WO2024046246A1 - 米托蒽醌脂质体联用卡培他滨治疗鼻咽癌的用途 - Google Patents

米托蒽醌脂质体联用卡培他滨治疗鼻咽癌的用途 Download PDF

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WO2024046246A1
WO2024046246A1 PCT/CN2023/115149 CN2023115149W WO2024046246A1 WO 2024046246 A1 WO2024046246 A1 WO 2024046246A1 CN 2023115149 W CN2023115149 W CN 2023115149W WO 2024046246 A1 WO2024046246 A1 WO 2024046246A1
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Prior art keywords
mitoxantrone
capecitabine
liposome
liposomes
administered
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PCT/CN2023/115149
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English (en)
French (fr)
Inventor
李春雷
刘延平
李萌萌
黄薇
杜艳玲
何丽娟
王世霞
董琪
王东
薛建飞
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石药集团中奇制药技术（石家庄）有限公司
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Publication of WO2024046246A1 publication Critical patent/WO2024046246A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention belongs to the field of anti-tumor, and specifically relates to the use of mitoxantrone liposomes and capecitabine in the treatment of nasopharyngeal carcinoma, especially recurrent and/or metastatic nasopharyngeal carcinoma.
  • Nasopharyngeal carcinoma is a common malignant tumor of the head and neck. It originates from the nasopharyngeal mucosa and mostly occurs in the pharyngeal recesses. It has an obvious regional high incidence rate and is highly prevalent in southern my country, Southeast Asia and North Africa. These areas The age-standardized incidence rate is 4-25 cases/100,000 people, which is 50-100 times higher than the incidence rate in other parts of the world. According to GLOBOCAN data released by the International Center for Research on Cancer in 2020, there are approximately 133,354 new cases worldwide, and more than 70% of the cases are concentrated in high-incidence areas.
  • first-line treatment for recurrent or metastatic nasopharyngeal carcinoma is a PD-1 inhibitor combined with gemcitabine and cisplatin.
  • PD-1 inhibitor combined with gemcitabine and cisplatin.
  • monotherapy with drugs including gemcitabine, docetaxel, capecitabine, toripalimab, etc.
  • Mitoxantrone is an anthracycline drug that has been used in more than 30 countries around the world. It has a therapeutic effect on hematological tumors such as acute leukemia, lymphoma and various solid tumors such as breast cancer. The main adverse reactions are bone marrow suppression, gastrointestinal reactions and cardiotoxicity. Liposomes are a new form of drug loading. Studies have shown that they can change the distribution of encapsulated drugs in the body, causing the drugs to accumulate mainly in tumor tissues, thereby improving the therapeutic index of the drug, reducing the therapeutic dose of the drug, and reducing drug toxicity. These characteristics make the application of liposome drug delivery in anti-tumor drug research highly valued. Some researchers have conducted studies on mitoxantrone liposome preparations.
  • WO2008/080367A1 discloses a mitoxantrone liposome (the disclosure content of which is incorporated herein by reference in its entirety), which is mixed with free mitoxantrone. Compared with quinones, it has better anti-tumor effect and reduced toxicity. Based on these favorable properties of mitoxantrone liposomes, it is expected that it will show beneficial effects in the treatment of more types of tumors.
  • the purpose of the present invention is to provide new drugs and therapies for the treatment of nasopharyngeal carcinoma, especially recurrent and/or metastatic nasopharyngeal carcinoma, which can improve the disease remission rate, prolong survival, and are safely tolerated.
  • the present invention relates to the use of mitoxantrone liposome combined with capecitabine in the treatment of nasopharyngeal cancer.
  • a first aspect of the present invention relates to the use of mitoxantrone liposomes and capecitabine in the preparation of medicaments for the treatment of nasopharyngeal cancer.
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer. In some embodiments, the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer that has failed previous first-line or second-line platinum-containing regimens.
  • mitoxantrone liposomes and capecitabine are present in the same formulation. In some embodiments, mitoxantrone liposomes and capecitabine are each present in separate formulations.
  • the preparation can be any clinically accepted dosage form, such as injection dosage form, oral dosage form, etc.
  • the injection dosage forms include liquid injections, injection powders, injection tablets, etc.; the oral dosage forms include tablets, capsules, oral liquid preparations, etc.
  • mitoxantrone liposomes are in the form of injections, including liquid injections, powders for injection, tablets for injection, and the like.
  • the mitoxantrone liposome is a liquid injection
  • the active ingredient is 0.5-5 mg/ml, preferably 1-2 mg/ml, and more preferably 1 mg/ml based on mitoxantrone.
  • capecitabine is a tablet, with a specification of 0.15g/tablet or 0.5g/tablet
  • Tablets with specifications of 0.15g/tablet or 0.5g/tablet refer to: Each tablet contains 0.15g or 0.5g capecitabine.
  • the use of mitoxantrone liposomes and capecitabine in the preparation of a medicament for the treatment of recurrent and/or metastatic nasopharyngeal carcinoma is provided.
  • the use of mitoxantrone liposomes and capecitabine in the preparation of medicaments for the treatment of recurrent and/or metastatic nasopharyngeal carcinoma that has failed previous first-line or second-line platinum-containing regimens is provided.
  • the mitoxantrone liposome is an injection, containing 0.5-5 mg/ml of active ingredient based on mitoxantrone;
  • the capecitabine is a tablet, with a specification of 0.15g/tablet or 0.5g/ piece.
  • a second aspect of the present invention relates to the use of mitoxantrone liposomes in the preparation of a medicament for improving the efficacy of capecitabine in the treatment of nasopharyngeal carcinoma.
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer. In some embodiments, the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer that has failed previous first-line or second-line platinum-containing regimens.
  • mitoxantrone liposomes are in the form of injections, including liquid injections, powders for injection, tablets for injection, and the like.
  • the mitoxantrone liposome is a liquid injection
  • the active ingredient is 0.5-5 mg/ml, preferably 1-2 mg/ml, and more preferably 1 mg/ml based on mitoxantrone.
  • capecitabine is a tablet with a specification of 0.15g/tablet or 0.5g/tablet, wherein a tablet with a specification of 0.15g/tablet or 0.5g/tablet means: each tablet contains 0.15 g or 0.5 g of capecitabine.
  • the use of mitoxantrone liposomes in the preparation of a medicament for improving the efficacy of capecitabine in the treatment of recurrent and/or metastatic nasopharyngeal carcinoma is provided.
  • the use of mitoxantrone liposomes in preparing a medicament for improving the efficacy of capecitabine in the treatment of recurrent and/or metastatic nasopharyngeal carcinoma that has failed previous first-line or second-line platinum-containing regimens is provided.
  • the mitoxantrone liposome is an injection, containing 0.5-5 mg/ml of active ingredient based on mitoxantrone;
  • the capecitabine is a tablet, with a specification of 0.15g/tablet or 0.5g/ piece.
  • a third aspect of the present invention relates to the use of capecitabine in the preparation of a medicament for improving the efficacy of mitoxantrone liposome in the treatment of nasopharyngeal carcinoma.
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer. In some embodiments, the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer that has failed previous first-line or second-line platinum-containing regimens.
  • mitoxantrone liposomes are in the form of injections, including liquid injections, powders for injection, tablets for injection, and the like.
  • mitoxantrone liposome is a liquid injection
  • Mitoxantrone contains an active ingredient of 0.5-5 mg/ml, preferably 1-2 mg/ml, and more preferably 1 mg/ml.
  • capecitabine is a tablet with a specification of 0.15g/tablet or 0.5g/tablet, wherein a tablet with a specification of 0.15g/tablet or 0.5g/tablet means: each tablet contains 0.15 g or 0.5 g of capecitabine.
  • the use of capecitabine in the preparation of a medicament for improving the efficacy of mitoxantrone liposomes in the treatment of recurrent and/or metastatic nasopharyngeal carcinoma is provided.
  • the use of capecitabine in preparing a medicament for improving the efficacy of mitoxantrone liposomes in the treatment of recurrent and/or metastatic nasopharyngeal carcinoma that has failed previous first-line or second-line platinum-containing regimens is provided.
  • the mitoxantrone liposome is an injection, containing 0.5-5 mg/ml of active ingredient based on mitoxantrone;
  • the capecitabine is a tablet, with a specification of 0.15g/tablet or 0.5g/ piece.
  • a fourth aspect of the present invention relates to a method of treating nasopharyngeal carcinoma, the method comprising administering to a patient with nasopharyngeal carcinoma a therapeutically effective amount of mitoxantrone liposomes and capecitabine.
  • the fifth aspect of the present invention relates to a method for improving the efficacy of capecitabine in the treatment of nasopharyngeal carcinoma.
  • the method includes, on the basis of administering capecitabine to patients with nasopharyngeal carcinoma, further combined with the administration of a therapeutically effective amount of rice. Toxantrone liposomes.
  • the sixth aspect of the present invention relates to a method for improving the efficacy of mitoxantrone liposomes in treating nasopharyngeal cancer.
  • the method includes, on the basis of administering mitoxantrone liposomes to patients with nasopharyngeal cancer, further combining A therapeutically effective amount of capecitabine is administered.
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer. In some embodiments, the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer that has failed previous first-line or second-line platinum-containing regimens.
  • mitoxantrone is administered liposomally by injection.
  • mitoxantrone liposomes are administered by injection in a therapeutically effective amount of 8-30 mg/m 2 , preferably 12-24 mg/m 2 , more preferably 12-20 mg/m 2 .
  • mitoxantrone liposomes are administered on Day 1 of each dosing cycle.
  • mitoxantrone liposomes are administered by injection at a therapeutically effective amount of 8-30 mg/m on Day 1 of each dosing cycle.
  • mitoxantrone liposomes are administered on Day 1 of each dosing cycle at, for example, 12 mg/m 2 , 14 mg/m 2 , 15 mg/m 2 , 16 mg/m 2 , 18 mg/m 2 , A therapeutically effective dose of 20 mg/m 2 or 24 mg/m 2 is administered by injection.
  • the dosing period is 3 weeks.
  • mitoxantrone liposome is administered intravenously through 30min-120min, preferably 60min-120min.
  • capecitabine is administered orally. In some embodiments, cape Tabine is administered orally at doses of 500 mg/m 2 , 750 mg/m 2 , or 1000 mg/m 2 . In some embodiments, capecitabine is administered twice daily. In some embodiments, capecitabine is administered on days 1-14 of each dosing cycle. In some embodiments, capecitabine is administered in tablet form. In some embodiments, capecitabine is administered orally twice daily at a dose of 500 mg/m 2 , 750 mg/m 2 , or 1000 mg/m 2 on days 1-14 of each dosing cycle. In some embodiments, capecitabine is administered orally in tablet form at a dose of 1000 mg/m twice daily on days 1-14 of each dosing cycle. Preferably, the dosing period is 3 weeks.
  • mitoxantrone liposome is administered once per dosing cycle and capecitabine is administered continuously for 14 days.
  • the therapeutically effective amounts of mitoxantrone liposomes and capecitabine are administered in any order to the nasopharyngeal cancer patients on day 1 of each dosing cycle, and then continued twice daily on days 2-14. Administer capecitabine.
  • mitoxantrone liposomes are administered by injection at a therapeutically effective amount of 8-30 mg/m and at 500 mg/ m , 750 mg/ m , or 1000 mg on Day 1 of each dosing cycle.
  • Capecitabine was administered orally at a dose of / m2 , followed by oral administration of capecitabine at a dose of 500 mg/ m2 , 750 mg/ m2 , or 1000 mg/ m2 on days 2-14 of the cycle.
  • mitoxantrone liposomes are administered once by injection at a therapeutically effective amount of 12-24 mg/m and orally at a dose of 1000 mg/m on Day 1 of each dosing cycle.
  • a seventh aspect of the present invention relates to a medicament for treating nasopharyngeal cancer, the medicament comprising mitoxantrone liposomes and capecitabine.
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer. In some embodiments, the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer that has failed previous first-line or second-line platinum-containing regimens.
  • mitoxantrone liposomes and capecitabine are present in the same formulation. In some embodiments, mitoxantrone liposomes and capecitabine are each present in separate formulations.
  • the preparation can be any clinically accepted dosage form, such as injection dosage form, oral dosage form, etc.
  • the injection dosage forms include liquid injections, injection powders, injection tablets, etc.; the oral dosage forms include tablets, capsules, oral liquid preparations, etc.
  • mitoxantrone liposomes are in the form of injections, including liquid injections, powders for injection, tablets for injection, and the like.
