin with 5-FU or paclitaxel drugs, optionally further combined with cetuximab. In some embodiments, the pharmaceutical composition is in an injectable form, such as a liquid injectable, an injectable powder (powder injectable) or an injectable tablet.

[0015] In some embodiments, the pharmaceutical composition is a liquid injectable. In some embodiments, the content of the active ingredient in the pharmaceutical composition is 0.5 to 5 mg / mL, for example 1 to 2 mg / mL, or 1 mg / mL, based on mitoxantrone. In some embodiments, the pharmaceutical composition is administered intravenously, for example, in a single intravenous administration, the infusion time of the pharmaceutical composition is 30 minutes to 120 minutes, for example 60 minutes to 120 minutes, or 60±15 minutes. In some embodiments, the dosing cycle is once every 4 weeks or 3 weeks, for example, once every 3 weeks. In some embodiments, the therapeutically effective amount is 8 to 30 mg / m based on mitoxantrone. 2 , for example 12 to 20 mg / m 2 or 20 mg / m 2 It is.

[0016] According to a third aspect, the present invention provides the use of a pharmaceutical composition comprising mitoxantrone liposomes hydrochloride in the treatment of ovarian cancer, gastric cancer or head and neck squamous cell carcinoma. In some embodiments, mitoxantrone hydrochloride liposomes are the only active ingredient in the pharmaceutical composition. In some embodiments, the pharmaceutical composition or mitoxantrone hydrochloride liposomes have one or more of the following properties: (i) the particle size of the mitoxantrone hydrochloride liposome is about 30 to 80 nm, for example, about 35 to 75 nm, about 40 to 70 nm, about 40 to 60 nm, or about 60 nm; (ii) the formation of poorly soluble precipitates between mitoxantrone hydrochloride and polyvalent counterions (e.g., sulfate, citrate or phosphate) in liposomes; (iii) the phospholipid bilayer in the mitoxantrone hydrochloride liposomes comprises a phospholipid having a phase transition temperature (Tm) greater than body temperature, whereby the phase transition temperature of the liposome is greater than body temperature, and the phospholipid is selected from, for example, hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, lecithin dipalmitate, lecithin distearate, or any combination thereof; (iv) the phospholipid bilayer in the mitoxantrone hydrochloride liposomes has one or more properties selected from the group consisting of properties comprising hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine (DSPE-PEG2000).

[0017] In some embodiments, the phospholipid bilayer in the mitoxantrone hydrochloride liposomes contains hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of about 3:1:1, mitoxantrone hydrochloride and polyvalent acid ions in the liposomes form a poorly soluble precipitate, and the particle size of the mitoxantrone hydrochloride liposomes in the pharmaceutical preparation is about 60 nm. In some embodiments, the ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer. In some embodiments, the gastric cancer is advanced gastric cancer. In some embodiments, the head and neck squamous cell carcinoma is a squamous cell carcinoma occurring in the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, larynopharynx, cervical esophagus, thyroid, salivary glands, oral cavity, larynx, and / or ear.

[0018] In some embodiments, the head and neck squamous cell carcinoma is recurrent or metastatic head and neck squamous cell carcinoma that has failed first-line treatment, e.g., a combination of cisplatin / carboplatin with 5-FU or paclitaxel drugs, optionally further combined with cetuximab. In some embodiments, the pharmaceutical composition is in an injectable form, such as a liquid injectable, an injectable powder, or an injectable tablet. In some embodiments, the pharmaceutical composition is a liquid injectable. In some embodiments, the content of the active ingredient in the pharmaceutical composition is 0.5 to 5 mg / mL, for example 1 to 2 mg / mL, or 1 mg / mL, based on mitoxantrone. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Mitoxantrone hydrochloride is an anthraquinone antitumor drug. Its FDA approved indications are multiple sclerosis, prostate cancer, and acute myeloid leukemia. Clinical studies have shown that it has a certain therapeutic effect on malignant lymphoma, breast cancer, acute myeloid leukemia, lung cancer, melanoma, soft tissue sarcoma, multiple myeloma, liver cancer, colon cancer, kidney cancer, prostate cancer, endometrial cancer, testicular tumor, ovarian cancer, and head and neck cancer. For example, due to the existence of serious side effects such as bone marrow suppression, leukopenia and thrombocytopenia (which are dose-limiting toxicities), palpitations, premature contractions, and electrocardiogram abnormalities, the clinical dosage of mitoxantrone hydrochloride is limited and it must always be used in combination. However, previous studies have shown that the efficacy of these drug combination treatment plans (combination regimens) is not high. How to further improve the antitumor therapeutic effect without incurring serious toxicity and side effects is a difficult problem facing the clinical application of mitoxantrone hydrochloride.

[0020] Liposomes are a new drug-carrying form. In pharmacology, liposomal drugs generally refer to microvesicles formed by encapsulating drugs in lipidoid bilayers. Research has shown that liposomal drugs can change the distribution of encapsulated drugs in vivo, leading to the accumulation of drugs mainly in tissues and organs such as the liver, spleen, lungs and bone marrow, thus improving the therapeutic index of drugs, reducing the therapeutic dose of drugs and reducing the toxicity of drugs. Due to these characteristics, the application of liposomal drugs in antitumor drug research is of great importance. The researchers who are the applicants of the present invention are conducting research into mitoxantrone liposomal formulations. For example, Chinese Patent Application No. 200610102339.8, filed on December 29, 2006, and PCT Application WO2008 / 080367A1, filed on December 29, 2007, disclose mitoxantrone liposomes, and the entire contents disclosed in the above patent applications are incorporated herein in their entirety for all purposes.

[0021] Mitoxantrone liposomal preparation is a special preparation different from ordinary mitoxantrone injection, and the absorption, distribution and metabolism of the two after entering the body are obviously different, so it is difficult to derive the treatment of different indications, especially the treatment of different tumors, based on the indications of the compound itself, or between different tumor types. Therefore, the therapeutic effect and indications of mitoxantrone liposomal preparation should be independently studied. For this purpose, the inventor of the present invention has deeply studied the efficacy of mitoxantrone liposomal preparation in intractable ovarian cancer, gastric cancer or head and neck squamous cell carcinoma, and has completed each invention of the present invention.

[0022] In the following detailed description, unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Notwithstanding the numerical ranges and parameter approximations set forth in the broad scope of the invention, the numerical values ​​set forth in the specific embodiments are described as precisely as possible. However, any numerical value inherently contains a certain degree of error due to the standard deviation present in each measurement. Also, all ranges disclosed herein should be understood to cover all subranges contained within the range. For example, a recited range of "1-10" should be considered to include any and all subranges between a minimum value of 1 and a maximum value of 10 (including the endpoints), i.e., all subranges beginning with a minimum value of 1 or more, e.g., 1-6.1, and subranges ending with a maximum value of 10 or less, e.g., 5.5-10. In this specification, when "about" is used in a numerical value or numerical range, it represents the degree of numerical variation that is acceptable in the art, and typically represents within ±10% of the numerical value or numerical range, such as ±9%, or ±8%, or ±7%, or ±6%, or ±5%, or ±4%, or ±3%, or ±2%, or ±1%.

