WO2020011189A1 - 米托蒽醌脂质体治疗非霍奇金淋巴瘤的用途 - Google Patents

米托蒽醌脂质体治疗非霍奇金淋巴瘤的用途 Download PDF

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WO2020011189A1
WO2020011189A1 PCT/CN2019/095396 CN2019095396W WO2020011189A1 WO 2020011189 A1 WO2020011189 A1 WO 2020011189A1 CN 2019095396 W CN2019095396 W CN 2019095396W WO 2020011189 A1 WO2020011189 A1 WO 2020011189A1
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liposome
mitoxantrone
lymphoma
cell lymphoma
subject
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PCT/CN2019/095396
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English (en)
French (fr)
Inventor
李春雷
彭悦颖
娄琨
王雅鹃
汪玉梅
陈珊
孟志宾
薛建飞
原静
罗红梅
姚雪坤
王世霞
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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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Priority to AU2019301101A priority Critical patent/AU2019301101B2/en
Priority to CU2021000003A priority patent/CU20210003A7/es
Priority to EP19833348.6A priority patent/EP3821887B1/en
Priority to BR112021000452A priority patent/BR112021000452A8/pt
Priority to FIEP19833348.6T priority patent/FI3821887T3/fi
Priority to KR1020217001296A priority patent/KR20210031695A/ko
Priority to US17/258,801 priority patent/US11583508B2/en
Priority to CA3105698A priority patent/CA3105698A1/en
Priority to SG11202013236XA priority patent/SG11202013236XA/en
Priority to MX2020014107A priority patent/MX2020014107A/es
Priority to JP2021500673A priority patent/JP2021530489A/ja
Priority to CN201980046225.1A priority patent/CN112384207B/zh
Publication of WO2020011189A1 publication Critical patent/WO2020011189A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of antitumor, and particularly relates to the use of mitoxantrone liposomes to treat lymphoma, especially diffuse large B-cell lymphoma and peripheral T-cell lymphoma.
  • ML Malignant lymphoma
  • HL Hodgkin's lymphoma
  • NHL non-Hodgkin's lymphoma
  • NHL is a group of heterogeneous lymphoid tissue proliferative malignant lymphoma with different clinical manifestations and treatment responses. NHL can be divided into two major types of aggressive lymphoma and indolent lymphoma according to the speed of progression and the degree of malignancy. Invasive lymphomas mainly include diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma (Burkitt's lymphoma), transformed follicular lymphoma (TFL), and peripheral T-cell lymphoma (PTCL), etc. (Pralatrexate) With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results From the Pivotal PROPEL Study, JClin Oncol, O'Connor et.
  • DLBCL diffuse large B-cell lymphoma
  • MCL mantle cell lymphoma
  • Burkitt's lymphoma Burkitt's lymphom
  • NHL is of B-cell origin, and diffuse large B-cell lymphoma is the most common subtype of NHL.
  • DLBCL diffuse large B-cell lymphoma
  • the incidence of DLBCL accounts for more than 30% of NHL (The Aggressive Peripheral T-cell Lymphomas, Journal of Am J Hematol, Joe Shapiro et al., 2017, Vol. 92, pp.706-715. How I treat the peripheral T-cell lymphomas, Journal of BLOOD, Alison J. Moskowitz et al., 2014, Vol. 123, pp. 2636-2644).
  • NCN National Comprehensive Cancer Network
  • DLBCL refractory and relapsed.
  • DLBCL refractory relapsed.
  • ICE ifosfamide + carboplatin + etoposide
  • R-ESHAP rituximab-etoposide + methylprednisolone + cytarabine + cis
  • Platinum etc.
  • PTCL is a group of malignant diseases of the lymphatic system derived from mature T lymphocytes after thymus, which accounts for about 10% -20% of all non-Hodgkin's lymphoma cases, and has a higher incidence in Asia (The aggressive peripheral T-cell lymphomas, Journal of Am J, Hematol, Joe, Shapiro et al., 2017, Vol. 92, pp. 706-715. How to treat the peripheral T-cell lymphomas, Journal of BLOOD, Alison J. Moskowitz et al., 2014, Vol. 123, pp. 2636-2644).
  • Anthracycline-based therapies are often used as first-line treatments for PTCL, such as CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone), but these treatments cannot make PTCL subjects sustainable. Relief (How to Treat the T-cell Lymphomas, Journal of BLOOD, Alison J. Moskowitz et al., 2014, Vol. 123, pp. 2636-2644).
  • RR-PTCL single drugs recommended for relapsed / refractory PTCL
  • pula Qu Sha Pula Qu Sha (Pralatrexate, Patients, Relapsed, Refractory, Peripheral, T-Cell, Lymphoma: Results, From, Pivotal, PROPEL, Study, J Clin Oncol, O'Connor, et al., 2011, Vol.
  • HDAC inhibitor histone deacetylase inhibitor
  • ORR overall response rate
  • Mitoxantrone hydrochloride is a widely used drug in clinical practice. It was first synthesized by American researchers in 1979 and demonstrated its antitumor activity. It was first listed in the United States and Canada in 1984, and was approved for production by the US Food and Drug Administration at the end of 1987. So far, it has been used in more than 30 countries. China officially went into production in February 1991. FDA-approved indications are multiple sclerosis, prostate cancer, and acute myeloid leukemia.
  • the clinical application areas are mainly malignant lymphoma, breast cancer and acute myeloid leukemia, lung cancer, melanoma, soft tissue sarcoma, multiple myeloma, liver cancer, colorectal cancer, kidney cancer, prostate cancer, endometrial cancer, testicular tumor, ovary Both cancer and head and neck cancer have some effect.
  • Mitoxantrone is an anthraquinone antibiotic antitumor drug. Its main mechanism of action is the insertion of DNA through hydrogen bonding, causing cross-linking and cleavage of the DNA structure. It can interfere with RNA; Mitoxantrone is also topologically isomeric II.