  • the mitoxantrone liposome is a liquid injection
  • the active ingredient is 0.5-5 mg/ml, preferably 1-2 mg/ml, and more preferably 1 mg/ml based on mitoxantrone.
  • capecitabine is a tablet, with a specification of 0.15g/tablet or 0.5g/tablet
  • Tablets with specifications of 0.15g/tablet or 0.5g/tablet refer to: Each tablet contains 0.15g or 0.5g capecitabine.
  • the medicine may further comprise other medicines for the treatment of nasopharyngeal cancer, including medicines approved by the drug regulatory authorities of China or other countries and regions (such as the United States, the European Union, Japan, South Korea, etc.) for the treatment of nasopharyngeal cancer. drug.
  • mitoxantrone is administered liposomally by injection.
  • mitoxantrone liposomes are administered by injection in a therapeutically effective amount of 8-30 mg/m 2 , preferably 12-24 mg/m 2 , more preferably 12-20 mg/m 2 .
  • mitoxantrone liposomes are administered on Day 1 of each dosing cycle.
  • mitoxantrone liposomes are administered by injection at a therapeutically effective amount of 8-30 mg/m on Day 1 of each dosing cycle.
  • mitoxantrone liposomes are administered on Day 1 of each dosing cycle at, for example, 12 mg/m 2 , 14 mg/m 2 , 15 mg/m 2 , 16 mg/m 2 , 18 mg/m 2 , A therapeutically effective dose of 20 mg/m 2 or 24 mg/m 2 is administered by injection.
  • the dosing period is 3 weeks.
  • mitoxantrone liposome is administered intravenously through 30min-120min, preferably 60min-120min.
  • capecitabine is administered orally. In some embodiments, capecitabine is administered orally at a dose of 500 mg/m 2 , 750 mg/m 2 , or 1000 mg/m 2 . In some embodiments, capecitabine is administered twice daily. In some embodiments, capecitabine is administered on days 1-14 of each dosing cycle. In some embodiments, capecitabine is administered in tablet form. In some embodiments, capecitabine is administered orally twice daily at a dose of 500 mg/m 2 , 750 mg/m 2 , or 1000 mg/m 2 on days 1-14 of each dosing cycle. In some embodiments, capecitabine is administered orally in tablet form at a dose of 1000 mg/m twice daily on days 1-14 of each dosing cycle. Preferably, the dosing period is 3 weeks.
  • mitoxantrone liposome is administered once per dosing cycle and capecitabine is administered continuously for 14 days.
  • the therapeutically effective amounts of mitoxantrone liposomes and capecitabine are administered in any order to the nasopharyngeal cancer patients on day 1 of each dosing cycle, and then continued twice daily on days 2-14. Administer capecitabine.
  • mitoxantrone liposomes are administered by injection at a therapeutically effective amount of 8-30 mg/m and at 500 mg/ m , 750 mg/ m , or 1000 mg on Day 1 of each dosing cycle.
  • Capecitabine was administered orally at a dose of / m2 , followed by oral administration of capecitabine at a dose of 500 mg/ m2 , 750 mg/ m2 , or 1000 mg/ m2 on days 2-14 of the cycle.
  • mitoxantrone liposomes are administered once by injection at a therapeutically effective amount of 12-24 mg/m and orally at a dose of 1000 mg/m on Day 1 of each dosing cycle.
  • Capecitabine was administered orally twice daily at a dose of 1000 mg/ m2 .
  • An eighth aspect of the present invention relates to a medicament for improving the efficacy of capecitabine in treating nasopharyngeal carcinoma, the medicament comprising mitoxantrone liposomes.
  • a ninth aspect of the present invention relates to a drug for improving the efficacy of mitoxantrone liposome in treating nasopharyngeal cancer, the drug comprising capecitabine.
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer. In some embodiments, the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer that has failed previous first-line or second-line platinum-containing regimens.
  • mitoxantrone liposomes are in the form of injections, including liquid injections, powders for injection, tablets for injection, and the like.
  • the mitoxantrone liposome is a liquid injection
  • the active ingredient is 0.5-5 mg/ml, preferably 1-2 mg/ml, and more preferably 1 mg/ml based on mitoxantrone.
  • capecitabine is a tablet with a specification of 0.15g/tablet or 0.5g/tablet, wherein a tablet with a specification of 0.15g/tablet or 0.5g/tablet means: each tablet contains 0.15 g or 0.5 g of capecitabine.
  • mitoxantrone is administered liposomally by injection.
  • mitoxantrone liposomes are administered by injection in a therapeutically effective amount of 8-30 mg/m 2 , preferably 12-24 mg/m 2 , more preferably 12-20 mg/m 2 .
  • mitoxantrone liposomes are administered on Day 1 of each dosing cycle.
  • mitoxantrone liposomes are administered by injection at a therapeutically effective amount of 8-30 mg/m on Day 1 of each dosing cycle.
  • mitoxantrone liposomes are administered on Day 1 of each dosing cycle at, for example, 12 mg/m 2 , 14 mg/m 2 , 15 mg/m 2 , 16 mg/m 2 , 18 mg/m 2 , A therapeutically effective dose of 20 mg/m 2 or 24 mg/m 2 is administered by injection.
  • the dosing period is 3 weeks.
  • mitoxantrone liposome is administered intravenously through 30min-120min, preferably 60min-120min.
  • capecitabine is administered orally. In some embodiments, capecitabine is administered orally at a dose of 500 mg/m 2 , 750 mg/m 2 , or 1000 mg/m 2 . In some embodiments, capecitabine is administered twice daily. In some embodiments, capecitabine is administered on days 1-14 of each dosing cycle. In some embodiments, capecitabine is administered in tablet form. In some embodiments, capecitabine is administered orally twice daily at a dose of 500 mg/m 2 , 750 mg/m 2 , or 1000 mg/m 2 on days 1-14 of each dosing cycle. In some embodiments, capecitabine is administered orally in tablet form at a dose of 1000 mg/m twice daily on days 1-14 of each dosing cycle. Preferably, the dosing period is 3 weeks.
  • mitoxantrone liposome is administered once per dosing cycle and capecitabine is administered continuously for 14 days.
  • the therapeutically effective amounts of mitoxantrone liposomes and capecitabine are administered in any order to the nasopharyngeal cancer patients on day 1 of each dosing cycle, and then continued twice daily on days 2-14. Administer capecitabine.
  • mitoxantrone liposomes are administered by injection at a therapeutically effective amount of 8-30 mg/m and at 500 mg/ m , 750 mg/ m , or 1000 mg on Day 1 of each dosing cycle.
  • Capecitabine was administered orally at a dose of / m2 , followed by oral administration of capecitabine at a dose of 500 mg/ m2 , 750 mg/ m2 , or 1000 mg/ m2 on days 2-14 of the cycle.
  • mitoxantrone liposomes are administered once by injection at a therapeutically effective amount of 12-24 mg/m and orally at a dose of 1000 mg/m on Day 1 of each dosing cycle.
  • a tenth aspect of the present invention relates to a composition for treating nasopharyngeal cancer, said composition comprising mitoxantrone liposomes and capecitabine.
  • An eleventh aspect of the present invention relates to a pharmaceutical combination for treating nasopharyngeal cancer, the pharmaceutical combination comprising mitoxantrone liposomes and capecitabine.
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer. In some embodiments, the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer that has failed previous first-line or second-line platinum-containing regimens.
  • mitoxantrone liposomes are in the form of injections, including liquid injections, powders for injection, tablets for injection, and the like.
  • the mitoxantrone liposome is a liquid injection
  • the active ingredient is 0.5-5 mg/ml, preferably 1-2 mg/ml, and more preferably 1 mg/ml based on mitoxantrone.
  • capecitabine is a tablet with a specification of 0.15g/tablet or 0.5g/tablet, wherein a tablet with a specification of 0.15g/tablet or 0.5g/tablet means: each tablet contains 0.15 g or 0.5 g of capecitabine.
  • mitoxantrone is administered liposomally by injection.
  • mitoxantrone liposomes are administered by injection in a therapeutically effective amount of 8-30 mg/m 2 , preferably 12-24 mg/m 2 , more preferably 12-20 mg/m 2 .
  • mitoxantrone liposomes are administered on Day 1 of each dosing cycle.
  • mitoxantrone liposomes are administered by injection at a therapeutically effective amount of 8-30 mg/m on Day 1 of each dosing cycle.
  • mitoxantrone liposomes are administered on Day 1 of each dosing cycle at, for example, 12 mg/m 2 , 14 mg/m 2 , 15 mg/m 2 , 16 mg/m 2 , 18 mg/m 2 , Treatment with 20mg/ m2 or 24mg/ m2 An effective amount is administered by injection.
  • the dosing period is 3 weeks.
  • mitoxantrone liposome is administered intravenously through 30min-120min, preferably 60min-120min.
  • capecitabine is administered orally. In some embodiments, capecitabine is administered orally at a dose of 500 mg/m 2 , 750 mg/m 2 , or 1000 mg/m 2 . In some embodiments, capecitabine is administered twice daily. In some embodiments, capecitabine is administered on days 1-14 of each dosing cycle. In some embodiments, capecitabine is administered in tablet form. In some embodiments, capecitabine is administered orally twice daily at a dose of 500 mg/m 2 , 750 mg/m 2 , or 1000 mg/m 2 on days 1-14 of each dosing cycle. In some embodiments, capecitabine is administered orally in tablet form at a dose of 1000 mg/m twice daily on days 1-14 of each dosing cycle. Preferably, the dosing period is 3 weeks.
  • mitoxantrone liposome is administered once per dosing cycle and capecitabine is administered continuously for 14 days.
  • the therapeutically effective amounts of mitoxantrone liposomes and capecitabine are administered in any order to the nasopharyngeal cancer patients on day 1 of each dosing cycle, and then continued twice daily on days 2-14. Administer capecitabine.
  • mitoxantrone liposomes are administered by injection at a therapeutically effective amount of 8-30 mg/m and at 500 mg/ m , 750 mg/ m , or 1000 mg on Day 1 of each dosing cycle.
  • Capecitabine was administered orally at a dose of / m2 , followed by oral administration of capecitabine at a dose of 500 mg/ m2 , 750 mg/ m2 , or 1000 mg/ m2 on days 2-14 of the cycle.
  • mitoxantrone liposomes are administered once by injection at a therapeutically effective amount of 12-24 mg/m and orally at a dose of 1000 mg/m on Day 1 of each dosing cycle.
  • a twelfth aspect of the present invention relates to a kit for treating nasopharyngeal cancer, the kit comprising mitoxantrone liposomes and capecitabine.
  • the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer. In some embodiments, the nasopharyngeal cancer is recurrent and/or metastatic nasopharyngeal cancer that has failed previous first-line or second-line platinum-containing regimens.
  • mitoxantrone liposomes and capecitabine are each separate formulations.
  • mitoxantrone liposomes are in the form of injections, including liquid injections, powders for injection, tablets for injection, and the like.
  • the mitoxantrone liposome is a liquid injection
  • the active ingredient is 0.5-5 mg/ml, preferably 1-2 mg/ml, and more preferably 1 mg/ml based on mitoxantrone.
  • capecitabine is a tablet with a specification of 0.15g/tablet or 0.5g/tablet, wherein a tablet with a specification of 0.15g/tablet or 0.5g/tablet means: each tablet contains 0.15 g or 0.5g Capecitabine.
  • capecitabine may be provided in the form of a pharmaceutical preparation, such as a tablet.
  • a pharmaceutical preparation such as a tablet.
  • Such pharmaceutical preparations are commercially available.
  • mitoxantrone includes mitoxantrone and its pharmaceutically acceptable salts, preferably mitoxantrone hydrochloride.
  • Mitoxantrone liposomes are preferably mitoxantrone hydrochloride liposomes.
  • mitoxantrone liposomes are not particularly limited. Without being bound by any particular theory, the inventors of the present application have discovered that one or more of the following properties are advantageous for liposomal formulations of mitoxantrone:
  • Mitoxantrone liposomes are mitoxantrone hydrochloride liposomes
  • the particle size of mitoxantrone liposomes is about 30-80nm, such as about 35-75nm, about 40-70nm, about 40-60nm or about 60nm; for example, about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or 80nm.
  • NanoZS NanoZS
  • Mitoxantrone forms an insoluble precipitate with multivalent counterions (such as sulfate, citrate or phosphate) in the liposome;
  • the phospholipid bilayer in mitoxantrone liposomes contains phospholipids with a phase transition temperature (Tm) higher than body temperature, so the phase transition temperature of the liposomes is higher than body temperature.