[0023] The term "pharmaceutical composition" as used herein means a combination of at least one drug and any pharmaceutical acceptable carrier or auxiliary material that are combined together to achieve a certain pharmaceutical purpose. In the technical background of the liposome formulation of the present invention, the pharmaceutical acceptable carrier is usually an aqueous carrier such as water, buffered aqueous solution, isotonic salt solution (e.g., physiological saline, phosphate buffer solution (PBS)), sugar solution, etc. In the technical background of the present invention, an injection is a suitable dosage form (and there are also types of pharmaceutical acceptable carriers that are compatible with it), but those skilled in the art can understand that other types of pharmaceutical acceptable carriers may be selected when other dosage forms may be selected (e.g., oral).

[0024] As used herein, "therapeutically effective amount" or "effective amount" refers to a dose sufficient to show its benefit to the subject (individual). The amount actually administered, the rate of administration and the time course will vary depending on the condition and severity of the subject being treated. The prescription for treatment (e.g., the determination of dosage, etc.) is ultimately the responsibility of and will be determined by specialists and other physicians, and will generally take into account the disease being treated, the condition of the individual patient, the delivery site, the method of administration, and other factors known to physicians.

[0025] As used herein, an "individual," "subject," or "patient" includes all members of the animal kingdom, including, but not limited to, mammals (e.g., mice, rats, cats, monkeys, dogs, horses, pigs, etc.) and humans. Preferably, the individual is a human individual. Unless otherwise indicated, the terms "patient," "subject," or "individual" can be used interchangeably.

[0026] 1. Mitoxantrone hydrochloride liposomes and preparations Mitoxantrone HCl is an anthraquinone antitumor drug whose structure is: [ka]

[0027] Broadly speaking, liposomes are artificial membranes. The hydrophilic heads of phospholipid molecules are inserted into water, and the hydrophobic tails of the liposomes are extended toward the air, followed by stirring to form spherical liposomes of bilayer lipid molecules. In the biopharmaceutical field, liposomes are often used in transgenic technology and drug preparation, and the liposomes' ability to fuse with cell membranes is utilized to deliver drugs into cells. In pharmacology, liposomal drugs generally refer to microvesicles formed by encapsulating drugs within lipidoid bilayers. The chemical composition of liposomes often includes phospholipids (including natural and synthetic phospholipids) and cholesterol.

[0028] There are many reports on the preparation techniques of liposomal pharmaceutical preparations in the art, and those skilled in the art can prepare mitoxantrone hydrochloride liposomal preparations by referring to the relevant technical guidance. In some embodiments, mitoxantrone liposomes are the only active ingredient in the medicament. In the technical background of the present invention, the inventors of the present invention found that the mitoxantrone hydrochloride liposome formulation prepared by the method disclosed in Chinese Patent Application No. 200610102339.8 or PCT Application WO2008 / 080367A1 has good efficacy.

[0029] Without being bound to any particular theory, the present inventors have discovered that one or more or all of the following characteristics are advantageous in mitoxantrone hydrochloride liposomal formulations. I. In the liposomal preparation / medicine, the particle size of the mitoxantrone hydrochloride liposomes is about 30-80 nm, for example, about 30, 25, 40, 45, 50, 55, 60, 65, 70, 75, or 80 nm. More preferred ranges are about 35-75 nm, about 40-70 nm, and about 40-60 nm. In one example (see Examples below), the particle size of the mitoxantrone hydrochloride liposomes is about 60 nm. Methods for measuring particle size include, but are not limited to, NanoZS.

[0030] II. Mitoxantrone hydrochloride forms a poorly soluble precipitate with polyvalent counterions (eg, sulfate, citrate, or phosphate) within liposomes.

[0031] III. The phospholipid bilayer in mitoxantrone hydrochloride liposomes contains phospholipids with a phase transition temperature (Tm) higher than body temperature (e.g., 36-38°C), so that the phase transition temperature of the liposomes is higher than body temperature. Phospholipid molecules are essential components of liposomes, and liposomes formed by different types of phospholipid molecules have solid-gel-liquid phase transition properties at different temperatures, and the composition of phospholipids largely determines the phase transition temperature of the liposomes. The types of phospholipids suitable for achieving the desired phase transition temperature of the present invention include, but are not limited to, hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dipalmitic acid lecithin, distearic acid lecithin, or combinations thereof. Furthermore, a person skilled in the art can select other suitable types and blending ratios of phospholipids based on phase transition temperature tests. In some embodiments, in addition to cholesterol, the phospholipid molecules included in the phospholipid bilayer in the mitoxantrone hydrochloride liposomes of the present invention are hydrogenated soybean lecithin and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine (DSPE-PEG2000).

[0032] In some specific embodiments, the phospholipid bilayer in the mitoxantrone hydrochloride liposomes comprises hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of about 3:1:1, mitoxantrone hydrochloride and polyvalent acid ions in the liposomes form a poorly soluble precipitate, and the particle size of the mitoxantrone hydrochloride liposomes in the pharmaceutical preparation is about 60 nm.

[0033] In the liposomal pharmaceutical formulation, the "lipid / drug ratio" refers to the mass ratio of the components of the phospholipid bilayer in the liposome (including phospholipids and cholesterol) to the drug (mitoxantrone in the present invention). For example, in the exemplary liposomal pharmaceutical formulation of the present invention, it refers to the mass ratio of the components of the phospholipid bilayer in the liposome (including HSPC, DSPE-PEG2000, and Chol) to mitoxantrone.

[0034] As a non-limiting example, the mitoxantrone hydrochloride liposomal formulation of the present invention can be prepared in the following manner. Hydrogenated soybean lecithin (HSPC), cholesterol (Chol) and polyethylene glycol 2000 modified distearylphosphatidylethanolamine (DSPE-PEG2000) were weighed in a mass ratio of 3:1:1 and dissolved in 95% ethanol to obtain a clear solution (ethanol solution of phospholipids). The ethanol solution of phospholipids was mixed with 300 mM ammonium sulfate solution and hydrated by shaking for 1 h at 60-65°C to obtain heterogeneous multi-layered liposomes. The particle size of the liposomes was then reduced using a microjet device. The obtained sample was diluted 200 times with a 0.9% NaCl solution and detected with NanoZS. The average particle size of the particles was about 60 nm, with the main peak concentrated at 40-60 nm. Then, the external phase of the blank liposome, ammonium sulfate, is removed using an ultrafiltration device, and the external phase is replaced with 290 mM sucrose and 10 mM glycine to form a transmembrane ammonium sulfate gradient. A mitoxantrone hydrochloride solution (10 mg / mL based on mitoxantrone) was added to the blank liposome at a lipid / drug ratio of 16:1, and after incubation at 60-65°C for about 1h, gel exclusion chromatography was performed, proving that the encapsulation efficiency was about 100%. The product thus obtained was named PLM60 and will be used in the examples described below. The weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone in PLM60 is 9.58:3.19:3.19:1, and the osmotic pressure of the sucrose-glycine solution is close to the physiological value.