  • An effective inhibitor which has a killing effect on both proliferative and non-proliferative cancer cells in the human body, and is a cell cycle non-specific drug.
  • HDAC inhibitors can inhibit tumor cell proliferation and induce cell differentiation and / or apoptosis by increasing the degree of acetylation of histones in the cell and increasing the expression level of genes such as p21.
  • Histone deacetylase inhibitors have become a new research hotspot in tumor targeted therapy, and their inhibitory effects on tumor cell migration, invasion, metastasis, and anti-tumor angiogenesis have also been confirmed.
  • the mechanism of mitoxantrone as a chemotherapeutic agent and a targeted drug HDAC inhibitor supports the treatment of PTCL, but the mechanism of action is different.
  • Chemotherapy drugs can increase the effect by increasing the dose, while targeted drugs have the phenomenon of target saturation, that is, the effect of increasing the dose may not increase.
  • the combined regimen containing mitoxantrone in the DLBCL protocol has only second-line treatment options MINE (mesadium + ifosfamide + mitoxantrone + etoposide). ).
  • the mitoxantrone quinone liposome preparation used in this patent application is further optimized based on the Chinese patent application 200610102339.8 filed on December 29, 2006 and the PCT application WO2008 / 080367A1 filed on December 29, 2007.
  • the liposome pharmaceutical preparation of the present invention has a particle size of about 30-80 nm, and contains a phospholipid having a Tm higher than the body temperature in the phospholipid bilayer, so that the phase transition temperature of the liposome is higher than the body temperature.
  • the phospholipid is phosphatidylcholine, hydrogenated soy lecithin (HSPC), hydrogenated egg yolk lecithin, bispalmitate lecithin (DPPC) or bisstearate lecithin (DSPC), or any combination thereof.
  • the normal body temperature of the human body is generally 36-38 ° C, for example, the typical value is 37 ° C. Body temperature varies with factors such as age, gender, day and night, mood, and measurement location.
  • the liposome pharmaceutical preparation wherein the phospholipid having a Tm higher than the body temperature in the phospholipid bilayer accounts for about 50-100 mol / mol%, preferably about 55-95 mol / mol%, more preferably about 60- 90mol / mol%.
  • the liposome pharmaceutical preparation optionally contains other phospholipids in the phospholipid bilayer, such as phospholipids having a Tm value not higher than the body temperature, such as dimyristoyl lecithin (DMPC) and the like.
  • phospholipids having a Tm value not higher than the body temperature such as dimyristoyl lecithin (DMPC) and the like.
  • the liposome pharmaceutical preparation optionally contains cholesterol, and its content is 2-60 mol / mol%, for example, 5-55 mol / mol%, especially 10-50 mol / mol, of the total moles of each component of the liposome. %, Especially 15-45 mol / mol%, more particularly 20-40 mol / mol%.
  • the liposome pharmaceutical preparation optionally contains other excipients, for example, excipients for further modifying the surface characteristics of the liposome, such as a lipid substance modified with a hydrophilic polymer, which can be selected from, for example, polyethylene Alcohol-modified distearoylphosphatidylethanolamine (DSPE-PEG), polyethylene glycol-modified distearylphosphatidylglycerol (DSPG-PEG), polyethylene glycol-modified cholesterol (chol-PEG), povidone Ketone modified distearyl phosphatidylethanolamine (DSPE-PVP), polyethylene glycol modified distearylphosphatidylglycerol (DSPG-PVP) or polyethylene glycol modified cholesterol (chol-PVP), or a combination thereof
  • it is present in an amount of 0.1-20 mol / mol% of phospholipids, such as 0.3-18 mol / mol%, 0.5-15 mol / mol%, 0.8-12 mol / mol
  • the liposome pharmaceutical preparation has a particle size of 35-75 nm, preferably 40-70 nm, especially 40-60 nm.
  • the liposome pharmaceutical preparation contains hydrogenated soybean lecithin, cholesterol, and polyethylene glycol distearoyl phosphatidylethanolamine, and its mass ratio is 3: 1: 1, and the polyethylene glycol is preferably modified.
  • Distearylphosphatidyethanolamine is a polyethylene glycol 2000 modified distearylphosphatidyethanolamine.
  • the liposome pharmaceutical preparation contains an active pharmaceutical ingredient, preferably a multivalent ionic drug.
  • the liposome pharmaceutical preparation wherein the active pharmaceutical ingredient has two or more dissociable groups having a dissociation constant pKa between 4.5 and 9.5, and preferably a dissociation constant pKa between 5.0 and 9.5. It is more preferably between 5.5 and 9.5, particularly preferably between 6.0 and 9.0, and especially between 6.5 and 9.0.
  • the liposome pharmaceutical preparation wherein the multivalent ionic drug is mitoxantrone.
  • the liposome pharmaceutical preparation wherein the content of the medicine is 0.1-50 wt%, preferably 0.5-40 wt%, more preferably 1-35 wt%, particularly preferably 3-30 wt%, based on the total weight of the pharmaceutical preparation, or 5-25 wt%, or 8-20 wt%.
  • the liposome pharmaceutical preparation optionally contains one or more other pharmaceutical ingredients, and / or a pharmaceutically acceptable carrier and / or excipient.
  • the liposome pharmaceutical preparation wherein the liposome contains a counterion, preferably a polyvalent counterion, such as an organic acid group, such as an acid group selected from the following saturated or unsaturated organic acids: citric acid, tartaric acid, fumaric acid , Oxalic acid, malonic acid, succinic acid, malic acid, and maleic acid, etc.
  • a counterion preferably a polyvalent counterion
  • organic acid group such as an acid group selected from the following saturated or unsaturated organic acids: citric acid, tartaric acid, fumaric acid , Oxalic acid, malonic acid, succinic acid, malic acid, and maleic acid, etc.
  • the inorganic acid group such as sulfate, phosphate or amino acid, such as the ionized form of cystine, is preferably citrate, sulfate or phosphate.