  • the phospholipids include, but are not limited to, hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dispalmitate lecithin, distearate lecithin or any combination of the above;
  • the phospholipid bilayer in mitoxantrone liposomes contains hydrogenated soy lecithin, cholesterol and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine (DSPE-PEG2000);
  • the phospholipid bilayer in the mitoxantrone liposome contains hydrogenated soy lecithin, cholesterol and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of about 3:1:1, hydrochloric acid Mitoxantrone forms an insoluble precipitate with the multivalent counterions in the liposomes, and the particle size of mitoxantrone hydrochloride liposomes is about 60 nm;
  • Mitoxantrone liposomes are mitoxantrone liposomes with national drug approval number H20220001.
  • the mitoxantrone liposome meets one or more of the following:
  • the mitoxantrone liposome is mitoxantrone hydrochloride liposome
  • the phospholipid bilayer in mitoxantrone liposomes contains phospholipids with a phase transition temperature (Tm) higher than body temperature, which are selected from hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, and double soft fat. acid lecithin, distearyl lecithin, or any combination of the above.
  • Tm phase transition temperature
  • the mitoxantrone liposome is mitoxantrone hydrochloride liposome.
  • the therapeutically effective amount or dose of the mitoxantrone liposome or mitoxantrone hydrochloride liposome is calculated in terms of mitoxantrone.
  • the mitoxantrone liposomes can be prepared by conventional methods in the art, or by any method disclosed in the prior art, for example, by the method disclosed in WO2008/080367 A1, the contents of which are disclosed in this patent. The entire text is incorporated by reference.
  • the mitoxantrone hydrochloride liposome preparation of the present application can be prepared according to the following method, where the "lipid-to-drug ratio" refers to the components of the phospholipid bilayer in the liposome (including HSPC, DSPE- Mass ratio of PEG2000 and Chol) to mitoxantrone:
  • Hydrogenated soy lecithin (HSPC), cholesterol (Chol) and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine (DSPE-PEG2000) were weighed according to the mass ratio of 3:1:1, and dissolved in 95% ethanol , a clear solution (i.e., ethanol solution of phospholipids) was obtained.
  • a clear solution i.e., ethanol solution of phospholipids
  • Mix the ethanol solution of phospholipids with 300mM ammonium sulfate solution shake and hydrate at 60-65°C for 1 hour to obtain uneven multi-chamber liposomes, and then use microfluidic equipment to reduce the particle size of the liposomes.
  • the obtained sample was diluted 200 times with a NaCl solution with a concentration of 0.9%, it was detected with NanoZS.
  • the average particle size was about 60nm, and the main peak was concentrated between 40-60nm.
  • an ultrafiltration device was used to remove the ammonium sulfate from the external phase of the blank liposome, and the external phase was replaced with 290mM sucrose and 10mM glycine to form a transmembrane ammonium sulfate gradient.
  • the ratio of lipid to drug of 16:1 add mitoxantrone hydrochloride solution (based on mitoxantrone, 10 mg/mL) to the blank liposomes, and carry out drug loading at 60-65°C. After approximately 1 h of incubation, the encapsulation efficiency was demonstrated to be approximately 100% using gel exclusion chromatography.
  • the resulting product was named PLM60.
  • 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.
  • amino acid species that can be replaced by glycine in the external phase to form a transmembrane ammonium sulfate gradient include, but are not limited to, histidine, asparagine, glutamic acid, leucine, proline, and alanine.
  • the mass ratio of HSPC, Chol and DSPE-PEG2000 can be appropriately adjusted.
  • those skilled in the art can design, Test and ultimately determine the appropriate lipid-to-drug ratio to maximize the drug loading capacity while reducing drug leakage.
  • lipid-to-drug ratio for the mitoxantrone hydrochloride liposome formulation of the present application, a wide range of lipid-to-drug ratio can be used, such as as low as 2:1 or as high as 30:1, 40:1 or 50:1, and more A suitable lipid-to-drug ratio may be about (15-20):1, such as about 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1. Therefore, several advantageous properties of the mitoxantrone hydrochloride liposome formulation described above are more important, and the methodologies for achieving these properties are diverse.
  • composition means a combination of two or more active ingredients, wherein the active ingredients may be present in the same formulation for administration together, or the active ingredients may be present in different formulations, in the same or different formulations.
  • Mode of administration Simultaneous or sequential administration. In this sense, “composition” and “combination” are used interchangeably.
  • the term "therapeutically effective amount” or “effective amount” refers to a dose that exhibits the desired benefit in a subject treated.
  • the “therapeutically effective amount” or “effective amount” will depend on the species of the subject being treated, the severity of the disease, the frequency of administration, the metabolic characteristics of the drug and other factors, and may be judged by the prescribing physician based on routine practice. It should be noted that all numerical ranges mentioned in this application include both endpoints of the range, all values within the range, and the subrange formed by any two values therein.
  • treatment refers to controlling, reducing or alleviating the pathological progression of a disease and prolonging the survival of a diseased subject.
  • the terms “subject”, “subject” and “patient” include individual animals to which the medicaments or compositions of the present application are intended to be administered, including but not limited to humans and other mammals, such as mice and rats. , cats, monkeys, dogs, horses, pigs, etc. Preferably, the subject is a human being. Unless otherwise indicated, the terms “subject,” “subject,” and “patient” are used interchangeably.
  • recurrent nasopharyngeal carcinoma used in this article refers to the clinical tumor disappearance of pathologically confirmed nasopharyngeal carcinoma after radical radiotherapy. Six months after the end of treatment, tumors with the same pathological type as the original tumor reappear locally or regionally.
  • metastatic nasopharyngeal carcinoma refers to nasopharyngeal carcinoma with distant metastasis.
  • the term “administered in any order” refers to mitoxantrone liposomes and The separate preparations of capecitabine are administered separately in a clinically acceptable manner, with no mandatory order of administration, and the drugs do not mix in vitro.
  • Embodiment 1 The use of mitoxantrone liposomes and capecitabine in the preparation of medicaments for the treatment of nasopharyngeal carcinoma.
  • the nasopharyngeal carcinoma is recurrent metastatic nasopharyngeal carcinoma.
  • the recurrence Metastatic nasopharyngeal carcinoma is a recurrent metastatic nasopharyngeal carcinoma that has failed to receive first-line or second-line platinum-containing regimens.
  • the recurrent metastatic nasopharyngeal carcinoma has at least 1 evaluable disease at baseline according to RECIST 1.1 criteria. The lesion must have not received radiotherapy in the past, or there must be evidence that the lesion has significantly progressed after the end of radiotherapy.
  • Embodiment 2 The use of mitoxantrone liposomes in preparing a drug for improving the efficacy of capecitabine treatment regimen in treating nasopharyngeal carcinoma.
  • the nasopharyngeal carcinoma is recurrent and metastatic nasopharyngeal carcinoma.
  • the recurrent and metastatic nasopharyngeal carcinoma is a recurrent and metastatic nasopharyngeal carcinoma that has failed to receive first-line or second-line platinum-containing regimens in the past.
  • the recurrent and metastatic nasopharyngeal carcinoma is one that has at least 100 patients at baseline according to RECIST 1.1 standards. 1 evaluable lesion, the area must not have received radiotherapy in the past, or there must be evidence that the lesion has significantly progressed after the end of radiotherapy.
  • Embodiment 3 The use according to embodiment 1 or 2, characterized in that the mitoxantrone liposome is mitoxantrone hydrochloride liposome.
  • Embodiment 4 The use as described in Embodiment 3, characterized in that the mitoxantrone hydrochloride liposome and capecitabine can be present in the same preparation, or can be prepared separately; when the above two drugs When prepared separately, the dosage forms may be the same or different; when the mitoxantrone hydrochloride liposome is a liquid injection, the active ingredient is 0.5-5 mg/ml, preferably 1-2 mg/ml based on mitoxantrone. , more preferably 1mg/ml; when capecitabine is in tablet form, the specification is 0.15g/tablet or 0.5g/tablet.
  • Embodiment 5 The use according to any one of embodiments 1 to 4, characterized in that the drug further contains other drugs for treating nasopharyngeal cancer.
  • Embodiment 6 A drug for treating nasopharyngeal cancer, characterized by comprising mitoxantrone liposomes and capecitabine; the mitoxantrone liposomes are preferably mitoxantrone hydrochloride liposomes;
  • the mitoxantrone hydrochloride liposomes and capecitabine can be present in the same preparation, or they can be prepared independently; when the above two drugs are prepared separately, the dosage forms can be the same or different; when the mitoxantrone hydrochloride liposomes
  • the active ingredient is 0.5-5 mg/ml based on mitoxantrone, preferably 1-2 mg/ml, and more preferably 1 mg/ml; when capecitabine is a tablet,
  • the specifications are 0.15g/piece or 0.5g/piece.
  • Embodiment 7 The drug according to Embodiment 6, characterized in that the drug further contains other drugs for treating nasopharyngeal cancer.
  • Embodiment 8 A method for treating nasopharyngeal cancer, characterized by: using effective therapeutic doses of mitoxantrone hydrochloride liposomes and capecitabine for nasopharyngeal cancer patients; Administration is preferably by injection; capecitabine is preferably administered orally; preferably, based on mitoxantrone, the effective therapeutic dose of the mitoxantrone hydrochloride liposome is 8-30 mg/m 2 , more preferably It is 12-20 mg/m 2 ; capecitabine is 1000 mg/m 2 , administered twice a day.
  • Embodiment 9 A method for improving the efficacy of capecitabine treatment for nasopharyngeal carcinoma, which is characterized by: on the basis of using capecitabine for patients with nasopharyngeal carcinoma, further combined with the use of an effective therapeutic dose of rice hydrochloride. Toxantrone liposomes.
  • Embodiment 10 A composition for treating nasopharyngeal cancer, comprising mitoxantrone hydrochloride liposome and capecitabine, characterized in that, on the first day of each dosing cycle, the nasopharyngeal cancer patients are treated in any order Administer effective therapeutic doses of mitoxantrone hydrochloride liposome and capecitabine, and continue to administer capecitabine from days 2 to 14. Preferably, the administration cycle is once every 3 weeks.
  • Embodiment 11 A drug for improving the efficacy of capecitabine treatment regimen in treating nasopharyngeal carcinoma, which is characterized in that it contains mitoxantrone hydrochloride liposome, and the mitoxantrone hydrochloride liposome is described on the first day of each administration cycle.
  • Quinone liposomes are administered at any time before and after administration of capecitabine, at a dose of 8-30 mg/m 2 , more preferably 12-20 mg/m 2 , and administered once every 3 weeks.
  • Embodiment 12 The use according to any one of embodiments 1-5, wherein the mitoxantrone liposome has one or more of the following properties:
  • the particle size of mitoxantrone hydrochloride liposomes is about 30-80nm, such as about 35-75nm, about 40-70nm, about 40-60nm or about 60nm;
  • Mitoxantrone hydrochloride forms an insoluble precipitate with multivalent counterions (such as sulfate, citrate or phosphate) in the liposome;
  • the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains a phospholipid with a phase transition temperature (Tm) higher than body temperature, so that the phase transition temperature of the liposome is higher than body temperature, for example, the phospholipid is selected from hydrogenated Soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dispalmitate lecithin, distearate lecithin, or any combination of the above;
  • the phospholipid bilayer in mitoxantrone hydrochloride liposomes contains hydrogenated soy lecithin, cholesterol and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine (DSPE-PEG2000);
  • the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains a mass ratio of approximately 3:1:1 Hydrogenated soy lecithin, cholesterol and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine, mitoxantrone hydrochloride forms an insoluble precipitate with polyvalent acid ions in the liposome, and the mitoxantrone hydrochloride
  • the particle size of the quinone liposomes in the drug is about 60 nm.
  • Embodiment 13 The medicament according to embodiments 6, 7 or 11, the method according to 8 or 9, or the composition according to claim 10, wherein the mitoxantrone liposome has one of the following One or more properties:
  • the particle size of mitoxantrone hydrochloride liposomes is about 30-80nm, such as about 35-75nm, about 40-70nm, about 40-60nm or about 60nm;
  • Mitoxantrone hydrochloride forms an insoluble precipitate with multivalent counterions (such as sulfate, citrate or phosphate) in the liposome;
  • the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains a phospholipid with a phase transition temperature (Tm) higher than body temperature, so that the phase transition temperature of the liposome is higher than body temperature, for example, the phospholipid is selected from hydrogenated Soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dispalmitate lecithin, distearate lecithin, or any combination of the above;
  • the phospholipid bilayer in mitoxantrone hydrochloride liposomes contains hydrogenated soy lecithin, cholesterol and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine (DSPE-PEG2000);
  • the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains hydrogenated soy lecithin, cholesterol and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of about 3:1:1, Mitoxantrone hydrochloride forms an insoluble precipitate with polyvalent acid ions in the liposome, and the particle size of the mitoxantrone hydrochloride liposome in the drug is about 60 nm.