[0035] In addition, a number of technical details and parameters in the above exemplary preparation method can be adjusted and determined within a reasonable range by a person skilled in the art. For example, the types of amino acids that can be substituted for glycine in the external phase forming the transmembrane ammonium sulfate gradient include, but are not limited to, histidine, asparagine, glutamic acid, leucine, proline, and alanine. In addition, for example, the mass ratio of HSPC, Chol, and DSPE-PEG2000 can be appropriately adjusted. Also, for example, regarding the parameters of lipid / drug ratio in the preparation of a particular liposomal pharmaceutical formulation, those skilled in the art can design, test and finally obtain a suitable lipid / drug ratio to maximize drug loading and reduce drug leakage, and for the mitoxantrone hydrochloride liposomal formulation of the present invention, the lipid / drug ratio that can be used is in a wide range, for example, 2:1 or less, 30:1, 40:1 or 50:1 or more, and a more suitable lipid / drug ratio may be about (15-20):1, for example, about 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1. Therefore, some advantageous properties of the mitoxantrone hydrochloride liposomal formulation described above are more important, and the methodologies to realize these properties are diverse.

[0036] 2. Indications In the present invention, the suitability of mitoxantrone hydrochloride liposomal formulation includes ovarian cancer, gastric cancer, and head and neck squamous cell carcinoma. In the present invention, the first-line, second-line, or higher-line medicines used for the treatment of ovarian cancer, gastric cancer, and head and neck squamous cell carcinoma refer to the first-line, second-line, or higher-line medicines approved for the treatment of ovarian cancer, gastric cancer, and head and neck squamous cell carcinoma by the medical management departments of China and other countries and regions (e.g., the United States, the European Union, Japan, South Korea, etc.), including, but not limited to, FDA-approved bevacizumab, PD-1 inhibitors, trastuzumab, apatinib, etc.

[0037] 2.1 Ovarian cancer In some embodiments, the indication for the mitoxantrone hydrochloride liposomal formulation is ovarian cancer, hi some embodiments, mitoxantrone hydrochloride liposomal is used as the only active ingredient in the medicament / pharmaceutical composition of the present invention for treating ovarian cancer. In some embodiments, the ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer. Platinum-refractory or platinum-resistant recurrent ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer that has failed treatment with at least a standard platinum-based regimen.

[0038] The preferred pharmaceutical dosage forms are injection forms, including liquid injections, powders for injections, and tablets for injections. When the pharmaceutical is a liquid injection, the content of the active ingredient of the pharmaceutical is 0.5-5 mg / mL, more preferably 1-2 mg / mL or 1 mg / mL, based on mitoxantrone. During treatment, the therapeutically effective dose is usually 8-30 mg / m2 based on the surface area of ​​the individual and based on mitoxantrone. 2 and a more appropriate range is 12-20 mg / m 2 , e.g., 12 mg / m 2 , 14 mg / m 2 , 16 mg / m 2 , 18 mg / m 2 , 20 mg / m 2 Includes.

[0039] The suitable administration method of the mitoxantrone hydrochloride liposomal formulation of the present invention is intravenous administration. In some embodiments, the administration cycle is once every 4 weeks or 3 weeks. In some specific embodiments, the infusion administration time of the liposomal pharmaceutical formulation per intravenous administration is 30 minutes to 120 minutes, and more suitable ranges include 60 minutes to 120 minutes and 90±15 minutes.

[0040] 2.2 Stomach cancer In some embodiments, the indication for the mitoxantrone hydrochloride liposomal formulation is gastric cancer, hi some embodiments, mitoxantrone hydrochloride liposomal is used as the only active ingredient in the medicament / pharmaceutical composition of the present invention for treating gastric cancer. In some embodiments, the gastric cancer is advanced gastric cancer, which refers to histopathologically confirmed advanced gastric cancer that has metastasized, including gastroesophageal junction cancer. The preferred pharmaceutical dosage forms are injection dosage forms, including liquid injections, powders for injections, and tablets for injections. When the pharmaceutical is a liquid injection, the content of the active ingredient of the pharmaceutical is 0.5-5 mg / mL, more preferably 1-2 mg / mL or 1 mg / mL, based on mitoxantrone.

[0041] During treatment, the therapeutically effective dose is usually 8-30 mg / m2 based on the surface area of ​​the individual and based on mitoxantrone. 2 and a more appropriate range is 12-20 mg / m 2 , e.g., 12 mg / m 2 , 14 mg / m 2 , 16 mg / m 2 , 18 mg / m 2 , 20 mg / m 2 Includes. The suitable administration method of the mitoxantrone hydrochloride liposomal formulation of the present invention is intravenous administration. In some embodiments, the administration cycle is once every 4 weeks or 3 weeks. In some specific embodiments, the infusion administration time of the liposomal pharmaceutical formulation per intravenous administration is 30 minutes to 120 minutes, and more suitable ranges include 60 minutes to 120 minutes and 90±15 minutes.

[0042] 2.3. Head and neck squamous cell carcinoma In some embodiments, the indication for the mitoxantrone hydrochloride liposomal formulation is head and neck squamous cell carcinoma. In some embodiments, mitoxantrone hydrochloride liposomal is used as the only active ingredient in the medicament / pharmaceutical composition of the present invention for treating head and neck squamous cell carcinoma. Head and neck squamous cell carcinoma includes squamous cell carcinoma occurring in the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, larynopharynx, cervical esophagus, thyroid, salivary glands, oral cavity, larynx and / or ear, with nasopharyngeal carcinoma (nasopharyngeal carcinoma) being a type of cancer described herein.

[0043] In some embodiments, the head and neck squamous cell carcinoma is recurrent / metastatic head and neck squamous cell carcinoma. In some embodiments, the head and neck squamous cell carcinoma is recurrent / metastatic head and neck squamous cell carcinoma that has failed at least first-line treatment. In some embodiments, cisplatin in combination with 5-fluorouracil (5-FU) (PF regimen) or cisplatin in combination with paclitaxels are common choices for first-line chemotherapy regimens. If a patient is not suitable for administration of cisplatin, carboplatin can be substituted. All of the above first-line treatment regimens can be combined with cetuximab. The preferred pharmaceutical dosage forms are injection forms, including liquid injections, powders for injections, and tablets for injections. When the pharmaceutical is a liquid injection, the content of the active ingredient of the pharmaceutical is 0.5-5 mg / mL based on mitoxantrone, and more preferred ranges include 1-2 mg / mL or 1 mg / mL.

[0044] During treatment, the therapeutically effective dose is usually 8-30 mg / m2 based on the surface area of ​​the individual and based on mitoxantrone. 2 and a more appropriate range is 12-20 mg / m 2 , e.g., 12 mg / m 2 , 14 mg / m 2 , 16 mg / m 2 , 18 mg / m 2 , 20 mg / m 2 Includes. The suitable administration method of the mitoxantrone hydrochloride liposomal formulation of the present invention is intravenous administration. In some embodiments, the administration cycle is once every 4 weeks or 3 weeks. In some specific embodiments, the infusion administration time of the liposomal pharmaceutical formulation per intravenous administration is 30 minutes to 120 minutes, and more suitable ranges include 60 minutes to 120 minutes and 90±15 minutes.

[0045] 3. Dosage regimen As mentioned above, liposomal pharmaceutical preparations are a special type of medicine, and compared with free drugs, the absorption, distribution and metabolism of liposomal drugs after they enter the body are changed. Therefore, the dosage regimen obtained based on the design and testing of free drugs is not necessarily compatible with the liposomal preparation of the same medicine. Similarly, the dosage regimen obtained from the design and testing of liposomal pharmaceutical preparations in a certain type of cancer is not necessarily compatible with the application of liposomal pharmaceutical preparations in other types of cancer.