  • the liposome pharmaceutical preparation wherein the multivalent counter ion has two or more charges opposite to those of the active pharmaceutical ingredient.
  • the liposome pharmaceutical preparation wherein the liposome comprises phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, distearate lecithin or distearate lecithin, or a combination thereof.
  • the method for preparing the liposome pharmaceutical preparation may include the following steps: (1) preparing a liposome using a phospholipid having a Tm value higher than the body temperature and optionally other phospholipids and / or cholesterol; and (2) of interest Drugs, especially multivalent ionic drugs, are encapsulated in liposomes.
  • the present invention provides a liposome pharmaceutical formulation comprising mitoxantronequinone liposomes, the liposomes having a particle size of about 30-80 nm, containing the active ingredient mitoxantrone, mitoxant Anthraquinone and polyvalent counterions in the liposome form a difficult-to-dissolve precipitate.
  • the phospholipid bilayer of the liposome contains a phospholipid with a phase transition temperature (Tm) higher than the body temperature, thereby making the phase transition temperature of the liposome higher than the body temperature.
  • Tm phase transition temperature
  • the phospholipid having a Tm higher than body temperature is selected from the group consisting of phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, distearate lecithin, distearate lecithin And any combination thereof; and / or the particle size of the liposome is about 35-75 nm, preferably 40-70 nm, further preferably 40-60 nm, and particularly preferably 60 nm.
  • the phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000 distearoylphosphatidylethanolamine modified in a mass ratio of 3: 1: 1 And / or the particle size of the liposome is about 60 nm, and the counter ion is a sulfate ion.
  • the present invention provides the use of the above-mentioned liposome pharmaceutical preparation in the preparation of a medicament for treating lymphoma, wherein the lymphoma is preferably a non-Hodgkin's lymphoma, more preferably an invasive non-Hodgkin's lymphoma, and more preferably Diffuse large B-cell lymphoma or peripheral T-cell lymphoma, and still more preferably refractory diffuse large-B-cell lymphoma or peripheral T-cell lymphoma.
  • the lymphoma is preferably a non-Hodgkin's lymphoma, more preferably an invasive non-Hodgkin's lymphoma, and more preferably Diffuse large B-cell lymphoma or peripheral T-cell lymphoma, and still more preferably refractory diffuse large-B-cell lymphoma or peripheral T-cell lymphoma.
  • the invention provides the use of the above-mentioned liposome pharmaceutical preparation for preparing a medicament for treating lymphoma, wherein the liposome pharmaceutical preparation is used as a single antitumor therapeutic agent and is not used in combination with other antitumor drugs.
  • the invention provides the use of the above-mentioned liposome pharmaceutical preparation for preparing a medicament for treating lymphoma, wherein the liposome pharmaceutical preparation is used for second-line and subsequent treatment of the lymphoma, and is preferably used for diffuse large B cells Third-line and later treatment of lymphoma, and second-line and later treatment for peripheral T-cell lymphoma.
  • the present invention provides the use of the above-mentioned liposome pharmaceutical preparation for preparing a medicament for treating lymphoma, wherein the administration cycle of the liposome pharmaceutical preparation is once every 1-4 weeks, preferably every 3-4 weeks It is administered once, and more preferably once every 4 weeks.
  • the invention provides the use of the above-mentioned liposome pharmaceutical preparation for preparing a medicament for treating lymphoma, wherein the liposome pharmaceutical preparation is administered at a dose of 6-30 mg / m 2 , preferably 14-24 mg / m 2 .
  • the invention provides the use of the above-mentioned liposome pharmaceutical preparation for preparing a medicament for treating lymphoma, wherein the infusion administration time of the liposome pharmaceutical preparation is 30min-120min, preferably 60min-120min, and further preferably a lot of In 60min, more preferably 60 ⁇ 5min.
  • the present invention provides the use of the above-mentioned liposome pharmaceutical preparation for preparing a medicament for treating lymphoma, wherein the total administration dose of the liposome pharmaceutical preparation to each patient does not exceed 200 mg / m 2 , and preferably does not exceed 160 mg. / m 2 , more preferably not more than 140 mg / m 2 .
  • the present invention provides a method for treating lymphoma using the above-mentioned liposome pharmaceutical preparation, comprising administering a mitoxantrone liposome pharmaceutical preparation to a subject in need thereof, wherein the lymphoma is preferably a non-Hodgkin's lymphoma Further preferred is invasive non-Hodgkin's lymphoma, more preferred is diffuse large B-cell lymphoma or peripheral T-cell lymphoma, and still more preferred is relapsed refractory diffuse large B-cell lymphoma or peripheral T-cell lymphoma.
  • the mitoxantrone liposomal drug preparation is administered as a single antitumor therapeutic agent without being combined with other antitumor drugs.
  • the subject has received at least first-line treatment
  • the subject has diffuse large B-cell lymphoma and has received at least first-line and / or second-line treatment
  • the subject has Peripheral T-cell lymphoma and has received at least first-line treatment.
  • the liposome pharmaceutical preparation is administered every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, preferably every 3-6 weeks, and more preferably every Administration once every 4 weeks; and / or administering the mitoxantronequinone liposome pharmaceutical formulation to the subject 1, 2, 3, 4, 5, or 6 times, such as 2, 3, 4, or 5 times.
  • the liposome pharmaceutical preparation is administered at a dose of 6-30 mg / m 2 , such as 8 , 10 , 12 , 14, 16 , 18, 20 , 22 , 24 , 26 , 28 Or 30 mg / m 2 , preferably 14-24 mg / m 2 .
  • the liposome pharmaceutical preparation is administered to the subject by intravenous drip, and the drip administration time is not less than 30, 40, 45, 50, 60, 70, 75, 80, 90, 100, 110, or 120 min, which is 30 min-120 min, preferably 40 min-80 min, 60 min-120 min, further preferably not less than 60 min, and more preferably 60 min.