  • the combined regimen of mitoxantrone liposomes and capecitabine of the present invention achieves better optimal results in the treatment of recurrent and/or metastatic nasopharyngeal carcinoma. It is effective, safe and tolerable, thus providing a new treatment option for patients with recurrent and/or metastatic nasopharyngeal carcinoma.
  • Example 1 Comparison of the follow-up of mitoxantrone hydrochloride liposome injection combined with capecitabine and capecitabine monotherapy in subjects with recurrent and/or metastatic nasopharyngeal carcinoma who failed platinum-containing regimen treatment Organized, open-label, positive-controlled, multicenter phase III clinical study
  • test drug mitoxantrone hydrochloride liposome injection
  • CSPC Zhongnuo Pharmaceutical Shijiazhuang Co., Ltd.
  • National Drug Approval No. H20220001 National Drug Approval No. H20220001
  • Capecitabine tablets are commercially available preparations.
  • This study is a randomized, open, positive-controlled, multi-center phase III clinical study.
  • the purpose is to evaluate the efficacy of mitoxantrone hydrochloride liposome injection combined with capecitabine compared with capecitabine monotherapy in relapse and/or or efficacy and safety in subjects with metastatic nasopharyngeal carcinoma.
  • This study is divided into a screening period (-28 days to 0 days), a treatment period, an end-of-treatment (EOT) visit period, and a follow-up period.
  • the enrolled population is subjects with recurrent and/or metastatic nasopharyngeal carcinoma who have failed first-line or second-line platinum-containing regimens. Qualified subjects will be stratified and randomized according to a 1:1 ratio (stratification factors: 1 ECOG score: 0 points vs. 1 point; 2 Whether there is liver metastasis: the presence of any liver metastasis vs. the absence of all liver metastases; 3 Gender: Males vs. females), entered into the experimental group and the control group respectively.
  • the experimental group received mitoxantrone hydrochloride liposome injection (20 mg/m 2 ) combined with capecitabine (1000 mg/m 2 , twice a day). Mitoxantrone hydrochloride liposome was administered on the 1st day of each cycle. It is administered every day, and capecitabine is administered from day 1 to day 14; combination therapy is administered every 3 weeks as a treatment cycle. After 8 cycles of mitoxantrone hydrochloride liposome administration, the investigator will evaluate the patient's risk-benefit ratio to decide whether to continue administration until disease progression or intolerance, while capecitabine will continue to be administered.
  • the control group received capecitabine monotherapy, administered from day 1 to day 14 of each cycle, and every 3 weeks constituted a treatment cycle. All subjects in the experimental group underwent sparse blood collection.
  • mitoxantrone hydrochloride lipids are only allowed to be reduced once per cycle. If necessary, the dose of capecitabine can be reduced during this treatment cycle.
  • IMC Independent Data Monitoring Committee
  • the investigator determines that the patient can continue to benefit from the experimental treatment, he or she can continue to receive the experimental treatment in this trial until the disease progresses as assessed by the IRC or the investigator It is judged that the patient no longer benefits.
  • ANC neutrophil count
  • Total bilirubin ⁇ 1.5 ⁇ ULN (for patients with liver metastasis, ⁇ 3 ⁇ ULN);
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • ⁇ Coagulation function prothrombin time (PT) international normalized ratio (INR) ⁇ 1.5 ⁇ ULN;
  • effective contraceptive measures such as combined hormones (including Estrogen and progesterone) combined to inhibit ovulation, progestin contraceptive combined to inhibit ovulation, intrauterine device, intrauterine hormone releasing system, bilateral fallopian tube ligation, vasectomy, avoidance of sexual intercourse, etc.
  • Active hepatitis B positive HbsAg or HBcAb and HBV DNA ⁇ 2000IU/mL
  • active hepatitis C positive HCV antibody and HCV RNA higher than the lower limit of the detection value of the research center
  • positive HIV antibody positive HIV antibody
  • Received anti-tumor treatment such as chemotherapy, small molecule inhibitors, immunotherapy (such as interleukin, interferon or thymosin) within 4 weeks or 5 half-lives (whichever is shorter but at least 2 weeks) before administration; Received treatment with proprietary Chinese medicines with anti-tumor activity within 14 days before administration;
  • immunotherapy such as interleukin, interferon or thymosin
  • Severe embolic events occurred in the past 6 months, such as cerebrovascular accidents (including transient ischemic attack) and pulmonary embolism;
  • Abnormal cardiac function including:
  • ⁇ Cardiac ejection fraction was lower than 50% or lower than the lower limit of the research center laboratory test value range in the past 6 months;
  • CTCAE5.0 version ⁇ grade 3 valvular heart disease
  • NCI CTCAE 5.0 The frequency and severity of AEs (NCI CTCAE 5.0); changes in vital signs, physical examination, electrocardiogram, and safety laboratory indicators
  • PFS progression-free survival, defined as the time between starting study drug and the date of disease progression (PD) or death, depending on which occurs first;
  • OS overall survival, defined as the time from the patient starting to take the study drug to death from any cause
  • ORR objective response rate, defined as the proportion of subjects with complete response (CR) and partial response (PR);
  • DCR disease control rate, defined as the proportion of subjects with complete response (CR), partial response (PR), and stable disease (SD);
  • DOR duration of response, defined as the time from the first assessment of CR or PR to the first assessment of PD or death from any cause.
  • a total of 5 subjects in the control group were evaluated for best response (BOR), of which 3 were PD (60%), 1 was SD (20%), and 1 was PR (20%).
  • SAE serious adverse events
  • hematological adverse events such as reduced white blood cell count, reduced neutrophil count, reduced platelet count and anemia, as well as hyponatremia, hypokalemia and pulmonary Infection, etc.
  • no serious cardiac adverse reactions were seen.
  • SAE serious adverse events
  • a total of 3 cases in the control group developed SAE, including bacterial pneumonia, severe pneumonia, and post-resuscitation syndrome from cardiac arrest.