[0046] Existing studies have shown that there may be relatively large differences in the safe and effective doses of the same drug when treating different indications. Doxil (doxorubicin hydrochloride liposomal) is approved by the FDA for three indications: (1) ovarian cancer, with a recommended dose of 50 mg / m 2 (2) For Kaposi's sarcoma, the recommended dose is 20 mg / m 2 (3) For multiple myeloma, the recommended dose is 30 mg / m 2 and will be administered intravenously on the fourth day after bortezomib.

[0047] Abraxane (paclitaxel for injection [albumin-bound]) also has different dosing schedules for the three FDA-approved indications: (1) Metastatic breast cancer: The recommended dose is 260 mg / m 2 and is administered by 30-minute intravenous infusion once every 3 weeks. (2) Non-small cell lung cancer: The recommended dose is 100 mg / m 2 The recommended dose is 125 mg / m2, administered intravenously for 30 minutes, with one cycle every 21 days, on days 1, 8, and 15. On day 1, paclitaxel (albumin-bound) is administered immediately followed by carboplatin, and then administered every 21 days. (3) Pancreatic cancer: The recommended dose is 125 mg / m2 2 The intravenous infusion is given over 30 to 40 minutes, with one cycle being every 28 days, and the drug is administered once on days 1, 8, and 15. Gemcitabine is administered immediately after administration of injectable paclitaxel (albumin-bound).

[0048] The starting dose of AmBisome (amphotericin B liposome for injection) is as follows when treating the following indications: (1) Empirical treatment: The recommended dose is 3 mg / kg / day. (2) Systemic fungal infections (Aspergillus, Candida, Cryptococcus): The recommended dose is 3-5 mg / kg / day. (3) Cryptococcal meningitis in HIV-infected patients: The recommended dose is 6 mg / kg / day (days 1-5), 3 mg / kg / day (days 4, 21). Visceral leishmaniasis patients with weakened immune systems: 4 mg / kg / day (days 1-5), 4 mg / kg / day (days 10, 17, 24, 31, 38). This shows that there are differences in the safe and effective doses of the same drug for the treatment of different indications. The dosage and administration data are individually determined based on the specific disease type and the actual condition of the patient, so as to achieve the maximum efficacy and the minimum toxicity or side effects, and to obtain the effect of treating the disease safely and effectively. Therefore, in the case of the mitoxantrone hydrochloride liposomal formulation of the present invention, there may be different optimal administration methods for different types of cancer. EXAMPLES

[0049] The present invention will be further described below with reference to specific examples. Note that these examples are only used to explain the present invention, and are not used to limit the scope of the present invention. Experimental methods without specific conditions described in the following examples are usually performed according to general conditions or conditions suggested by manufacturers.

[0050] Example 1 The present inventors have tested the effects of a mitoxantrone hydrochloride liposomal formulation (PLM60) in animal model experiments of ovarian cancer, gastric cancer, and head and neck squamous cell carcinoma (not shown in the present specification), and have demonstrated that PLM60 is effective in treating ovarian cancer, gastric cancer, and head and neck squamous cell carcinoma.

[0051] Example 2 Clinical Study of Mitoxantrone Hydrochloride Liposome Injection for the Treatment of Platinum-Refractory or Platinum-Resistant Recurrent Ovarian Cancer This example is a single-arm, open-label, multicenter Phase Ib study to evaluate the safety and efficacy of mitoxantrone liposomal hydrochloride injection in subjects with platinum-refractory or platinum-resistant recurrent ovarian cancer. Enrolled subjects will receive treatment with mitoxantrone liposomal hydrochloride injection (PLM60). In this and subsequent examples, the terms are abbreviated as complete response (CR), partial response (PR), disease stabilization (SD), objective response rate (ORR), and disease control rate (DCR).

[0052] First, test design 1. Test procedure All subjects in the study group received monotherapy with mitoxantrone liposomal hydrochloride injection at a dose of 20 mg / m 2 The drug was administered once every three weeks (q3w). More than 30 subjects were planned to be enrolled in the study. Screening-related tests were completed 28 days before administration, baseline evaluations were performed, and inclusion / exclusion criteria were determined before the subjects were enrolled in the study. All subjects enrolled in the study were treated for eight cycles, and treatment could be discontinued if the following circumstances occurred: progressive disease (PD), intolerable toxic reactions, death, or the investigator determined that the subject would not continue to benefit. For subjects who have already completed eight treatment cycles, if the subject is still benefiting from the treatment and can be tolerated, the investigator and the investigator will jointly discuss whether the subject can continue the treatment, and the initial therapeutic effect and safety can be observed and evaluated. The study flow for each subject was assigned as follows: screening period, treatment period, and follow-up period.

[0053] After the subjects signed the informed consent and completed all baseline examinations during the screening period, those who met the selection criteria were treated with mitoxantrone hydrochloride injection according to the order of entry into the study group. All subjects completed the relevant examinations specified in the treatment plan during the entire study period according to the treatment plan, and were observed for safety.

[0054] 2. Research Period In this study, the screening period was 4 weeks (28 days), the treatment period was 8 cycles (24 weeks), the final safety follow-up was 4 weeks (28 days) after the end of treatment, PFS follow-up was every 6 weeks thereafter, and survival follow-up was every 6 weeks after progression, and each patient's duration is expected to be approximately 12 months. The study will enroll more than 30 subjects in the study group, and the total duration of the study is expected to be 24 to 36 months.

[0055] Subject 2: Only subjects who meet all of the following inclusion criteria and do not meet any of the exclusion criteria will be selected for this clinical study. (1) Selection criteria: Subjects must meet all of the following criteria: 1) Subjects willingly participate in the study and sign informed consent; 2) Female subjects aged 18 years or older, 3) Histopathologically confirmed epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (excluding low-grade serous and mucinous cancers), 4) Patients with platinum-refractory or platinum-resistant relapses who have failed at least one standard platinum-containing regimen; 5) At least one measurable lesion meeting the definition of RECIST 1.1 at baseline; 6) ECOG score 0-2; 7) Survival period is 3 months or longer. 8) Toxicity from previous antitumor treatment has resolved to level 1 or less (excluding alopecia, pigmentation, or other toxicity that has not been determined to pose a safety risk to subjects in the study). 9) Subjects' laboratory values ​​must meet the following requirements: Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L (did not receive leukocytosis treatment with G-CSF within 1 week prior to the laboratory test), Hemoglobin (Hb) ≥ 9.0 g / dL (no red blood cell infusion therapy within 1 week prior to laboratory test); Platelets ≥ 75 × 10 9 / L (without having received platelet transfusions, thrombopoietin, interleukin-11, or other medical therapy for increasing platelets within 1 week prior to the laboratory test), Creatinine ≤ 1.5 × ULN, Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for patients with liver metastases), Alanine aminotransferase (AST) / aspartate aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastases), Albumin ≥ 3.0 g / dL, Coagulation function: Prothrombin time (PT), international normalized ratio (INR) ≦1.5×ULN, 10) Female subjects have negative HCG in urine or blood (except for menopause or hysterectomy) and female subjects of childbearing age and their spouses are using effective contraceptive measures (e.g., combined hormone (containing estrogen and progesterone) with ovulation suppression, combined progesterone contraception with ovulation suppression, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomy, abstinence from sexual activity, etc.) during the study and for 6 months after the end of the last dose. 11) Subjects must be able to communicate well with the researchers, understand the requirements of this study, and be able to comply with them voluntarily.