  • the total dose of the liposome pharmaceutical preparation to each subject (patient) does not exceed 200 mg / m 2 , preferably does not exceed 160 mg / m 2 , and further preferably does not exceed 140 mg / m 2 .
  • the administration route can be selected from oral administration, injection administration and local administration, preferably injection administration; further, injection administration can be selected from intravenous injection, subcutaneous injection, intramuscular injection, Intravenous injection is preferred; further, intravenous drip and intravenous bolus may be selected, and intravenous drip is preferred.
  • the method comprises formulating the liposome drug into a solution capable of being directly infused and then administering the solution to the subject, wherein the concentration of the formulated liposome solution capable of being directly infused is 0.05 mg. /ml-0.5mg/ml, preferably 0.08mg / ml-0.4mg / ml, more preferably 0.1mg / ml-0.3mg / ml, more preferably 0.1mg / ml, 0.15mg / ml, 0.2mg / ml, 0.25mg / ml or 0.3mg / ml.
  • each cycle means administration of the liposome drug formulation once
  • ORR HDAC inhibitor alone
  • the total response rate (ORR) of the method is at least 30%, preferably at least 40%; further, the total response rate is 30% -60 %.
  • the patient has previously experienced one, two or more treatments selected from the group consisting of: CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone), DICE (dexamethasone + ifosfion) Amide + carboplatin + etoposide), Gemox (gemcitabine + oxaliplatin), R-CHOP (rituximab-cyclophosphamide + doxorubicin + vincristine + prednisone), EP ( Etoposide + cisplatin), etoposide (etoposide), R-CHOP + ibrutinib (rituximab-cyclophosphamide + doxorubicin + vincristine + prednisone + ibrutinib) , ICE (Ifosfamide + Carboplatin + Etoposide), R-EPOCH (Rituximab-Etoposide), R-
  • the present invention provides a liposome pharmaceutical formulation comprising mitoxantronequinone liposomes containing the active ingredient mitoxantrone, wherein mitoxantrone and liposome
  • the valence counterion forms a precipitate that is difficult to dissolve.
  • the phospholipid bilayer of the liposome contains a phospholipid with a phase transition temperature (Tm) higher than the body temperature, so that the phase transition temperature of the liposome is higher than the body temperature.
  • Tm phase transition temperature
  • the particle size of the liposome is about 30-80 nm, such as about 35-75 nm, preferably 40-70 nm, further preferably 40-60 nm, and particularly preferably 60 nm.
  • the phospholipid with a Tm above body temperature is selected from the group consisting of phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, distearic acid lecithin, distearate lecithin, and any combination thereof.
  • the phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000-modified distearylphosphatidyethanolamine, with a mass ratio of 3: 1: 1, and the counter ion For sulfate ion.
  • the present invention provides a method for treating lymphoma, comprising administering a mitoxantrone liposome pharmaceutical preparation to a subject in need thereof, such as the liposome pharmaceutical preparation described in the above aspect of the invention .
  • the lymphoma is non-Hodgkin's lymphoma, more preferably invasive non-Hodgkin's lymphoma, more preferably diffuse large B-cell lymphoma or peripheral T-cell lymphoma, and still more preferably relapsed refractory diffuse large B Cell lymphoma or peripheral T-cell lymphoma
  • the peripheral T-cell lymphoma is selected from non-specified peripheral T-cell lymphoma, angioimmunoblast T-cell lymphoma, ALK + systemic anaplastic large T-cell lymphoma, ALK- Systemic anaplastic large T-cell lymphoma, extranodal NK / T-cell lymphoma, nasal type, bowel disease-related T-cell lymphoma, primary liver and spleen ⁇ T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma.
  • said administering is administering said mitoxantrone liposomal pharmaceutical formulation as a single anti-tumor therapeutic agent without combining it with other anti-tumor drugs.
  • the subject has received at least first-line therapy, for example, the subject has diffuse large B-cell lymphoma and has received at least first-line and / or second-line therapy, or, for example, the subject has peripheral T Cell lymphoma and have received at least first-line treatment.
  • the subject has previously undergone one, two or more treatments selected from the group consisting of: CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone), DICE ( Dexamethasone + Ifosfamide + Carboplatin + Etoposide), Gemox (Gemcitabine + Oxaliplatin), R-CHOP (Rituximab-Cyclophosphamide + Doxorubicin + Vincristine + Prednisone), EP (Etoposide + cisplatin), etoposide (etoposide), R-CHOP + ibrutinib (rituximab-cyclophosphamide + doxorubicin + vincristine + prednisolone) (Isotinib + Ibrutinib), ICE (Ifosfamide + Carboplatin + Etoposide), R-EPOCH (Rituximab-
  • the treatment can be performed as follows:
  • dose is preferably 14-24mg / m 2 is administered to said subject
  • the mitoxantronequinone liposome pharmaceutical preparation is preferably 14-24mg / m 2 is administered to said subject
  • the mitoxantronequinone liposome pharmaceutical preparation is preferably 14-24mg / m 2 is administered to said subject The mitoxantronequinone liposome pharmaceutical preparation.
  • the mitoxantrone liposome pharmaceutical preparation is administered to the subject by intravenous drip, and the drip time is not less than 30, 40, 45, 50, 60, 70, 75, 80 , 90, 100, 110 or 120 min, preferably 40-80 min, and more preferably about 60 min.
  • the total dose of said liposome pharmaceutical formulation administered to said subject does not exceed 200 mg / m 2 , such as not exceeding 120, 140, 160, 180 or 200 mg / m 2 , preferably not exceeding 160 mg / m 2 , more preferably not more than 140 mg / m 2 .
  • the method of treatment of the invention comprises administering to the subject 3 or more mitoxantronequinone liposomal pharmaceutical formulations for treatment, said method achieving a higher overall response than an HDAC inhibitor alone Rate (ORR).