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Abstract

一种米托蒽醌脂质体和卡培他滨在治疗鼻咽癌，尤其是复发和/或转移性鼻咽癌中的用途。本发明还提供一种治疗鼻咽癌，尤其是复发和/或转移性鼻咽癌的方法，所述方法包括对鼻咽癌患者施用治疗有效量的米托蒽醌脂质体和卡培他滨。所述米托蒽醌脂质体和卡培他滨的联合在鼻咽癌患者中实现了更好的疗效，从而为鼻咽癌患者提供了新的治疗选择。

Description

米托蒽醌脂质体联用卡培他滨治疗鼻咽癌的用途 技术领域
本发明属于抗肿瘤领域，具体涉及米托蒽醌脂质体和卡培他滨在治疗鼻咽癌，尤其是复发和/或转移性鼻咽癌中的用途。
背景技术
鼻咽癌(nasopharyngeal carcinoma，NPC)是头颈部常见恶性肿瘤，起源于鼻咽部黏膜，好发于咽隐窝，具有明显的地域高发现象，高发于我国南方、东南亚和北非地区，这些地区的年龄标准化发病率为4-25例/100,000人，是世界其他地区发病率的50-100倍。根据2020年国际癌症研究中心发布的GLOBOCAN数据，全球新发病例约133354例，超过70％病例集中在高发地区。早期鼻咽癌预后较好，5年生存率为80％-95％，但在晚期只有40％-50％。约30％的鼻咽癌患者经过首次治疗后仍会复发和/或转移，铂类药物联合吉西他滨化疗作为无法手术的复发或转移性鼻咽癌的标准一线治疗可以延长患者的生存期，中位总生存期(overall survival，OS)约为20个月(Ma SX，Zhou T，Huang Y，et al.The efficacy of first line chemotherapy in recurrent or metastatic nasopharyngeal carcinoma：a systematic review and meta analysis.Ann Transl Med，2018，6(11)：201)。
对于复发性鼻咽癌患者，只有少部分有可能再次接受根治性局部治疗如手术或放疗，大部分复发患者和转移性患者一样需要接受姑息性系统治疗或最佳支持治疗。目前针对复发或转移性鼻咽癌的标准一线治疗方案为PD-1抑制剂联合吉西他滨及顺铂。对于一线含铂方案治疗失败的患者，可用于一线化疗后病情恶化的复发性鼻咽癌患者的治疗方案很少，缺乏标准的挽救治疗方案，多鼓励患者参加临床试验，或通常选择一线未使用的药物进行单药治疗，包括吉西他滨、多西他赛、卡培他滨、特瑞普利单抗等。
综上所述，复发和/或转移性鼻咽癌的治疗棘手，特别是针对一线含铂方案治疗失败的患者，治疗药物(包括化疗、免疫治疗等)疗效欠佳，选择有限。因此，亟待探索新的治疗复发和/或转移性鼻咽癌的药物或疗法。
米托蒽醌(mitoxantrone)是一种蒽环类药物，至今已在全球30多个国家使用。其对于血液系统肿瘤如急性白血病、淋巴瘤以及多种实体肿瘤如乳腺癌等都具有治疗作用，不良反应主要表现为骨髓抑制、胃肠道反应和心脏毒性。脂质体是一种新型载药形式，研究显示，其可改变包封药物的体内分布，使药物主要在肿瘤组织中积蓄，从而提高药物的治疗指数、减少药物的治疗剂量和降低药物毒性。这些特性使得脂质体载药在抗肿瘤药物研究中的应用备受重视。有研究人员针对米托蒽醌脂质体制剂进行了研究，例如WO2008/080367A1公开了一种米托蒽醌脂质体(其公开内容在这里被全文引入作为参考)，其与游离米托蒽醌相比，具有更好的抗肿瘤效果和降低的毒性。基于米托蒽醌脂质体的这些有利的性质，预期其将在更多类型的肿瘤治疗中显示有益的效果。
发明内容
本发明的目的是提供新的治疗鼻咽癌，特别是复发和/或转移性鼻咽癌的药物和疗法，其能够提高疾病缓解率，延长生存期，并且安全耐受。
本发明涉及米托蒽醌脂质体联用卡培他滨在治疗鼻咽癌中的用途。
本发明的第一方面涉及米托蒽醌脂质体和卡培他滨在制备治疗鼻咽癌的药物中的用途。
在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌。在一些实施方案中，所述鼻咽癌为既往一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌。
在一些实施方案中，米托蒽醌脂质体和卡培他滨存在于同一制剂中。在一些实施方案中，米托蒽醌脂质体和卡培他滨各自存在于独立的制剂中。所述制剂可以是临床接受的任意一种剂型，例如注射剂型、口服剂型等。所述注射剂型包括液体注射剂、注射用粉剂、注射用片剂等；所述口服剂型包括片剂、胶囊剂、口服液体制剂等。
在一些实施方案中，米托蒽醌脂质体为注射剂，包括液体注射剂、注射用粉剂、注射用片剂等。当米托蒽醌脂质体为液体注射剂时，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
在一些实施方案中，卡培他滨为片剂，规格为0.15g/片或0.5g/片， 其中规格为0.15g/片或0.5g/片的片剂指的是：每片中含有0.15g或0.5g的卡培他滨。
在一些实施方案中，提供米托蒽醌脂质体和卡培他滨在制备治疗复发和/或转移性鼻咽癌的药物中的用途。在一些实施方案中，提供米托蒽醌脂质体和卡培他滨在制备治疗既往一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌的药物中的用途。在这些实施方案中，米托蒽醌脂质体为注射剂，以米托蒽醌计，含活性成分0.5-5mg/ml；卡培他滨为片剂，规格为0.15g/片或0.5g/片。
本发明的第二方面涉及米托蒽醌脂质体在制备改善卡培他滨治疗鼻咽癌的疗效的药物中的用途。
在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌。在一些实施方案中，所述鼻咽癌为既往一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌。
在一些实施方案中，米托蒽醌脂质体为注射剂，包括液体注射剂、注射用粉剂、注射用片剂等。当米托蒽醌脂质体为液体注射剂时，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
在一些实施方案中，卡培他滨为片剂，规格为0.15g/片或0.5g/片，其中规格为0.15g/片或0.5g/片的片剂指的是：每片中含有0.15g或0.5g的卡培他滨。
在一些实施方案中，提供米托蒽醌脂质体在制备改善卡培他滨治疗复发和/或转移性鼻咽癌的疗效的药物中的用途。在一些实施方案中，提供米托蒽醌脂质体在制备改善卡培他滨治疗既往一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌的疗效的药物中的用途。在这些实施方案中，米托蒽醌脂质体为注射剂，以米托蒽醌计，含活性成分0.5-5mg/ml；卡培他滨为片剂，规格为0.15g/片或0.5g/片。
本发明的第三方面涉及卡培他滨在制备改善米托蒽醌脂质体治疗鼻咽癌的疗效的药物中的用途。
在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌。在一些实施方案中，所述鼻咽癌为既往一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌。
在一些实施方案中，米托蒽醌脂质体为注射剂，包括液体注射剂、注射用粉剂、注射用片剂等。当米托蒽醌脂质体为液体注射剂时，以 米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
在一些实施方案中，卡培他滨为片剂，规格为0.15g/片或0.5g/片，其中规格为0.15g/片或0.5g/片的片剂指的是：每片中含有0.15g或0.5g的卡培他滨。
在一些实施方案中，提供卡培他滨在制备改善米托蒽醌脂质体治疗复发和/或转移性鼻咽癌的疗效的药物中的用途。在一些实施方案中，提供卡培他滨在制备改善米托蒽醌脂质体治疗既往一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌的疗效的药物中的用途。在这些实施方案中，米托蒽醌脂质体为注射剂，以米托蒽醌计，含活性成分0.5-5mg/ml；卡培他滨为片剂，规格为0.15g/片或0.5g/片。
本发明的第四方面涉及一种治疗鼻咽癌的方法，所述方法包括对鼻咽癌患者施用治疗有效量的米托蒽醌脂质体和卡培他滨。
本发明的第五方面涉及一种改善卡培他滨治疗鼻咽癌的疗效的方法，所述方法包括在对鼻咽癌患者施用卡培他滨的基础上，进一步联合施用治疗有效量的米托蒽醌脂质体。
本发明的第六方面涉及一种改善米托蒽醌脂质体治疗鼻咽癌的疗效的方法，所述方法包括在对鼻咽癌患者施用米托蒽醌脂质体的基础上，进一步联合施用治疗有效量的卡培他滨。
在上述第四至六方面中，包括以下实施方案。
在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌。在一些实施方案中，所述鼻咽癌为既往一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌。
在一些实施方案中，米托蒽醌脂质体注射给药。在一些实施方案中，米托蒽醌脂质体以8-30mg/m2，优选12-24mg/m2，更优选12-20mg/m2的治疗有效量注射给药。在一些实施方案中，米托蒽醌脂质体在每个给药周期的第1天给药。在一些实施方案中，米托蒽醌脂质体在每个给药周期的第1天以8-30mg/m2的治疗有效量注射给药。在一些实施方案中，米托蒽醌脂质体在每个给药周期的第1天以例如12mg/m2、14mg/m2、15mg/m2、16mg/m2、18mg/m2、20mg/m2或24mg/m2的治疗有效量注射给药。优选地，给药周期为3周。优选地，米托蒽醌脂质体经30min-120min，优选60min-120min静脉滴注给药。
在一些实施方案中，卡培他滨口服给药。在一些实施方案中，卡培 他滨以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药。在一些实施方案中，卡培他滨每天给药两次。在一些实施方案中，卡培他滨在每个给药周期的第1-14天给药。在一些实施方案中，卡培他滨以片剂形式给药。在一些实施方案中，卡培他滨在每个给药周期的第1-14天以500mg/m2、750mg/m2或1000mg/m2的剂量每天两次口服给药。在一些实施方案中，卡培他滨在每个给药周期的第1-14天以1000mg/m2的剂量每天两次以片剂形式口服给药。优选地，给药周期为3周。
在一些实施方案中，在每个给药周期中，米托蒽醌脂质体给药一次，卡培他滨连续给药14天。优选地，在每个给药周期的第1天对鼻咽癌患者按照任意先后顺序施用治疗有效量的米托蒽醌脂质体和卡培他滨，然后在第2-14天继续每天两次施用卡培他滨。在一些实施方案中，在每个给药周期的第1天以8-30mg/m2的治疗有效量注射给药米托蒽醌脂质体和以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨，然后在该周期的第2-14天继续以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨。在一些实施方案中，在每个给药周期的第1天以12-24mg/m2的治疗有效量注射给药米托蒽醌脂质体一次和以1000mg/m2的剂量口服给药卡培他滨两次，然后在该周期的第2-14天继续以1000mg/m2的剂量每天两次口服给药卡培他滨。
本发明的第七方面涉及一种用于治疗鼻咽癌的药物，所述药物包含米托蒽醌脂质体和卡培他滨。
在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌。在一些实施方案中，所述鼻咽癌为既往一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌。
在一些实施方案中，米托蒽醌脂质体和卡培他滨存在于同一制剂中。在一些实施方案中，米托蒽醌脂质体和卡培他滨各自存在于独立的制剂中。所述制剂可以是临床接受的任意一种剂型，例如注射剂型、口服剂型等。所述注射剂型包括液体注射剂、注射用粉剂、注射用片剂等；所述口服剂型包括片剂、胶囊剂、口服液体制剂等。
在一些实施方案中，米托蒽醌脂质体为注射剂，包括液体注射剂、注射用粉剂、注射用片剂等。当米托蒽醌脂质体为液体注射剂时，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
在一些实施方案中，卡培他滨为片剂，规格为0.15g/片或0.5g/片， 其中规格为0.15g/片或0.5g/片的片剂指的是：每片中含有0.15g或0.5g的卡培他滨。
在一些实施方案中，所述药物可进一步包含其他治疗鼻咽癌的药物，包括中国或其它国家和地区(例如美国、欧盟、日本、韩国等等)药物管理部门批准用于鼻咽癌治疗的药物。
在一些实施方案中，米托蒽醌脂质体注射给药。在一些实施方案中，米托蒽醌脂质体以8-30mg/m2，优选12-24mg/m2，更优选12-20mg/m2的治疗有效量注射给药。在一些实施方案中，米托蒽醌脂质体在每个给药周期的第1天给药。在一些实施方案中，米托蒽醌脂质体在每个给药周期的第1天以8-30mg/m2的治疗有效量注射给药。在一些实施方案中，米托蒽醌脂质体在每个给药周期的第1天以例如12mg/m2、14mg/m2、15mg/m2、16mg/m2、18mg/m2、20mg/m2或24mg/m2的治疗有效量注射给药。优选地，给药周期为3周。优选地，米托蒽醌脂质体经30min-120min，优选60min-120min静脉滴注给药。
在一些实施方案中，卡培他滨口服给药。在一些实施方案中，卡培他滨以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药。在一些实施方案中，卡培他滨每天给药两次。在一些实施方案中，卡培他滨在每个给药周期的第1-14天给药。在一些实施方案中，卡培他滨以片剂形式给药。在一些实施方案中，卡培他滨在每个给药周期的第1-14天以500mg/m2、750mg/m2或1000mg/m2的剂量每天两次口服给药。在一些实施方案中，卡培他滨在每个给药周期的第1-14天以1000mg/m2的剂量每天两次以片剂形式口服给药。优选地，给药周期为3周。
在一些实施方案中，在每个给药周期中，米托蒽醌脂质体给药一次，卡培他滨连续给药14天。优选地，在每个给药周期的第1天对鼻咽癌患者按照任意先后顺序施用治疗有效量的米托蒽醌脂质体和卡培他滨，然后在第2-14天继续每天两次施用卡培他滨。在一些实施方案中，在每个给药周期的第1天以8-30mg/m2的治疗有效量注射给药米托蒽醌脂质体和以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨，然后在该周期的第2-14天继续以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨。在一些实施方案中，在每个给药周期的第1天以12-24mg/m2的治疗有效量注射给药米托蒽醌脂质体一次和以1000mg/m2的剂量口服给药卡培他滨两次，然后在该周期的第2-14天继续以 1000mg/m2的剂量每天两次口服给药卡培他滨。