[0056] (2) Exclusion criteria: Subjects who meet any of the following criteria will be excluded from this study: 1) Severe allergy to mitoxantrone or liposomes. 2) brain or meningeal metastases, 3) Clinically symptomatic pericardial effusion, 4) History of allogeneic organ transplantation or allogeneic bone marrow transplantation 5) Patients with active hepatitis B (HbsAg or HBcAb positive, HBV DNA ≥ 2000 IU / mL), active hepatitis C (HCV antibody positive, HCV RNA above the lower limit of detection at the research center), or HIV antibody positive. 6) Having an active bacterial, fungal, or viral infection requiring systematic treatment, or interstitial pneumonia within 1 week prior to the first dose. 7) Receiving antitumor treatment within 4 weeks prior to the first dose. 8) Having received treatment with other investigational drugs within 4 weeks prior to the first dose. 9) Have undergone major surgery (surgical grade: level 3-4 surgery, excluding intravenous port graft surgery) within 3 months prior to the first administration, or are scheduled to undergo major surgery during the study period. 10) Within the past 6 months, cerebrovascular disease (including transient ischemic attack), pulmonary embolism, or other thrombosis or embolism has occurred. 11) Previous active malignant tumor within the past 3 years (excluding locally treatable cancers that have already been cured), such as basal or squamous cell carcinoma, superficial bladder cancer, or in situ prostate, cervical, or breast cancer; 12) Cardiac dysfunction, including: Long QTc syndrome or QTc interval greater than 480 ms, Complete left bundle branch block, second-degree or third-degree atrioventricular block, severe uncontrolled arrhythmias requiring medical treatment; NYHA≧3 grade, Cardiac ejection fraction less than 50% or below the lower limit of the laboratory range at the study center; CTCAE>2 grade valvular heart disease; uncontrolled hypertension (defined as multiple measurements of systolic blood pressure above 150 mmHg or diastolic blood pressure above 90 mmHg under medical control); History of myocardial infarction, unstable angina, significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormality within 6 months prior to screening.

[0057] 13) Patients have received doxorubicin or other anthracyclines with a cumulative doxorubicin dose of 350 mg / m 2(Equivalent amount calculation for anthracyclines: 1mg doxorubicin = 2mg epinorubicin = 2mg daunomycin = 0.5mg demethoxydaunomycin = 0.45mg mitoxantrone) 14) Pregnant or breastfeeding women, 15) Having a severe and / or uncontrolled medical condition that, in the opinion of the investigator, may affect the patient's participation in the study (including, but not limited to, ineffectively controlled diabetes, kidney disease requiring dialysis, severe liver disease, life-threatening autoimmune or bleeding disorders, medication abuse, or neurological disease). 16) Other researchers have determined the participant to be ineligible to participate.

[0058] (3) Exit / termination criteria Subjects must discontinue treatment with the study drug if any of the following conditions occur during the study: 1) the subject experienced intolerable toxicity and the investigator believed that continued treatment with the study drug offered greater risks than benefits; 2) radiologically assessed disease progression; 3) Clinically assessed disease progression, significant protocol noncompliance, or poor subject compliance such that the investigator judged the subject would not benefit from continued treatment with the study drug; 4) pregnancy of the subject; 5) death; 6) Meeting any of the study withdrawal criteria. All subjects who discontinue treatment are required to have ongoing follow-up according to the study protocol, except for subjects who discontinue treatment due to death or who meet any of the study discontinuation criteria listed below.

[0059] Subjects have the right to withdraw from the study at any time and for any reason. A subject will exit the study if any of the following situations occur: 1) Lost visits, 2) The subject withdrew informed consent or the subject or a family member requested withdrawal from the study; 3) End of study; 4)Others.

[0060] 3. Research results The treatment effects of the subjects were evaluated according to RECIST 1.1 criteria, and all adverse events occurring in the subjects were evaluated according to CTCAE 5.0 criteria. The inventors of the present invention use mitoxantrone liposomes, which, after the medicine enters the human body through intravenous administration, has the effects of sustained release, targeting, attenuation and increased efficacy. Not only is the dosage higher than that of ordinary injections, but it is also a single-drug treatment, which can increase efficacy while reducing the probability of side effects.

[0061] As of October 31, 2021 (the study is ongoing), a total of 47 subjects have been enrolled, including 13 platinum-refractory and 34 platinum-resistant patients. Thirty-nine subjects underwent at least one treatment response evaluation, with an overall ORR of 17.9% (7 / 39) and DCR of 59.0% (23 / 39). Among subjects with platinum resistance and the number of previous therapies at or above third-line (third-line) therapy, a total of 24 subjects underwent at least one treatment response evaluation, with an ORR of 29.2% (7 / 24) and DCR of 62.5% (15 / 24). None of the subjects experienced intolerable side effects.

[0062] Based on the current experimental results, the mitoxantrone hydrochloride liposomal formulation of the present invention can improve the treatment regimen of ovarian cancer and lay the foundation for subsequent first- and second-line treatment with combined drug administration.

[0063] Example 3 Clinical study on the treatment of advanced gastric cancer with mitoxantrone hydrochloride liposome injection This example is a single-arm, open-label, multicenter Phase Ib study to evaluate the safety and efficacy of mitoxantrone liposomal hydrochloride injection in subjects with advanced gastric cancer, with enrolled subjects receiving treatment with mitoxantrone liposomal hydrochloride injection (PLM60).

[0064] First, test design 1. Test procedure All subjects in the study group received monotherapy with mitoxantrone liposomal hydrochloride injection at a dose of 20 mg / m 2 The dose was administered once every 3 weeks (q3w). In this study, 30-60 subjects (both male and female) with advanced gastric cancer were planned to be enrolled in the test group. Screening-related tests were completed 28 days before administration, baseline evaluations were performed, and inclusion / exclusion criteria were determined before subjects were enrolled in the test group. All subjects enrolled in the test group were treated for up to 8 cycles, and treatment could be discontinued if the following circumstances occurred: disease progression (PD), intolerable toxic reactions, death, or failure to continue to derive benefit as determined by the investigator. Delayed administration after the second cycle was permitted, but the delay should not exceed 3 weeks. Dose adjustments could be made after the second cycle, with a minimum of 12 mg / m 2 The baseline tumor burden can be reduced to as low as 100%. After administration, safety and therapeutic efficacy evaluations were performed according to the treatment plan. Follow-up was performed for 28 days after the last dose. Subjects who were withdrawn from the study early must complete follow-up after the last dose as soon as possible. Subjects who completed treatment entered the follow-up period. Except for subjects who discontinued treatment due to radiologically assessed disease progression or those who received new antitumor treatment, subjects who discontinued treatment due to other reasons were evaluated for tumors every 6 weeks until disease progression. If a subject showed radiologically assessed disease progression or started new tumor treatment, survival follow-up was performed every 6 weeks.