  • ORR HDAC inhibitor alone Rate
  • the method of treatment of the present invention comprises administering to the subject 3 or more mitoxantronequinone liposome pharmaceutical formulations for treatment, the method having a total response rate (ORR) of at least 30%, preferably At least 40%; further, the overall response rate is 30% -60%.
  • ORR total response rate
  • HSPC, Chol and DSPE-PEG2000 were weighed according to the mass ratio of (3: 1: 1) and dissolved in 95% ethanol to obtain a clear solution.
  • the ethanol solution of phospholipid was mixed with 300 mM ammonium sulfate solution, and hydrated by shaking at 60-65 ° C. for 1 h to obtain heterogeneous multi-chamber liposomes.
  • the particle size of the liposomes was then reduced using a microfluidic device.
  • the obtained sample was diluted 200-fold with a 0.9% NaCl solution, and then detected by NanoZS.
  • the average particle size of the particles was about 60 nm, and the main peak was concentrated between 40-60 nm.
  • the ultrafiltration device was then used to remove the ammonium sulfate from the outer phase of the blank lipid, and the outer phase was replaced with 290 mM sucrose and 10 mM glycine to form a transmembrane ammonium sulfate gradient.
  • mitoxantrone hydrochloride solution (10 mg / mL) was added to the blank liposomes, and drug loading was performed at 60-65 ° C. After incubation for about 1 h, gel exclusion chromatography was used to demonstrate that the encapsulation efficiency was about 100%.
  • the weight ratio of HSPC: Chol: DSPE-PEG2000: mitoxantrone was 9.58: 3.19: 3.19: 1, and the osmotic pressure of the sucrose glycine solution was close to the physiological value.
  • the mitoxantronequinone liposomes prepared by the above method were respectively prepared with a 5% glucose injection solution, a 0.9% sodium chloride injection solution (physiological saline) as a diluent, and a glass infusion bottle as a container, and the preparation concentrations were 0.1 mg / ml and 0.2. mg / ml two specifications, the pH of the solution and the average of the liposomes were examined at 0 ° C, 2h, 4h, 6h, 8h, and 24h respectively at 30 ° C, 30 ° C, protected from light, and 2-8 ° C under refrigeration. Parameters such as particle size, encapsulated drug concentration, phospholipids, lysolecithin, related substances, and content are shown in Table 1-4 below.
  • the time-dependent pH, average particle size, encapsulated drug concentration, phospholipids of solutions of mitoxantrone liposome drug concentrations of 0.1 mg / ml and 0.2 mg / ml , Lysolecithin, related substances, content and other parameters were not significantly different.
  • the mitoxantronequinone liposome (specification 10 mg / 10 ml / branch) obtained above was dissolved in 250 ml of a 5% glucose injection solution, and the drip time was 60 minutes. Intravenous drip from one side of the forearm, semi-recumbent position during administration, the intravenous administration process is under the supervision of a clinician.
  • the target tumor should be separated by at least 4 weeks after the last chemotherapy, radiotherapy, biotherapy, stem cell transplant or other experimental drug treatment;
  • the level of organ function is basically normal.
  • Safety assessments include adverse events, physical examinations and other tests (blood routine, urine routine, blood biochemistry, electrocardiogram, cardiac color Doppler ultrasound), and early withdrawal from safety or tolerability reasons.
  • Safety evaluation standard NCI-CTC4.0.
  • the ORR of the combined chemotherapy regimen is about 60% -70% (ICE regimen: the ORR of the three drugs, ifosfamide, carboplatin, and etoposide is 66%; rituximab, etoposide, and methylprednisolone
  • ICE regimen the ORR of the three drugs, ifosfamide, carboplatin, and etoposide is 66%; rituximab, etoposide, and methylprednisolone
  • PR Local remission, defined as a measurable reduction in lesions without new lesions.
  • PD disease progression, defined as the appearance of any new lesions, or an increase of 50% or more from the original lesion.
  • SD Stable disease, defined as not a condition.
  • Mitoxantronequinone liposomes developed by our company are positioned as second-line therapy in the treatment of PTCL.
  • the ORR of this product in clinical research is 52.9%, and the current second-line recommended HDAC inhibitors include pratraza, romidepsin , Belinstat and Cedaramide (HDAC inhibitor is an oral preparation, administered once a day, the ORR is less than 30%), which is much higher than HDAC inhibitors.
  • Patients who achieve remission in a short time can undergo bone marrow transplantation in time.
  • Mitoxantrone liposomes injection a dose of 14,16,20mg / m 2 or 24mg / m 2, 28 times a day dosing.
  • the subjects in this study received an average of 3.6 ⁇ 1.8 cycles of treatment.
  • grade 3-4 hematological toxicity is similar, the incidence of grade 4 neutropenia and grade 3-4 thrombocytopenia is lower than the CMD protocol reported in the previous literature.