本发明的第八方面涉及一种用于改善卡培他滨治疗鼻咽癌的疗效的药物，所述药物包含米托蒽醌脂质体。
本发明的第九方面涉及一种用于改善米托蒽醌脂质体治疗鼻咽癌的疗效的药物，所述药物包含卡培他滨。
在上述第八和九方面中，包括以下实施方案。
在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌。在一些实施方案中，所述鼻咽癌为既往一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌。
在一些实施方案中，米托蒽醌脂质体为注射剂，包括液体注射剂、注射用粉剂、注射用片剂等。当米托蒽醌脂质体为液体注射剂时，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
在一些实施方案中，卡培他滨为片剂，规格为0.15g/片或0.5g/片，其中规格为0.15g/片或0.5g/片的片剂指的是：每片中含有0.15g或0.5g的卡培他滨。
在一些实施方案中，米托蒽醌脂质体注射给药。在一些实施方案中，米托蒽醌脂质体以8-30mg/m2，优选12-24mg/m2，更优选12-20mg/m2的治疗有效量注射给药。在一些实施方案中，米托蒽醌脂质体在每个给药周期的第1天给药。在一些实施方案中，米托蒽醌脂质体在每个给药周期的第1天以8-30mg/m2的治疗有效量注射给药。在一些实施方案中，米托蒽醌脂质体在每个给药周期的第1天以例如12mg/m2、14mg/m2、15mg/m2、16mg/m2、18mg/m2、20mg/m2或24mg/m2的治疗有效量注射给药。优选地，给药周期为3周。优选地，米托蒽醌脂质体经30min-120min，优选60min-120min静脉滴注给药。
在一些实施方案中，卡培他滨口服给药。在一些实施方案中，卡培他滨以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药。在一些实施方案中，卡培他滨每天给药两次。在一些实施方案中，卡培他滨在每个给药周期的第1-14天给药。在一些实施方案中，卡培他滨以片剂形式给药。在一些实施方案中，卡培他滨在每个给药周期的第1-14天以500mg/m2、750mg/m2或1000mg/m2的剂量每天两次口服给药。在一些实施方案中，卡培他滨在每个给药周期的第1-14天以1000mg/m2的剂量每天两次以片剂形式口服给药。优选地，给药周期为3周。
在一些实施方案中，在每个给药周期中，米托蒽醌脂质体给药一次，卡培他滨连续给药14天。优选地，在每个给药周期的第1天对鼻咽癌患者按照任意先后顺序施用治疗有效量的米托蒽醌脂质体和卡培他滨，然后在第2-14天继续每天两次施用卡培他滨。在一些实施方案中，在每个给药周期的第1天以8-30mg/m2的治疗有效量注射给药米托蒽醌脂质体和以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨，然后在该周期的第2-14天继续以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨。在一些实施方案中，在每个给药周期的第1天以12-24mg/m2的治疗有效量注射给药米托蒽醌脂质体一次和以1000mg/m2的剂量口服给药卡培他滨两次，然后在该周期的第2-14天继续以1000mg/m2的剂量每天两次口服给药卡培他滨。
本发明的第十方面涉及一种用于治疗鼻咽癌的组合物，所述组合物包含米托蒽醌脂质体和卡培他滨。
本发明的第十一方面涉及一种用于治疗鼻咽癌的药物组合，所述药物组合包含米托蒽醌脂质体和卡培他滨。
在上述第十和十一方面中，包括以下实施方案。
在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌。在一些实施方案中，所述鼻咽癌为既往一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌。
在一些实施方案中，米托蒽醌脂质体为注射剂，包括液体注射剂、注射用粉剂、注射用片剂等。当米托蒽醌脂质体为液体注射剂时，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
在一些实施方案中，卡培他滨为片剂，规格为0.15g/片或0.5g/片，其中规格为0.15g/片或0.5g/片的片剂指的是：每片中含有0.15g或0.5g的卡培他滨。
在一些实施方案中，米托蒽醌脂质体注射给药。在一些实施方案中，米托蒽醌脂质体以8-30mg/m2，优选12-24mg/m2，更优选12-20mg/m2的治疗有效量注射给药。在一些实施方案中，米托蒽醌脂质体在每个给药周期的第1天给药。在一些实施方案中，米托蒽醌脂质体在每个给药周期的第1天以8-30mg/m2的治疗有效量注射给药。在一些实施方案中，米托蒽醌脂质体在每个给药周期的第1天以例如12mg/m2、14mg/m2、15mg/m2、16mg/m2、18mg/m2、20mg/m2或24mg/m2的治疗 有效量注射给药。优选地，给药周期为3周。优选地，米托蒽醌脂质体经30min-120min，优选60min-120min静脉滴注给药。
在一些实施方案中，卡培他滨口服给药。在一些实施方案中，卡培他滨以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药。在一些实施方案中，卡培他滨每天给药两次。在一些实施方案中，卡培他滨在每个给药周期的第1-14天给药。在一些实施方案中，卡培他滨以片剂形式给药。在一些实施方案中，卡培他滨在每个给药周期的第1-14天以500mg/m2、750mg/m2或1000mg/m2的剂量每天两次口服给药。在一些实施方案中，卡培他滨在每个给药周期的第1-14天以1000mg/m2的剂量每天两次以片剂形式口服给药。优选地，给药周期为3周。
在一些实施方案中，在每个给药周期中，米托蒽醌脂质体给药一次，卡培他滨连续给药14天。优选地，在每个给药周期的第1天对鼻咽癌患者按照任意先后顺序施用治疗有效量的米托蒽醌脂质体和卡培他滨，然后在第2-14天继续每天两次施用卡培他滨。在一些实施方案中，在每个给药周期的第1天以8-30mg/m2的治疗有效量注射给药米托蒽醌脂质体和以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨，然后在该周期的第2-14天继续以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨。在一些实施方案中，在每个给药周期的第1天以12-24mg/m2的治疗有效量注射给药米托蒽醌脂质体一次和以1000mg/m2的剂量口服给药卡培他滨两次，然后在该周期的第2-14天继续以1000mg/m2的剂量每天两次口服给药卡培他滨。
本发明的第十二方面涉及一种用于治疗鼻咽癌的试剂盒，所述试剂盒包含米托蒽醌脂质体和卡培他滨。
在一些实施方案中，所述鼻咽癌为复发和/或转移性鼻咽癌。在一些实施方案中，所述鼻咽癌为既往一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌。
在一些实施方案中，米托蒽醌脂质体和卡培他滨各自为独立制剂。
在一些实施方案中，米托蒽醌脂质体为注射剂，包括液体注射剂、注射用粉剂、注射用片剂等。当米托蒽醌脂质体为液体注射剂时，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
在一些实施方案中，卡培他滨为片剂，规格为0.15g/片或0.5g/片，其中规格为0.15g/片或0.5g/片的片剂指的是：每片中含有0.15g或0.5g的 卡培他滨。
在上述各方面中，卡培他滨可以以药物制剂，例如片剂的形式提供。这样的药物制剂是市售可得的。
在上述各方面中，“米托蒽醌”包括米托蒽醌及其药学上可接受的盐，优选米托蒽醌盐酸盐。米托蒽醌脂质体优选为盐酸米托蒽醌脂质体。
在上述各方面中，对米托蒽醌脂质体无特别限制。不被任何特定理论所束缚，本申请的发明人发现以下一项或多项性质对于米托蒽醌脂质体制剂是有利的：
(i)米托蒽醌脂质体为盐酸米托蒽醌脂质体；
(ii)米托蒽醌脂质体的粒径为约30-80nm，例如约35-75nm、约40-70nm、约40-60nm或约60nm；例如约30、35、40、45、50、55、60、65、70、75或80nm。粒径测定的方式有多种，包括但不限于NanoZS；
(iii)米托蒽醌与脂质体内的多价反离子(例如硫酸根、柠檬酸根或磷酸根)形成难以溶解的沉淀；
(iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，从而脂质体的相转变温度高于体温。所述磷脂包括但不限于氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合；
(v)米托蒽醌脂质体中的磷脂双分子层含有氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PEG2000)；
(vi)米托蒽醌脂质体中的磷脂双分子层含有质量比为约3∶1∶1的氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，盐酸米托蒽醌与脂质体内的多价反离子形成难以溶解的沉淀，并且盐酸米托蒽醌脂质体的粒径为约60nm；
(vii)采用中国专利申请200610102339.8号或PCT申请WO2008/080367A1公开的方法制备的米托蒽醌脂质体制剂；和
(viii)米托蒽醌脂质体为国药准字H20220001的米托蒽醌脂质体。
优选地，所述米托蒽醌脂质体满足以下一项或多项：
(i)所述米托蒽醌脂质体为盐酸米托蒽醌脂质体；
(ii)米托蒽醌脂质体的粒径为30-80nm；
(iii)米托蒽醌与脂质体内的多价反离子形成难以溶解的沉淀；和
(iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，其选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合。
优选地，所述米托蒽醌脂质体为盐酸米托蒽醌脂质体。所述米托蒽醌脂质体或盐酸米托蒽醌脂质体的治疗有效量或剂量均以米托蒽醌计。
所述米托蒽醌脂质体可以采用本领域常规方法制备，也可以采用现有技术公开的任意一种方法制备，例如采用WO2008/080367 A1公开的方法制备，该专利公开的内容在此被全文引入作为参考。作为非限制性的实例，本申请的盐酸米托蒽醌脂质体制剂可以按照以下方法制备，其中“脂药比”是指脂质体中磷脂双分子层的组成成分(包含HSPC、DSPE-PEG2000和Chol)与米托蒽醌的质量比：
将氢化大豆卵磷脂(HSPC)、胆固醇(Chol)和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PEG2000)按照3∶1∶1的质量比称重，溶解于95％乙醇中，得到澄明溶液(即磷脂的乙醇溶液)。将磷脂的乙醇溶液与300mM的硫酸铵溶液混合，在60-65℃震荡水化1h，得到不均匀的多室脂质体，之后使用微射流设备降低脂质体的粒度。将所获得的样品用浓度0.9％的NaCl溶液稀释200倍后，用NanoZS进行检测，粒子的平均粒度约为60nm，主峰集中在40-60nm之间。之后使用超滤装置移去空白脂质体外相的硫酸铵，将外相置换成290mM蔗糖及10mM甘氨酸，以便形成跨膜硫酸铵梯度。按照脂药比16∶1的比例，在空白脂质体中加入盐酸米托蒽醌溶液(以米托蒽醌计，10mg/mL)，在60-65℃进行载药。孵育约1h后，使用凝胶排阻色谱可证明包封效率约为100％。由此得到的产品被命名为PLM60。PLM60中HSPC∶Chol∶DSPE-PEG2000∶米托蒽醌的重量比为9.58∶3.19∶3.19∶1，蔗糖甘氨酸溶液的渗透压与生理值接近。
应当理解的是，上述示例性制备方法中的多个技术细节和参数可以由本领域技术人员在合理的范围内进行调试和确定。例如，用于形成跨膜硫酸铵梯度的外相中的甘氨酸可替换的氨基酸种类包括但不限于组氨酸、天冬酰胺、谷氨酸、亮氨酸、脯氨酸、丙氨酸。再例如，HSPC、Chol和DSPE-PEG2000的质量比可以进行适当的调整。还例如，对于制备具体脂质体药物制剂中的脂药比参数，本领域技术人员可以设计、 测试并最终得出合适的脂药比，以尽量提高载药量同时减少药物漏出量。对于本申请的盐酸米托蒽醌脂质体制剂而言，可以使用的脂药比是宽范围的，例如低至2∶1或高至30∶1、40∶1或50∶1，更为适合的脂药比可以为约(15-20)∶1，例如约15∶1、16∶1、17∶1、18∶1、19∶1或20∶1。因此，上文描述的盐酸米托蒽醌脂质体制剂的数点有利性质是更为重要的，实现这些性质的方法学是多样的。
在本发明的上下文中，除非另有定义，否则所使用的所有科技术语具有本领域普通技术人员所理解的相同含义。
本文使用的术语“包含(或其等同术语例如“包括”、“含有”等)”包括“由......组成”的情况，除非另外说明。
本文使用的术语“组合物”表示两种或更多种活性成分的组合，其中各活性成分可存在于同一制剂中一起施用，或者各活性成分可以存在于不同的制剂中，以相同或不同的施用方式同时或相继施用。在此意义上，“组合物”和“组合”可互换使用。
本文使用的术语“治疗有效量”或“有效量”是指在治疗的对象中显示期望益处的剂量。“治疗有效量”或“有效量”将取决于接受治疗的对象的种属、疾病的严重程度、施用频率、药物的代谢特征等因素，并可由处方医师根据常规实践来判断。需要注意的是，本申请中提及的所有数值范围均包括该范围的两个端点、该范围之内的所有数值以及由其中任意两个数值形成的子范围。
本文使用的术语“治疗”是指控制、减轻或缓解疾病的病理学进展和延长患病对象的存活期。
本文使用的术语“对象”、“受试者”、“患者”包括预期要对其施用本申请的药物或组合物的动物个体，包括但不限于人类和其它哺乳动物，例如小鼠、大鼠、猫、猴子、狗、马、猪等。优选地，所述对象是人类。除非标明，否则术语“对象”、“受试者”、“患者”可以互换使用。
本文使用的术语“复发性鼻咽癌”是指病理确诊的鼻咽癌在根治性放疗后临床肿瘤全消，治疗结束6个月以后，局部或区域再次出现与原肿瘤病理类型相同的肿瘤。
本文使用的术语“转移性鼻咽癌”是指存在远处转移的鼻咽癌。
本文使用的术语“按照任意先后顺序施用”是指米托蒽醌脂质体和 卡培他滨的单独的制剂以临床可接受的方式分别给药，对给药的先后顺序无强制规定，各药物在体外不发生混合。
本发明的另外的实施方案
实施方案1.米托蒽醌脂质体和卡培他滨在制备治疗鼻咽癌的药物中的用途，优选地，所述鼻咽癌为复发转移性鼻咽癌，优选地，所述复发转移性鼻咽癌为既往接受过一线或二线含铂方案治疗失败的复发转移性鼻咽癌，再优选地，所述复发转移性鼻咽癌为根据RECIST 1.1标准，基线至少有1个可评估病灶，该区域既往必须没有接受过放疗，或者有证据表明该病灶在放疗结束后明显进展。