[0065] The study flow for each subject was assigned as follows: screening period, treatment period, and follow-up period. After the subjects signed the informed consent and completed all baseline examinations during the screening period, those who met the selection criteria were treated with mitoxantrone hydrochloride injection according to the order of entry into the study group. All subjects completed the relevant examinations specified in the treatment plan during the entire study period according to the treatment plan, and were observed for safety.

[0066] 2. Research Period In this study, the screening period will be 4 weeks (28 days), the treatment period will be up to 8 cycles (24 weeks), the final safety follow-up will be 4 weeks (28 days) after the end of treatment, and then PFS follow-up will be every 6 weeks, and survival follow-up will be every 6 weeks after progression, and each patient's duration is expected to be approximately 12 months. The study will enroll 30-60 subjects in each group, with the total study duration planned to be 24-36 months.

[0067] Subject 2: Only subjects who meet all of the following inclusion criteria and do not meet any of the exclusion criteria will be selected for this clinical study. (1) Selection criteria: Subjects must meet all of the following criteria: 1) Subjects willingly participate in the study and sign informed consent; 2) Age 18 or older, regardless of gender, 3) Subjects with histopathologically confirmed, metastatic, advanced gastric cancer (including gastroesophageal junction cancer), 4) The investigators assess that the patient is appropriate to receive treatment with mitoxantrone liposomal hydrochloride injection. 5) At least one measurable lesion meeting the definition of RECIST 1.1 at baseline; 6) ECOG score 0-2; 7) Survival period is 3 months or longer. 8) Toxicity from previous antitumor treatment has resolved to level 1 or less (excluding alopecia, pigmentation, or other toxicity not considered to pose a safety risk to subjects in the study); 9) Subjects' laboratory values ​​must meet the following requirements: Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L (did not receive G-CSF leukocytosis within 1 week prior to laboratory testing); Hemoglobin (Hb) ≥ 9.0 g / dL (no red blood cell infusion within 1 week prior to laboratory test; no erythropoietin therapy within 2 weeks). Platelets ≥ 75 × 10 9 / L (no platelet transfusions within 1 week prior to laboratory testing; no thrombopoietin, interleukin-11, or other platelet-raising medications within 2 weeks), Creatinine ≤ 1.5 × ULN Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for patients with liver metastases); Alanine aminotransferase (AST) / aspartate aminotransferase (ALT) ≤ 2.5xULN (≤ 5xULN for patients with liver metastases), Albumin ≥ 3.0 g / dL, Coagulation function: Prothrombin time (PT), international normalized ratio (INR) ≦1.5×ULN, 10) Female subjects have negative HCG in urine or blood (except for menopause or hysterectomy) and female subjects of childbearing age are using effective contraceptive measures (e.g., combined hormone (containing estrogen and progesterone) with ovulation suppression, combined progesterone contraception with ovulation suppression, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomy, abstinence from sexual activity, etc.) for the duration of the study and for 6 months after the end of the last dose. 11) Male subjects and their spouses agree to use one of the contraceptive measures specified in Article 10. 12) Subjects must be able to communicate well with the researchers, understand the requirements of this study, and be able to comply with them voluntarily.

[0068] (2) Exclusion criteria: Subjects who meet any of the following criteria will be excluded from this study: 1) Severe allergy to mitoxantrone or liposomes. 2) Subjects with brain or meningeal metastases; 3) Patients whose gastric cancer may be suitable for curative resection; 4) Subjects with obvious clinical symptoms of pleural, pericardial, or peritoneal effusion (excluding subjects who had undergone drainage treatment within one month prior to screening, had no obvious clinical symptoms, and only showed a small amount of effusion on imaging). 5) Patients with ileus who have obvious clinical symptoms and require intervention. 6) CTCAE grade 3 or 4 gastrointestinal bleeding occurred within 3 months prior to the first administration. 7) History of allogeneic organ transplantation or allogeneic bone marrow transplantation 8) Patients with active hepatitis B (HbsAg or HBcAb positive, HBV DNA ≥ 2000 IU / mL), active hepatitis C (HCV antibody positive, HCV RNA above the lower limit of detection at the research center), or HIV antibody positive. 9) Active bacterial, fungal, or viral infection requiring systematic treatment, or interstitial pneumonia within 1 week prior to the first dose. 10) Subjects who have received antitumor treatment within 4 weeks prior to the first administration 11) Having received treatment with other investigational drugs within 4 weeks prior to the first dose. 12) Have undergone major surgery (surgical grade: level 3-4 surgery, excluding intravenous port transplant surgery) within 3 months prior to the first administration, or are scheduled to undergo major surgery during the study period 13) If you have had a cerebrovascular event (including a transient ischemic attack) or a pulmonary embolism or other thrombosis or embolism within the past 6 months. 14) Previous active malignant tumor within the past 3 years (excluding locally treatable cancers that have already been cured), such as basal cell or squamous cell carcinoma, superficial bladder cancer, or in situ prostate, cervical, or breast cancer; 15) Cardiac dysfunction, including: Long QTc syndrome or QTc interval greater than 480 ms, Complete left bundle branch block, second-degree or third-degree atrioventricular block, severe uncontrolled arrhythmias requiring medical treatment; NYHA≧3 grade, Cardiac ejection fraction less than 50% or below the lower limit of the laboratory range at the study center; CTCAE>2 grade valvular heart disease; uncontrolled hypertension (defined as multiple measurements of systolic blood pressure above 150 mmHg or diastolic blood pressure above 90 mmHg under medical control); History of myocardial infarction, unstable angina, significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormality within 6 months prior to screening. 16) Patients have received doxorubicin or other anthracyclines with a cumulative doxorubicin dose of 350 mg / m 2 (Equivalent amount calculation for anthracyclines: 1mg doxorubicin = 2mg epinorubicin = 2mg daunomycin = 0.5mg demethoxydaunomycin = 0.45mg mitoxantrone) 17) Pregnant or breastfeeding women, 18) Serious and / or uncontrolled illness or other illness that, in the investigator's judgment, may affect the patient's participation in the study (including, but not limited to, ineffectively controlled diabetes, kidney disease requiring dialysis, severe liver disease, life-threatening autoimmune or bleeding disorders, medication abuse, or neurological disorders). 19) Other researchers have determined the participant to be ineligible to participate.

[0069] (3) Exit / termination criteria Subjects must discontinue treatment with the study drug if any of the following conditions occur during the study: 1) the subject experienced intolerable toxicity and the investigator believed that continued treatment with the study drug offered greater risks than benefits; 2) radiologically assessed disease progression; 3) Clinically assessed disease progression, significant protocol noncompliance, or poor subject compliance such that the investigator judged the subject would not benefit from continued treatment with the study drug; 4) pregnancy of the subject; 5) death; 6) Meeting any of the study withdrawal criteria. All subjects who discontinue treatment are required to have ongoing follow-up according to the study protocol, except for subjects who discontinue treatment due to death or who meet any of the study discontinuation criteria listed below. Subjects have the right to withdraw from the study at any time and for any reason. A subject will exit the study if any of the following situations occur: 1) Lost visits, 2) The subject withdraws informed consent or the subject or family member withdraws from the study; 3) End of study; 4)Others.