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Abstract

米托蒽醌脂质体药物制剂在制备用于治疗淋巴瘤的药物中的用途，所述淋巴瘤优选非霍奇金淋巴瘤，进一步优选侵袭性非霍奇金淋巴瘤，更优选弥漫大B细胞淋巴瘤或外周T细胞淋巴瘤，更进一步优选复发难治性的弥漫大B细胞淋巴瘤或外周T细胞淋巴瘤。所述米托蒽醌脂质体作为单一抗肿瘤治疗剂，不与其他抗肿瘤药物联合应用。

Description

米托蒽醌脂质体治疗非霍奇金淋巴瘤的用途
与相关专利申请的交叉引用
本专利申请要求于2018年07月11日提交至中国专利局、申请号为201810756315.7、发明名称为“盐酸米托蒽醌脂质体治疗非霍奇金淋巴瘤的用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
本专利申请还引用2006年12月29日提出的中国专利申请200610102339.8和2007年12月29日提出的PCT申请WO2008/080367A1，其公开的内容在这里被全文引入作为参考。
技术领域
本发明属于抗肿瘤领域，具体涉及一种采用米托蒽醌脂质体治疗淋巴瘤、尤其是弥漫大B细胞淋巴瘤和外周T细胞淋巴瘤的用途。
背景技术
1.疾病背景
恶性淋巴瘤(ML)是一大组复杂的淋巴造血系统恶性肿瘤的总称，分为霍奇金淋巴瘤(HL)和非霍奇金淋巴瘤(NHL)两大类。
NHL是一组异质性淋巴组织增殖性恶性淋巴瘤，具有不同的临床表现及治疗反应。NHL根据进展速度及恶性程度又可分为侵袭性淋巴瘤及惰性淋巴瘤两大类。侵袭性淋巴瘤主要包括弥漫大B细胞淋巴瘤(DLBCL)、套细胞淋巴瘤(MCL)、伯基特氏淋巴瘤(Burkitt’s lymphoma)、转化的滤泡性淋巴瘤(TFL)和外周T细胞淋巴瘤(PTCL)等(Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma:Results From the Pivotal PROPEL Study,J Clin Oncol,O’Connor et al.,2011,Vol.29,pp.1182-1189)。
大多数NHL为B细胞来源，弥漫大B细胞淋巴瘤是NHL中最常见的亚型。在欧美国家，DLBCL的发病率约占NHL的30％以上(The aggressive  peripheral T-cell lymphomas,Journal of Am J Hematol,Joe Shapiro et al.,2017,Vol.92,pp.706-715.How I treat the peripheral T-cell lymphomas,Journal of BLOOD,Alison J.Moskowitz et al.,2014,Vol.123,pp.2636-2644)。根据2016年美国国立综合癌症网(NCCN)治疗指南，含蒽环类药物如RCHOP(利妥昔单抗-环磷酰胺+阿霉素+长春新碱+泼尼松)的化疗方案仍被认为是治疗DLBCL的一线治疗方案。
大约有三分之一的DLBCL是难治复发性的，对于难治复发性DLBCL而言，目前临床上有很多挽救治疗方案，但仍未有标准方案。虽然可应用挽救性联合化疗方案ICE(异环磷酰胺+卡铂+依托泊苷)、R-ESHAP(利妥昔单抗-依托泊苷+甲基强的松龙+阿糖胞苷+顺铂)等(Treatment challenges in the management of relapsed or refractory non-Hodgkin’s lymphoma–novel and emerging therapies,Journal of Cancer Management and Research,Mark P Chao et al.,2013,Vol.5,pp.251-269))，但有效的单药治疗方案少见。而难治复发性DLBCL患者，大多经过多线化疗方案治疗，全身情况尤其是骨髓功能低下，患者多不能耐受继续接受多周期联合化疗方案。因此，有效的单药治疗是难治复发性DLBCL的一种优选治疗方案。
PTCL是一组源于胸腺后成熟T淋巴细胞的淋巴系统恶性疾病，占所有非霍奇金淋巴瘤病例的10％-20％左右，在亚洲发病率较高(The aggressive peripheral T-cell lymphomas,Journal of Am J Hematol,Joe Shapiro et al.,2017,Vol.92,pp.706-715.How I treat the peripheral T-cell lymphomas,Journal of BLOOD,Alison J.Moskowitz et al.,2014,Vol.123,pp.2636-2644)。以蒽环类药物为基础的治疗方法常作为PTCL的一线治疗方案，比如CHOP(环磷酰胺+阿霉素+长春新碱+泼尼松)，但这些治疗方案不能使PTCL受试者获得持续缓解(How I treat the peripheral T-cell lymphomas,Journal of BLOOD,Alison J.Moskowitz et al.,2014,Vol.123,pp.2636-2644)。根据2016年美国国立综合癌症网(NCCN)治疗指南，含蒽环类药物(CHOP)的化疗仍被认为是一线治疗方案，推荐治疗复发/难治PTCL(RR-PTCL)的单药包括普拉曲沙(Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma:Results From the Pivotal PROPEL Study,J Clin Oncol,O’Connor et al.,2011,Vol.29,pp.1182-1189)、罗米地辛(Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma:pivotal study  update demonstrates durable responses,Journal of Hematology&Oncology,Coiffier et al.,2014,Vol 7,pp.1-9)、贝林司他(Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma:Results of the Pivotal Phase II BELIEF(CLN-19)Study,JOURNAL OF CLINICAL ONCOLOGY,O’Connor et al.,2015,Vol.33,pp.2492-2499)、西达本胺(Results from a multicenter,open-label,pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma,Annals of Oncology,Y.Shi et al.,2015,Vol.00,pp.1-6)等HDAC抑制剂作为二线治疗。上述组蛋白去乙酰化酶抑制剂(HDAC抑制剂)的特点是总缓解率(ORR)低，仅为30％左右，也就是说一线治疗失败的患者中有近70％的患者不能从HDAC抑制剂的治疗中获益。各HDAC抑制剂的ORR详见下表。