实施方案2.米托蒽醌脂质体在制备改善卡培他滨治疗方案治疗鼻咽癌的疗效的药物中的用途，优选地，所述鼻咽癌为复发转移性鼻咽癌，优选地，所述复发转移性鼻咽癌为既往接受过一线或二线含铂方案治疗失败的复发转移性鼻咽癌，再优选地，所述复发转移性鼻咽癌为根据RECIST 1.1标准，基线至少有1个可评估病灶，该区域既往必须没有接受过放疗，或者有证据表明该病灶在放疗结束后明显进展。
实施方案3.如实施方案1或2所述的用途，其特征在于，所述米托蒽醌脂质体为盐酸米托蒽醌脂质体。
实施方案4.如实施方案3所述的用途，其特征在于，所述盐酸米托蒽醌脂质体和卡培他滨可以存在于同一制剂中，也可分别独立制剂；当上述2种药物分别制剂时，剂型可以相同，也可以不同；当所述盐酸米托蒽醌脂质体为液体注射剂时，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml；当卡培他滨为片剂时，规格为0.15g/片或0.5g/片。
实施方案5.如实施方案1-4任一所述的用途，其特征在于，所述药物中进一步包含其他治疗鼻咽癌的药物。
实施方案6.一种治疗鼻咽癌的药物，其特征在于，包含米托蒽醌脂质体和卡培他滨；所述米托蒽醌脂质体优选盐酸米托蒽醌脂质体；所述盐酸米托蒽醌脂质体和卡培他滨可以存在于同一制剂中，也可分别独立制剂；当上述2种药物分别制剂时，剂型可以相同，也可以不同；当所述盐酸米托蒽醌脂质体为液体注射剂时，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml；当卡培他滨为片剂时，规格为0.15g/片或0.5g/片。
实施方案7.如实施方案6所述的药物，其特征在于，所述药物中进一步包含其他治疗鼻咽癌的药物。
实施方案8.一种治疗鼻咽癌的方法，其特征在于：对鼻咽癌患者使用有效治疗剂量的盐酸米托蒽醌脂质体和卡培他滨；盐酸米托蒽醌脂质体的施用优选注射给药；卡培他滨优选口服给药；优选的，以米托蒽醌计，所述盐酸米托蒽醌脂质体的有效治疗剂量是指8-30mg/m2，更优选为12-20mg/m2；卡培他滨为1000mg/m2，每天给药2次。
实施方案9.一种改善卡培他滨治疗方案对鼻咽癌的疗效的方法，其特征在于：在对鼻咽癌患者使用卡培他滨的基础上，进一步联合使用有效治疗剂量的盐酸米托蒽醌脂质体。
实施方案10.一种治疗鼻咽癌的组合物，包含盐酸米托蒽醌脂质体和卡培他滨，其特征在于，每个给药周期第一天对鼻咽癌患者按照任意先后顺序施用有效治疗剂量的盐酸米托蒽醌脂质体和卡培他滨，第2-14天继续施用卡培他滨，优选的，给药周期为每3周给药一次。
实施方案11.一种改善卡培他滨治疗方案治疗鼻咽癌的疗效的药物，其特征在于，含有盐酸米托蒽醌脂质体，每个给药周期第一天所述盐酸米托蒽醌脂质体在卡培他滨给药前、后的任意时间施用，剂量为8-30mg/m2，更优选为12-20mg/m2，每3周给药一次。
实施方案12.根据实施方案1-5任一项所述的用途，其中，所述米托蒽醌脂质体具有以下一项或多项性质：
(i)盐酸米托蒽醌脂质体的粒径为约30-80nm，例如约35-75nm、约40-70nm、约40-60nm或约60nm；
(ii)盐酸米托蒽醌与脂质体内的多价反离子(例如硫酸根、柠檬酸根或磷酸根)形成难以溶解的沉淀；
(iii)盐酸米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，从而脂质体的相转变温度高于体温，例如，所述磷脂选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合；
(iv)盐酸米托蒽醌脂质体中的磷脂双分子层含有氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PEG2000)；
(v)盐酸米托蒽醌脂质体中的磷脂双分子层含有质量比为约3∶1∶1 的氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，盐酸米托蒽醌与脂质体内的多价酸根离子形成难以溶解的沉淀，并且所述盐酸米托蒽醌脂质体在所述药物中的粒径为约60nm。
实施方案13.根据实施方案6、7或11所述的药物，8或9所述的方法，或根据权利要求10所述的组合物，其中，所述米托蒽醌脂质体具有以下一项或多项性质：
(i)盐酸米托蒽醌脂质体的粒径为约30-80nm，例如约35-75nm、约40-70nm、约40-60nm或约60nm；
(ii)盐酸米托蒽醌与脂质体内的多价反离子(例如硫酸根、柠檬酸根或磷酸根)形成难以溶解的沉淀；
(iii)盐酸米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，从而脂质体的相转变温度高于体温，例如，所述磷脂选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合；
(iv)盐酸米托蒽醌脂质体中的磷脂双分子层含有氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PEG2000)；
(v)盐酸米托蒽醌脂质体中的磷脂双分子层含有质量比为约3∶1∶1的氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，盐酸米托蒽醌与脂质体内的多价酸根离子形成难以溶解的沉淀，并且所述盐酸米托蒽醌脂质体在所述药物中的粒径为约60nm。
有益效果
与卡培他滨单药治疗方案相比，本发明的米托蒽醌脂质体与卡培他滨的联合方案在复发和/或转移性鼻咽癌的治疗中实现了更好的最佳疗效，且安全耐受，从而为复发和/或转移性鼻咽癌患者提供了新的治疗选择。
具体实施方式
以下实施例旨在对本发明进行具体说明，而不应解释为对本发明的范围构成限制。
实施例1比较盐酸米托蒽醌脂质体注射液联合卡培他滨与卡培他滨单药用于含铂方案治疗失败的复发和/或转移性鼻咽癌受试者的随 机、开放、阳性对照、多中心III期临床研究
受试药盐酸米托蒽醌脂质体注射液由石药集团中诺药业(石家庄)有限公司提供(国药准字H20220001)，1.0mg/ml。
卡培他滨片为市售制剂。
(一)研究目的
本研究是一项随机、开放、阳性对照、多中心的III期临床研究，目的是评价盐酸米托蒽醌脂质体注射液联合卡培他滨对比卡培他滨单药治疗在复发和/或转移性鼻咽癌受试者中的有效性与安全性。
(二)研究方法
1.研究设计
本研究分为筛选期(-28天至0天)、治疗期、治疗结束(EOT)访视期和随访期。
入组人群为一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌受试者。对筛选合格的受试者，按照1∶1比例进行分层随机(分层因素：①ECOG评分：0分vs1分；②是否存在肝转移：存在任何肝转移vs不存在所有肝转移；③性别：男性vs女性)，分别进入到试验组和对照组。
试验组接受盐酸米托蒽醌脂质体注射液(20mg/m2)联合卡培他滨(1000mg/m2，一天两次)治疗，盐酸米托蒽醌脂质体在每周期的第1天给药，卡培他滨在第1天至第14天给药；联合治疗每3周为一个治疗周期。盐酸米托蒽醌脂质体给药8周期后将由研究者评估患者风险获益比来决定是否继续给药至疾病进展或不能耐受，卡培他滨持续用药。对照组接受卡培他滨单药治疗，每周期第1天至第14天给药，每3周为一个治疗周期。试验组受试者均进行稀疏采血。
最低允许减量原则详见表1。如果需要更多的减量，则必须中止研究药物。一旦减了剂量，则其后所有周期给药应维持减量后的剂量水平，或者在必要时进一步减量。本研究中不能增加剂量。
如果受试者在给药后出现以下试验用药品相关不良事件的发生情况，经研究者评估后米托蒽醌可在下一治疗周期减量，每周期只允许下调一次盐酸米托蒽醌脂质体剂量水平，如必要，卡培他滨可在本治疗周期内减量。
表1剂量调整方案
研究期间独立数据监查委员会(IDMC)将在前40例入组的患者(每组约20例)治疗两个周期之后以及整个研究过程中，进行安全性评估。在安全评估期间，入组继续进行。所有受试者用药直至根据RECIST1.1标准判断的疾病进展、不可耐受的毒性、受试者撤回知情同意书、开始新的抗肿瘤治疗、失访、死亡或研究结束，以先发生者为准。在研究者首次判断患者疾病进展后如果患者没有更多治疗选择，经研究者判断患者可以继续从试验治疗中获益，则可以继续在本试验中接受试验治疗直至IRC评估的疾病进展或研究者判断患者不再获益。
2.试验人群：
2.1入选标准：
符合下列全部标准的患者方可入选本研究：
1)受试者自愿参加研究，并签署知情同意书；
2)年龄≥18周岁
3)经病理组织学确诊的鼻咽癌；
4)既往一线或二线含铂方案治疗失败的复发和/或转移性鼻咽癌；
5)根据RECIST 1.1标准，基线至少有1个可评估病灶；
6)ECOG评分0～1；
7)既往抗肿瘤治疗毒性恢复至≤1级(脱发、色素沉着或研究中认为对受试者无安全性风险的其他毒性除外)；
8)受试者实验室检查数值符合以下要求(在筛选期样本采集前≤14天内无需输血或生长因子治疗便可达到以下指标)：
●中性粒细胞绝对值(ANC)≥1.5×109/L；
●血红蛋白(Hb)≥9.0g/dL；
●血小板≥90×109/L；
●肌酐≤1.5×ULN；
●总胆红素≤1.5×ULN(对肝转移患者，≤3×ULN)；
●丙氨酸氨基转移酶(ALT)/天冬氨酸氨基转移酶(AST)≤2.5 ×ULN(对肝转移患者，≤5×ULN)；
●凝血功能：凝血酶原时间(PT)国际标准化比值(INR)≤1.5×ULN；
9)女性受试者血HCG阴性(绝经和子宫切除除外)，育龄期女性受试者及其伴侣在试验期间和末次用药结束后6个月内采取有效的避孕措施(例如：联合激素(含雌激素和孕激素)结合抑制排卵、孕激素避孕结合抑制排卵、宫内节育器、宫内激素释放系统、双侧输卵管结扎术、输精管切除术、避免性行为等)；
10)男性受试者及其伴侣同意采取第9条中所述的避孕措施之一。
2.2排除标准：
符合下列任何一项排除标准，不可入选本研究：
1)对米托蒽醌或脂质体有严重过敏；既往对氟尿嘧啶类有严重、非预期的反应或已知对氟尿嘧啶类过敏；
2)活动性软脑膜疾病或未能良好控制的脑转移。可疑的脑转移或确诊的脑转移患者如无明显症状，且研究药物首次给药前≥28天影像学结果显示疾病稳定，无需进行治疗(如放疗、手术或皮质类固醇治疗)以控制脑转移的症状，则允许入组；
3)预计生存时间＜3个月；
4)活动性乙型肝炎(HbsAg或HBcAb阳性且HBV DNA≥2000IU/mL)、活动性丙型肝炎(HCV抗体阳性且HCV RNA高于研究中心检测值下限)、HIV抗体阳性；
5)研究药物给药前1周内患有需要系统治疗的活动性细菌感染、真菌感染、病毒感染或间质性肺炎；
6)给药前4周或5个半衰期(以较短者为准但至少2周)内接受过化疗、小分子抑制剂、免疫治疗(如白介素、干扰素或胸腺素)等抗肿瘤治疗；给药前14天内接受过有抗肿瘤活性的中成药治疗；
7)在首次给药前4周内接受过其它临床研究药物治疗；
8)在首次给药前3个月内接受过重大手术，或者计划在研究期间进行重大手术者；
9)在过去6个月内出现严重栓塞事件，例如脑血管意外(包括短暂性脑缺血发作)、肺栓塞；
10)首次给药前2年内患有活动性恶性肿瘤，除外本试验中研究的 鼻咽癌以及任何已经接受过根治性治疗的的局部可治愈性的肿瘤(例如已切除的基底细胞或鳞状细胞皮肤癌、浅表性膀胱癌、宫颈或乳腺原位癌)；
11)心脏功能异常，包括：
●长QTc综合征或QTc间期＞480毫秒；
●完全性左束支传导阻滞，II度或III度房室传导阻滞；
●需要药物治疗的严重、未控制的心律失常；
●慢性充血性心力衰竭病史，且NYHA≥3级；
●既往6个月内心脏射血分数低于50％或低于研究中心实验室检查值范围下限；
●CTCAE5.0版≥3级的心脏瓣膜病；
●不可控的高血压(定义为在药物控制情况下，测量收缩压＞160mmHg或舒张压＞90mmHg)；
●在筛选前6个月内出现心肌梗死、不稳定心绞痛、严重的心包疾病病史、有急性缺血性或活动性传导系异常的心电图证据；
12)曾接受过阿霉素或其他蒽环类治疗，且阿霉素累积剂量超过350mg/m2(蒽环类等效剂量计算：1mg阿霉素＝2mg表柔比星＝2mg柔红霉素＝0.5mg去甲氧柔红霉素＝0.45mg米托蒽醌)；
13)怀孕或哺乳期妇女；
14)患有任何严重的和/或不可控制的疾病，经研究者判定，可能影响患者参加本研究的其他疾病(包括但不限于，未得到有效控制的糖尿病、需要透析的肾脏疾病、严重的肝脏疾病、危及生命的自身免疫系统疾病和出血性疾病、药物滥用、神经系统疾病等)；
15)其他研究者判定不适宜参加的情况。
3.评价标准
主要研究终点：
●独立评审委员会(IRC)评估的无进展生存期(PFS)
●总生存期(OS)
次要研究终点：
●研究者和IRC评估的客观缓解率(ORR)，疾病控制率(DCR)和缓解持续时间(DOR)
●研究者评估的无进展生存期(PFS)
●AE发生的频率和严重程度(NCI CTCAE 5.0)；生命体征、体格检查、心电图、安全性实验室指标的变化
●总米托蒽醌与游离米托蒽醌血药浓度。
注：上述各缩写含义如下：
PFS：无进展生存期，定义为开始使用研究药物至疾病进展(PD)或死亡日期之间的时间，取决于哪一个首先发生；
OS：总生存期，定义为患者开始使用研究药物至任何原因引起死亡的时间；
ORR：客观缓解率，定义为完全缓解(CR)和部分缓解(PR)的受试者所占的比例；
DCR：疾病控制率，定义为完全缓解(CR)、部分缓解(PR)和疾病稳定(SD)的受试者所占的比例；
DOR：缓解持续时间，定义为第一次评估为CR或PR开始到第一次评估为PD或任何原因死亡的时间。
(三)研究结果
截至2023年7月31日，本研究共入组62例，其中试验组32例，对照组30例；出组4例(对照组1例撤回知情，2例死亡；试验组1例死亡)，在组58例。
1.受试者基线特征
在试验组的32例受试者中，56.9％为转移性鼻咽癌患者，18.8％为复发性鼻咽癌患者，34.4％为复发和转移性鼻咽癌患者；在对照组的30例受试者中，30％为转移性鼻咽癌患者，13.3％为复发性鼻咽癌患者，56.7％为复发和转移性鼻咽癌患者(详见表2)。
表2受试者基线特征

2.疗效评价
截至2023年7月31日，试验组中共9例受试者进行了最佳疗效(BOR)评价，其中1例为PD(11.1％)，3例为SD(33.3％)，5例为PR(55.6％)。
表3试验组最佳疗效评价

对照组中共5例受试者进行了最佳疗效(BOR)评价，其中3例为PD(60％)，1例为SD(20％)，1例为PR(20％)。
表4对照组最佳疗效评价

由上述结果可见，米托蒽醌脂质体联合卡培他滨治疗复发和/或转移性鼻咽癌的疗效优于卡培他滨单药治疗。
3.安全性评价
试验组中共9例发生严重不良事件(SAE)，包括血液学不良事件，例如白细胞计数降低、中性粒细胞计数降低、血小板计数降低和贫血，以及低钠血症、低钾血症和肺部感染等，未见严重心脏不良反应。对照组中共3例发生SAE，包括细菌性肺炎、重症肺炎、心脏停搏复苏后综合征等。
表5对照组和试验组SAE概况表

Claims (49)

  1. 米托蒽醌脂质体和卡培他滨在制备治疗鼻咽癌的药物中的用途。
  2. 米托蒽醌脂质体在制备改善卡培他滨治疗鼻咽癌的疗效的药物中的用途。