[0070] 3. Research results The therapeutic effect of the subjects was evaluated according to RECIST 1.1 criteria, and all adverse events occurred in the subjects were evaluated according to CTCAE 5.0 criteria. The inventor of the present invention uses mitoxantrone liposome, which has the effects of sustained release, targeting, attenuation and increased efficacy after being administered intravenously into the human body, and the dosage is not only higher than that of ordinary injections, but also can increase efficacy and reduce the probability of side effects as a single drug treatment.

[0071] Example 4 Clinical Study of Mitoxantrone Hydrochloride Liposome Injection for Treating Recurrent / Metastatic Head and Neck Squamous Cell Carcinoma This example is a single-arm, open-label, multicenter Phase Ib study to evaluate the safety and efficacy of mitoxantrone liposomal hydrochloride injection in subjects with recurrent / metastatic head and neck squamous cell carcinoma treated with mitoxantrone liposomal hydrochloride injection (PLM60).

[0072] First, test design 1. Test procedure All subjects in the study group received monotherapy with mitoxantrone liposomal hydrochloride injection at a dose of 20 mg / m 2The dose was administered once every 3 weeks (q3w). In this study, more than 30 subjects (both male and female) with recurrent / metastatic head and neck squamous cell carcinoma were planned to be enrolled in the study group. Screening-related tests were completed 28 days before administration, baseline evaluations were performed, and inclusion / exclusion criteria were determined before subjects were enrolled in the study group. All subjects enrolled in the study group were treated for 8 cycles, and treatment could be discontinued if the following events occurred: disease progression (PD), intolerable toxic reactions, death, or failure to continue to derive benefit as determined by the investigator. Delayed administration after the second cycle was permitted, but the delay should not exceed 3 weeks. Dose adjustments could be made after the second cycle, with a minimum dose of 12 mg / m 2 After administration, safety and efficacy evaluations were performed according to the treatment plan. Follow-up was performed for 28 days after the last dose. Subjects who left the study early should complete follow-up after the last dose as soon as possible.

[0073] Subjects who completed treatment entered the follow-up period. Subjects who discontinued treatment for other reasons, except for those who underwent radiologically assessed disease progression or received new anti-tumor therapy, had tumor assessments every 6 weeks until disease progression. If subjects showed radiologically assessed disease progression or started new oncology therapy, survival follow-up was performed every 6 weeks. The study flow for each subject was assigned as follows: screening period, treatment period, and follow-up period.

[0074] After the subjects signed the informed consent and completed all baseline examinations during the screening period, those who met the selection criteria were treated with mitoxantrone hydrochloride injection according to the order of entry into the study group. All subjects completed the relevant examinations specified in the treatment plan during the entire study period according to the treatment plan, and were observed for safety.

[0075] 2. Research Period In this study, the screening period was 4 weeks (28 days), the treatment period was 8 cycles (24 weeks), the final safety follow-up was 4 weeks (28 days) after the end of treatment, PFS follow-up was performed every 6 weeks thereafter, and survival follow-up was performed every 6 weeks after progression, and each patient's duration is expected to be approximately 12 months. The study will enroll more than 30 subjects in the study group, and the total duration of the study is expected to be 24 to 36 months.

[0076] Subject 2: Only subjects who meet all of the following inclusion criteria and do not meet any of the exclusion criteria will be selected for this clinical study. (1) Selection criteria: Subjects must meet all of the following criteria: 1) Subjects voluntarily participated in the study and signed informed consent; 2) Age must be 18 years or older, regardless of gender. 3) Head and neck squamous cell carcinoma (including nasopharyngeal carcinoma) when confirmed by histopathological examination; 4) Patients with recurrent / metastatic head and neck squamous cell carcinoma who have failed at least first-line treatment; 5) At baseline, there must be at least one measurable lesion meeting the definition of RECIST 1.1. 6) ECOG score 0-1; 7) Toxicity from previous antineoplastic treatment has resolved to level 1 or less (excluding alopecia, pigmentation, or other toxicity not considered to pose a safety risk to subjects in the study); 8) Subjects' laboratory parameters meet the following requirements: Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L (did not receive G-CSF leukocytosis within 1 week prior to laboratory testing); hemoglobin (Hb) ≥ 8.0 g / dL (no red blood cell or erythropoietin infusion therapy within 3 months prior to laboratory testing); Platelets ≥ 75 × 10 9 / L (within 1 week prior to the laboratory test, no platelet transfusions, thrombopoietin, interleukin-11, or other medical therapy for increasing platelets), Creatinine ≤ 1.5 × ULN, Total bilirubin ≤ 1.5 × ULN (3 × ULN for patients with liver metastases); Alanine aminotransferase (AST) / aspartate aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastases), Albumin ≥ 3.0 g / dL, Coagulation function: Prothrombin time (PT), international normalized ratio (INR) ≦1.5×ULN, 9) Female subjects had negative HCG in urine or blood (except for menopause or hysterectomy), and female subjects of childbearing age were using effective contraceptive measures (e.g., combined hormone (containing estrogen and progesterone) with ovulation suppression, combined progesterone contraception with ovulation suppression, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomy, abstinence from sexual activity, etc.) during the study and within 6 months after the end of the last dose. 10) Male subjects and their spouses have agreed to take one of the contraceptive measures specified in Article 9.

[0077] (2) Exclusion criteria: Subjects who meet any of the following criteria will be excluded from this study: 1) You have a severe allergy to mitoxantrone or liposomes. 2) Subjects with brain or meningeal metastases; 3) Previous allogeneic organ transplant or allogeneic bone marrow transplant 4) expected survival time < 3 months; 5) Patients with active hepatitis B (HbsAg or HBcAb positive, HBV DNA ≥ 2000 IU / mL), active hepatitis C (HCV antibody positive, HCV RNA above the lower limit of detection at the research center), or HIV antibody positive. 6) Having active bacterial, fungal, or viral infection requiring systematic treatment, or interstitial pneumonia within 1 week prior to the first dose. 7) Receipt of antitumor treatment within 4 weeks prior to the first dose 8) Having received treatment with other investigational drugs within 4 weeks prior to the first dose. 9) Having undergone major surgery within 3 months prior to the first dose or scheduled for major surgery during the study period. 10) Occurrence of thrombosis or embolism within the past 6 months, such as cerebrovascular accident (including transient ischemic attack), pulmonary embolism, 11) Had other malignant active tumors within the past 3 years (excluding locally treatable cancers that have already been cured), such as basal or squamous cell carcinoma, superficial bladder cancer, or in situ prostate, cervical or breast cancer; 12) Cardiac dysfunction, including: Long QTc syndrome or QTc interval greater than 480 ms Complete left bundle branch block, second-degree or third-degree atrioventricular block, severe uncontrolled arrhythmias requiring medical treatment; A history of chronic congestive heart failure, NYHA class ≥3, A past cardiac ejection fraction below 50% or below the lower limit of the laboratory range at the study center; CTCAE>2 grade valvular heart disease; uncontrolled hypertension (defined as a measured systolic blood pressure above 150 mmHg or a diastolic blood pressure above 90 mmHg under medical control); History of myocardial infarction, unstable angina, significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormality within 6 months prior to screening.