Figure PCTCN2019095396-appb-000001
2.作用机制比较
盐酸米托蒽醌是一个目前临床应用广泛的药物。于1979年首先由美国研究人员合成并证明其抗瘤活性。1984年首先在美国、加拿大上市，1987年底美国食品药品监督管理局批准生产，至今已有30多个国家使用。中国于1991年2月正式投产上市。FDA批准的适应症为多发性硬化症、前列腺癌和急性髓性白血病。临床应用领域主要为恶性淋巴瘤、乳腺癌和急性髓性白血病、肺癌、黑色素瘤、软组织肉瘤、多发性骨髓瘤、肝癌、大肠癌、肾癌、前列腺癌、子宫内膜癌、睾丸肿瘤、卵巢癌和头颈部癌都有一定疗效。
米托蒽醌为蒽醌类抗生素类抗肿瘤药，主要作用机制为通过氢键结合插入脱氧核糖核酸，引起DNA结构的交联和断裂；能够干扰RNA；米托蒽醌还是拓扑异构II的有效抑制剂，其对人体中增生扩散和未增生扩散癌细胞都有杀伤作用，为细胞周期非特异性药物。
HDAC抑制剂通过增加细胞内组蛋白的乙酰化程度，提高p21等基 因的表达水平等途径，抑制肿瘤细胞的增殖，诱导细胞分化和(或)凋亡。组蛋白去乙酰化酶抑制剂已成为肿瘤靶向治疗的研究新热点，其对肿瘤细胞迁移、侵袭、转移的抑制作用和抗肿瘤血管生成作用也被证实。米托蒽醌作为化疗药物与靶向药物HDAC抑制剂的机制均支持治疗PTCL，但作用机制不同。化疗药物可通过增加剂量提高疗效，而靶向药物则有靶点饱和的现象，即增加剂量疗效不一定增加。
3.治疗方案
现有技术中，在DLBCL及PTCL的治疗中，采用了米托蒽醌的治疗方案均为多药物联合治疗方案。
根据2016年美国国立综合癌症网(NCCN)治疗指南，治疗DLBCL方案中含有米托蒽醌的联合方案仅有二线治疗方案MINE(美司钠+异环磷酰胺+米托蒽醌+依托泊苷)。
有报道(Phase II study of the irinotecan(CPT-11),mitoxantrone and dexamethasone regimen in elderly patients with relapsed or refractory peripheral T-cell lymphoma,Journal of Cancer Sci,Nozomi Niitsu et al.,2007,Vol.98,pp.109-112)为采用CMD方案(CPT-11-伊立替康,mitoxantrone[MIT]-米托蒽醌,dexamethasone[DEX]-地塞米松)治疗老年复发难治外周T(患者70岁-79岁)。该研究共入选30例患者，可评估疗效患者中ORR为60％。其中米托蒽醌的使用剂量为8mg/m 2，3周为一周期，共使用6个周期。在该研究中，18例(60％)发生了3-4级血液学毒性。8例(27％)尽管使用了升高白血胞的药物(G-CSF)仍发生了4级中性粒细胞降低。5例(16.7％)发生了3-4级血小板降低。2例(6.7％)发生了3级红细胞降低。
有报道(Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation,Journal of Leukemia,P Corradini et al.,2006,Vol.20,pp.1533-1538)采用了2个II期试验。第一个试验32例患者接受2周期APO方案(多柔比星+长春新碱+泼尼松)治疗，随后接受2周期DHAP(顺铂+阿糖胞苷+地塞米松)方案治疗，接受骨髓自体移植后有条件地使用高剂量米托蒽醌(60mg/m 2)联合马法兰(180mg/m 2)。该报道 未披露哪些患者在移植后有条件使用该化疗方案，且该方案在移植后使用，不能体现化疗方案的单独疗效。第二个试验30例患者接受MACOP(甲氨蝶呤+多柔比星+环磷酰胺+长春新碱+博莱霉素)方案8周后，接受3天米托蒽醌(8mg/m 2)联合阿糖胞苷治疗，接受骨髓自体移植后有条件地使用卡莫司汀联合依托泊苷。接受自体骨髓移植前，62例患者(2个试验合并统计，未分别统计疗效)中有35例出现CR(56％)，10例PR(16％)，15例(24％)PD。但该文献并未分别披露2个试验的疗效，试验二单独疗效未披露，且即便披露，由于先接受了8周MACOP，再接受3天米托蒽醌联合阿糖胞苷，不能体现后者单独疗效。
另有报道(High-dose therapy with autologous stem cell transplantation in patients with peripheral T cell lymphomas,Journal of Bone Marrow Transplantation,AK Blystad et al.,2001,Vol.27,pp.711-716)指出，所有患者均接受了含有蒽环类药物的一线治疗，二线治疗中有4例受试者接受了含有米托蒽醌的联合化疗方案(米托蒽醌+阿糖胞苷+依托泊苷+泼尼松)，但未报道该化疗方案使用剂量、使用周期及使用后的疗效评价。不能通过文献判断出该化疗方案对外周T细胞淋巴瘤的疗效。
4.米托蒽醌脂质体
本专利申请中所用米托蒽醌脂质体制剂，基于2006年12月29日提出的中国专利申请200610102339.8和2007年12月29日提出的PCT申请WO2008/080367A1的基础上进一步优化得出。
总之，对于DLBCL和PTCL治疗而言，目前采用的多药联合治疗方案在有效性和耐受性等方面不能令人满意，现有技术仍迫切需要一种具有更好的有效性和耐受性的治疗药物。
发明内容
本发明所述的脂质体药物制剂，其粒度为约30-80nm，并且在磷脂双分子层中含有Tm高于体温的磷脂，从而使脂质体的相转变温度高于体温，优选所述磷脂是磷脂酰胆碱、氢化大豆卵磷脂(HSPC)、氢化蛋黄卵磷脂、双软脂酸卵磷脂(DPPC)或双硬脂酸卵磷脂(DSPC)或者其任何组合。人体正常体温一般为36-38℃，例如典型值为37℃。体温随年龄、性别、昼 夜、情绪、测量部位等因素变动。