  3. 如权利要求1或2所述的用途，其中所述鼻咽癌为复发和/或转移性鼻咽癌，优选地，所述复发和/或转移性鼻咽癌为既往接受过一线或二线含铂方案治疗的复发和/或转移性鼻咽癌。
  4. 如权利要求1-3中任一项所述的用途，其中所述米托蒽醌脂质体满足以下一项或多项：
    (i)米托蒽醌脂质体为盐酸米托蒽醌脂质体；
    (ii)米托蒽醌脂质体的粒径为约30-80nm，例如约35-75nm、约40-70nm、约40-60nm或约60nm；
    (iii)米托蒽醌与脂质体内的多价反离子例如硫酸根、柠檬酸根或磷酸根形成难以溶解的沉淀；和
    (iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，其选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合，优选选自氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，更优选为质量比为约3∶1∶1的氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺。
  5. 如权利要求1-4中任一项所述的用途，其中所述米托蒽醌脂质体为盐酸米托蒽醌脂质体。
  6. 如权利要求1-5中任一项所述的用途，其中所述米托蒽醌脂质体为液体注射剂，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
  7. 如权利要求1-6中任一项所述的用途，其中卡培他滨为片剂。
  8. 如权利要求1-7中任一项所述的用途，其中所述药物进一步包含其他治疗鼻咽癌的药物。
  9. 一种用于治疗鼻咽癌的药物，其包含米托蒽醌脂质体和卡培他滨。
  10. 一种用于改善卡培他滨治疗鼻咽癌的疗效的药物，其包含米托 蒽醌脂质体。
  11. 如权利要求9或10所述的药物，其中所述鼻咽癌为复发和/或转移性鼻咽癌，优选地，所述复发和/或转移性鼻咽癌为既往接受过一线或二线含铂方案治疗的复发和/或转移性鼻咽癌。
  12. 如权利要求9-11中任一项所述的药物，其中所述米托蒽醌脂质体满足以下一项或多项：
    (i)米托蒽醌脂质体为盐酸米托蒽醌脂质体；
    (ii)米托蒽醌脂质体的粒径为约30-80nm，例如约35-75nm、约40-70nm、约40-60nm或约60nm；
    (iii)米托蒽醌与脂质体内的多价反离子例如硫酸根、柠檬酸根或磷酸根形成难以溶解的沉淀；和
    (iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，其选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合，优选选自氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，更优选为质量比为约3∶1∶1的氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺。
  13. 如权利要求9-12中任一项所述的药物，其中所述米托蒽醌脂质体为盐酸米托蒽醌脂质体。
  14. 如权利要求9-13中任一项所述的药物，其中所述米托蒽醌脂质体为液体注射剂，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
  15. 如权利要求9-14中任一项所述的药物，其中卡培他滨为片剂。
  16. 如权利要求9-15中任一项所述的药物，其中米托蒽醌脂质体注射给药，优选地，米托蒽醌脂质体在每个给药周期的第1天以8-30mg/m2，优选12-24mg/m2，更优选12-20mg/m2的治疗有效量注射给药。
  17. 如权利要求9-16中任一项所述的药物，其中卡培他滨口服给药，优选地，卡培他滨在每个给药周期的第1-14天以500mg/m2、750mg/m2或1000mg/m2的剂量每天两次口服给药。
  18. 如权利要求9-17中任一项所述的药物，其中所述治疗包括在每个给药周期的第1天以8-30mg/m2的治疗有效量注射给药米托蒽醌脂质体和以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨， 然后在该周期的第2-14天继续以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨。
  19. 如权利要求9-18中任一项所述的药物，其中所述治疗包括在每个给药周期的第1天以20mg/m2的治疗有效量注射给药米托蒽醌脂质体一次和以1000mg/m2的剂量口服给药卡培他滨两次，然后在该周期的第2-14天继续以1000mg/m2的剂量每天两次口服给药卡培他滨。
  20. 如权利要求16-19中任一项所述的药物，其中所述给药周期为三周。
  21. 如权利要求9-20中任一项所述的药物，其中所述药物进一步包含其他治疗鼻咽癌的药物。
  22. 一种治疗鼻咽癌的方法，其包括对鼻咽癌患者施用治疗有效量的米托蒽醌脂质体和卡培他滨。
  23. 一种改善卡培他滨治疗鼻咽癌的疗效的方法，其包括在对鼻咽癌患者施用卡培他滨的基础上，进一步联合施用治疗有效量的米托蒽醌脂质体。
  24. 如权利要求22或23所述的方法，其中所述鼻咽癌为复发和/或转移性鼻咽癌，优选地，所述复发和/或转移性鼻咽癌为既往接受过一线或二线含铂方案治疗的复发和/或转移性鼻咽癌。
  25. 如权利要求22-24中任一项所述的方法，其中所述米托蒽醌脂质体满足以下一项或多项：
    (i)米托蒽醌脂质体为盐酸米托蒽醌脂质体；
    (ii)米托蒽醌脂质体的粒径为约30-80nm，例如约35-75nm、约40-70nm、约40-60nm或约60nm；
    (iii)米托蒽醌与脂质体内的多价反离子例如硫酸根、柠檬酸根或磷酸根形成难以溶解的沉淀；和
    (iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，其选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合，优选选自氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，更优选为质量比为约3∶1∶1的氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺。
  26. 如权利要求22-25中任一项所述的方法，其中所述米托蒽醌脂 质体为盐酸米托蒽醌脂质体。
  27. 如权利要求22-26中任一项所述的方法，其中所述米托蒽醌脂质体为液体注射剂，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
  28. 如权利要求22-27中任一项所述的方法，其中卡培他滨为片剂。
  29. 如权利要求22-28中任一项所述的方法，其中米托蒽醌脂质体注射给药，优选地，米托蒽醌脂质体在每个给药周期的第1天以8-30mg/m2，优选12-24mg/m2，更优选12-20mg/m2的治疗有效量注射给药。
  30. 如权利要求22-29中任一项所述的方法，其中卡培他滨口服给药，优选地，卡培他滨在每个给药周期的第1-14天以500mg/m2、750mg/m2或1000mg/m2的剂量每天两次口服给药。
  31. 如权利要求22-30中任一项所述的方法，其中所述方法包括在每个给药周期的第1天以8-30mg/m2的治疗有效量注射给药米托蒽醌脂质体和以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨，然后在该周期的第2-14天继续以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨。
  32. 如权利要求22-31中任一项所述的方法，其中所述方法包括在每个给药周期的第1天以20mg/m2的治疗有效量注射给药米托蒽醌脂质体一次和以1000mg/m2的剂量口服给药卡培他滨两次，然后在该周期的第2-14天继续以1000mg/m2的剂量每天两次口服给药卡培他滨。
  33. 如权利要求29-32中任一项所述的方法，其中所述给药周期为三周。
  34. 一种用于治疗鼻咽癌的药物组合，其包含米托蒽醌脂质体和卡培他滨。
  35. 如权利要求34所述的药物组合，其中所述鼻咽癌为复发和/或转移性鼻咽癌，优选地，所述复发和/或转移性鼻咽癌为既往接受过一线或二线含铂方案治疗的复发和/或转移性鼻咽癌。
  36. 如权利要求34或35所述的药物组合，其中所述米托蒽醌脂质体满足以下一项或多项：
    (i)米托蒽醌脂质体为盐酸米托蒽醌脂质体；
    (ii)米托蒽醌脂质体的粒径为约30-80nm，例如约35-75nm、约40-70nm、约40-60nm或约60nm；
    (iii)米托蒽醌与脂质体内的多价反离子例如硫酸根、柠檬酸根或磷酸根形成难以溶解的沉淀；和
    (iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，其选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合，优选选自氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，更优选为质量比为约3∶1∶1的氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺。
  37. 如权利要求34-36中任一项所述的药物组合，其中所述米托蒽醌脂质体为盐酸米托蒽醌脂质体。
  38. 如权利要求34-37中任一项所述的药物组合，其中所述米托蒽醌脂质体为液体注射剂，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
  39. 如权利要求34-38中任一项所述的药物组合，其中卡培他滨为片剂。
  40. 如权利要求34-39中任一项所述的药物组合，其中米托蒽醌脂质体注射给药，优选地，米托蒽醌脂质体在每个给药周期的第1天以8-30mg/m2，优选12-24mg/m2，更优选12-20mg/m2的治疗有效量注射给药。
  41. 如权利要求34-40中任一项所述的药物组合，其中卡培他滨口服给药，优选地，卡培他滨在每个给药周期的第1-14天以500mg/m2、750mg/m2或1000mg/m2的剂量每天两次口服给药。
  42. 如权利要求34-41中任一项所述的药物组合，其中所述治疗包括在每个给药周期的第1天以8-30mg/m2的治疗有效量注射给药米托蒽醌脂质体和以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨，然后在该周期的第2-14天继续以500mg/m2、750mg/m2或1000mg/m2的剂量口服给药卡培他滨。
  43. 如权利要求34-42中任一项所述的药物组合，其中所述治疗包括在每个给药周期的第1天以20mg/m2的治疗有效量注射给药米托蒽醌脂质体一次和以1000mg/m2的剂量口服给药卡培他滨两次，然后在该周期的第2-14天继续以1000mg/m2的剂量每天两次口服给药卡培他滨。
  44. 如权利要求40-43中任一项所述的药物组合，其中所述给药周 期为三周。
  45. 一种试剂盒，其包含米托蒽醌脂质体和卡培他滨。
  46. 如权利要求45所述的试剂盒，其中所述米托蒽醌脂质体满足以下一项或多项：
    (i)米托蒽醌脂质体为盐酸米托蒽醌脂质体；
    (ii)米托蒽醌脂质体的粒径为约30-80nm，例如约35-75nm、约40-70nm、约40-60nm或约60nm；
    (iii)米托蒽醌与脂质体内的多价反离子例如硫酸根、柠檬酸根或磷酸根形成难以溶解的沉淀；和
    (iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，其选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合，优选选自氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，更优选为质量比为约3∶1∶1的氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺。
  47. 如权利要求45或46所述的试剂盒，其中所述米托蒽醌脂质体为盐酸米托蒽醌脂质体。
  48. 如权利要求45-47中任一项所述的试剂盒，其中所述米托蒽醌脂质体为液体注射剂，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
  49. 如权利要求45-48中任一项所述的试剂盒，其中卡培他滨为片剂。
PCT/CN2023/115149 2022-08-29 2023-08-28 米托蒽醌脂质体联用卡培他滨治疗鼻咽癌的用途 WO2024046246A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056379A1 (en) * 2002-12-23 2004-07-08 Panagin Pharmaceuticals Inc. Saponins and sapogenins for use in combination therapy for cancer
WO2022127760A1 (zh) * 2020-12-15 2022-06-23 石药集团中奇制药技术（石家庄）有限公司 盐酸米托蒽醌脂质体的用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056379A1 (en) * 2002-12-23 2004-07-08 Panagin Pharmaceuticals Inc. Saponins and sapogenins for use in combination therapy for cancer
WO2022127760A1 (zh) * 2020-12-15 2022-06-23 石药集团中奇制药技术（石家庄）有限公司 盐酸米托蒽醌脂质体的用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XIAOJIU: "[Nasopharyngeal Cancer] Recruitment of patients with nasopharyngeal cancer treated with the marketed drug Duenda Injection combined with capecitabine", YUGE MEDICAL, 7 July 2023 (2023-07-07), XP093145686 *

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