[0078] 13) Previous treatment with doxorubicin or other anthracyclines with a cumulative doxorubicin dose of 350 mg / m 2 (Equivalent amount calculation for anthracyclines: 1mg doxorubicin = 2mg epinorubicin = 2mg daunomycin = 0.5mg demethoxydaunomycin = 0.45mg mitoxantrone), 14) Pregnant or breastfeeding women, 15) Serious or uncontrolled illness or other condition that, in the opinion of the investigator, may affect the patient's participation in the study (including, but not limited to, ineffectively controlled diabetes, kidney disease requiring dialysis, severe liver disease, life-threatening autoimmune or bleeding disorders, medication abuse, or neurological disorders). 16) Other researchers have determined the participant to be ineligible to participate.

[0079] (3) Exit / termination criteria Subjects must discontinue treatment with the study drug if any of the following conditions occur during the study: 1) the subject experienced intolerable toxicity and the investigator believed that continued treatment with the study drug offered greater risks than benefits; 2) radiologically assessed disease progression; 3) Clinically assessed disease progression, significant protocol noncompliance, or poor subject compliance such that the investigator judged the subject would not benefit from continued treatment with the study drug; 4) pregnancy of the subject; 5) death; 6) Meeting any of the study withdrawal criteria. All subjects who discontinue treatment are required to have ongoing follow-up according to the study protocol, except for subjects who discontinue treatment due to death or who meet any of the study discontinuation criteria listed below. Subjects have the right to withdraw from the study at any time and for any reason. A subject will exit the study if any of the following situations occur: 1) Lost visits, 2) The subject withdraws informed consent or the subject or a family member requests withdrawal from the study; 3) End of study; 4)Others.

[0080] 3. Research results The treatment effects of the subjects were evaluated according to RECIST 1.1 criteria, and all adverse events occurring in the subjects were evaluated according to CTCAE 5.0 criteria. The inventors of the present invention use mitoxantrone liposomes, which, after the medicine enters the human body through intravenous administration, has the effects of sustained release, targeting, attenuation and increased efficacy. Not only is the dosage higher than that of ordinary injections, but it is also a single-drug treatment, which can increase efficacy while reducing the probability of side effects.

[0081] As of November 5, 2021 (the study is ongoing), a total of 34 subjects in the study group, including 23 cases of nasopharyngeal cancer and 11 cases of non-nasopharyngeal cancer (five cases of tongue cancer, two cases of hypopharyngeal cancer, two cases of tonsillar cancer, and one each of laryngeal cancer and gingival cancer), were all receiving mitoxantrone hydrochloride liposome injection 20 mg / m 2 The patients were administered 100 mg once every 3 weeks (q3w). The efficacy of treatment was evaluated after every 2 cycles. Nineteen subjects underwent at least one efficacy evaluation (including 18 subjects with nasopharyngeal carcinoma and 1 subject with non-nasopharyngeal carcinoma (hypopharyngeal carcinoma)). The analysis results of efficacy were as follows: Overall ORR was 42.1% (8 / 19), DCR was 78.9% (15 / 19). In nasopharyngeal carcinoma, ORR was 38.8% (7 / 18), DCR was 77.8% (14 / 18). In one case of hypopharyngeal carcinoma, the efficacy of treatment was evaluated as PR. No intolerable side effects were observed in any of the subjects.

[0082] Based on the current experimental results, the mitoxantrone hydrochloride liposome preparation provided in the present invention is expected to fill the gap in second-line treatment of head and neck squamous cell carcinoma and lay the foundation for subsequent first-line treatment with combination drugs.

[0083] The above description is merely a preferred embodiment used as an example only, without limiting the combination of features necessary for carrying out the present invention. The titles presented are not intended to limit the various embodiments of the present invention. For example, the terms "include", "comprise", and "containing" are not intended to be limiting. Furthermore, unless otherwise stated, the absence of a numeral modifier means "or", "or", "alternative", "and / or", "and / or". Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as those commonly understood by those of ordinary skill in the art. All disclosures and patents described herein are incorporated by reference. Various modifications and variations of the methods and compositions described herein will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the present invention. Although the present invention has been described by certain preferred embodiments, it should be understood that the claimed invention should not be unduly limited to these specific embodiments. Indeed, various modifications for carrying out the aspects described herein that are apparent to those of ordinary skill in the art are intended to be included within the scope of the appended claims.

Claims

1. A pharmaceutical composition for treating ovarian cancer, gastric cancer or head and neck squamous cell carcinoma comprising mitoxantrone hydrochloride liposome, wherein the ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer, the gastric cancer is advanced gastric cancer, and the head and neck squamous cell carcinoma is recurrent or metastatic head and neck squamous cell carcinoma that has failed first-line treatment.

2. 2. The pharmaceutical composition of claim 1, wherein said mitoxantrone hydrochloride liposome is the only active ingredient in said pharmaceutical composition.

3. The pharmaceutical composition or the mitoxantrone hydrochloride liposome comprises: (i) the particle size of the mitoxantrone hydrochloride liposome is about 30-80 nm; (ii) the property that mitoxantrone hydrochloride and multivalent counterions in liposomes form a poorly soluble precipitate; (iii) the phospholipid bilayer in the mitoxantrone hydrochloride liposomes contains phospholipids having a phase transition temperature (Tm) higher than body temperature, thereby providing the liposomes with a phase transition temperature higher than body temperature; and (iv) the phospholipid bilayer in the mitoxantrone hydrochloride liposome has one or more properties selected from the group consisting of properties comprising hydrogenated soy lecithin, cholesterol and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine (DSPE-PEG2000); The pharmaceutical composition of claim 1.

4. The pharmaceutical composition of claim 3, wherein the particle size of the mitoxantrone hydrochloride liposome is about 40-60 nm.

5. The pharmaceutical composition of claim 3 , wherein the multivalent counterion is a sulfate ion, a citrate ion, or a phosphate ion.

6. 4. The pharmaceutical composition of claim 3, wherein the phospholipid is selected from hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, lecithin dipalmitate, lecithin distearate, or any combination thereof.

7. 2. The pharmaceutical composition of claim 1, wherein the phospholipid bilayer in the mitoxantrone hydrochloride liposome comprises hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of approximately 3:1:1, mitoxantrone hydrochloride and polyvalent acid ions in the liposome form a poorly soluble precipitate, and the particle size of the mitoxantrone hydrochloride liposome in the pharmaceutical is approximately 60 nm.

8. 2. The pharmaceutical composition of claim 1, wherein the head and neck squamous cell carcinoma is squamous cell carcinoma occurring in the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, larynopharynx, cervical esophagus, thyroid gland, salivary gland, oral cavity, larynx and / or ear.

9. The first-line treatment is a combination treatment of cisplatin / carboplatin and 5-FU or paclitaxel drug, optionally further combined with cetuximab; The pharmaceutical composition of claim 1.

10. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is in an injectable form.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is a liquid injection, an injection powder, or an injection tablet.

12. The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is a liquid injection and the content of the active ingredient in the pharmaceutical composition is 0.5-5 mg / mL based on mitoxantrone.

13. The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is a liquid injection and the content of the active ingredient in the pharmaceutical composition is 1-2 mg / mL based on mitoxantrone.

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