所述的脂质体药物制剂，其中所述磷脂双分子层中Tm高于体温的磷脂占总磷脂含量的约50-100mol/mol％，优选约55-95mol/mol％，更优选约60-90mol/mol％。
所述的脂质体药物制剂，其中可选地在所述磷脂双分子层中含有其它磷脂，例如Tm值不高于体温的磷脂，如双肉豆寇酸卵磷脂(DMPC)等。
所述的脂质体药物制剂，其中可选地含有胆固醇，其含量为脂质体各成分总摩尔数的2-60mol/mol％，例如5-55mol/mol％，尤其是10-50mol/mol％，特别地15-45mol/mol％，更特别地20-40mol/mol％。
所述的脂质体药物制剂，其中可选地包含其他的辅料，例如进一步修饰脂质体表面特征的辅料，如用亲水性聚合物修饰的脂类物质，其可选自例如聚乙二醇修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PEG)、聚乙二醇修饰的二硬脂酰磷脂酰甘油(DSPG-PEG)、聚乙二醇修饰的胆固醇(chol-PEG)、聚维酮修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PVP)、聚乙二醇修饰的二硬脂酰磷脂酰甘油(DSPG-PVP)或者聚乙二醇修饰的胆固醇(chol-PVP)或者其组合，优选其存在量以摩尔数计是磷脂的0.1-20mol/mol％，例如0.3-18mol/mol％、0.5-15mol/mol％、0.8-12mol/mol％、1-10mol/mol％、2-8mol/mol％、2.5-7mol/mol％或者3-6mol/mol％等。
所述的脂质体药物制剂，其粒度为35-75nm，优选40-70nm，尤其是40-60nm。
所述的脂质体药物制剂，其中包含氢化大豆卵磷脂、胆固醇和聚乙二醇修饰的二硬脂酰磷脂酰乙醇胺，其质量比为3:1:1，优选所述聚乙二醇修饰的二硬脂酰磷脂酰乙醇胺是聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺。
所述的脂质体药物制剂，其中包含活性药物成分，优选多价离子药物。
所述的脂质体药物制剂，其中所述活性药物成分具有两个或两个以上的解离常数pKa在4.5-9.5之间的可解离基团，优选解离常数pKa在5.0-9.5 之间，更优选在5.5-9.5之间，特别优选在6.0-9.0之间，尤其是6.5-9.0之间。
所述的脂质体药物制剂，其中所述多价离子药物为米托蒽醌。
所述的脂质体药物制剂，其中以药物制剂的总重量计，所述药物的含量为0.1-50wt％，优选0.5-40wt％，更优选1-35wt％，特别优选3-30wt％，或者5-25wt％，或者8-20wt％。
所述的脂质体药物制剂，其中任选地含有一种或多种其它药物成分，和/或药学上可接受的载体和/或赋型剂。
所述的脂质体药物制剂，其中所述脂质体内含有反离子，优选多价反离子，例如有机酸根，比如选自以下饱和或不饱和有机酸的酸根：柠檬酸、酒石酸、富马酸、草酸、丙二酸、琥珀酸、苹果酸，以及马来酸等，无机酸根比如硫酸根、磷酸根或者氨基酸、比如胱氨酸的离子化形式，优选柠檬酸根、硫酸根或者磷酸根。
所述的脂质体药物制剂，其中所述多价反离子具有两个或两个以上与活性药物成分相反的电荷。
所述的脂质体药物制剂，其中所述脂质体中包含磷脂酰胆碱、氢化大豆卵磷脂、氢化蛋黄卵磷脂、双软脂酸卵磷脂或者双硬脂酸卵磷脂，或者其组合。
制备所述脂质体药物制剂的方法，可包括如下步骤：(1)利用Tm值高于体温的磷脂以及可选地其它磷脂和/或胆固醇，制备脂质体；和(2)将感兴趣的药物，特别是多价离子药物包封在脂质体内。
在第一方面，本发明提供一种脂质体药物制剂，其包含米托蒽醌脂质体，所述脂质体的粒径为约30-80nm，含有活性成分米托蒽醌，米托蒽醌和脂质体内的多价反离子形成难以溶解的沉淀，脂质体的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，从而使脂质体的相转变温度高于体温。
优选地，在上述脂质体药物制剂中，所述Tm高于体温的磷脂选自磷脂酰胆碱、氢化大豆卵磷脂、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂 酸卵磷脂及其任何组合；和/或所述脂质体的粒径为约35-75nm，优选40-70nm，进一步优选40-60nm，特别优选60nm。
优选地，在上述脂质体药物制剂中，所述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，其质量比为3:1:1，和/或所述脂质体的粒径为约60nm，所述反离子为硫酸根离子。
第二方面，本发明提供上述脂质体药物制剂在制备用于治疗淋巴瘤的药物中的用途，其中淋巴瘤优选非霍奇金淋巴瘤，进一步优选侵袭性非霍奇金淋巴瘤，更优选弥漫大B细胞淋巴瘤或外周T细胞淋巴瘤，更进一步优选复发难治性的弥漫大B细胞淋巴瘤或外周T细胞淋巴瘤。
本发明提供上述脂质体药物制剂在制备用于治疗淋巴瘤的药物中的用途，其中所述脂质体药物制剂作为单一抗肿瘤治疗剂，不与其他抗肿瘤药物联合应用。
本发明提供上述脂质体药物制剂在制备用于治疗淋巴瘤的药物中的用途，其中所述脂质体药物制剂用于所述淋巴瘤的二线及之后的治疗，优选用于弥漫大B细胞淋巴瘤的三线及之后的治疗，以及用于外周T细胞淋巴瘤的二线及之后的治疗。
本发明提供上述脂质体药物制剂在制备用于治疗淋巴瘤的药物中的用途，其中所述脂质体药物制剂的给药周期为每1-4周给药一次，优选每3-4周给药一次，进一步优选为每4周给药一次。
本发明提供上述脂质体药物制剂在制备用于治疗淋巴瘤的药物中的用途，其中所述脂质体药物制剂的给药剂量为6-30mg/m 2，优选14-24mg/m 2。
本发明提供上述脂质体药物制剂在制备用于治疗淋巴瘤的药物中的用途，其中所述脂质体药物制剂的滴注给药时间为30min-120min，优选60min-120min，进一步优选不少于60min，更优选为60±5min。
本发明提供上述脂质体药物制剂在制备用于治疗淋巴瘤的药物中的用途，其中所述脂质体药物制剂给予每个病人的总给药剂量不超过200mg/m 2，优选不超过160mg/m 2，进一步优选不超过140mg/m 2。
第三方面，本发明提供一种采用上述脂质体药物制剂治疗淋巴瘤的方法，包括向有此需要的对象施用米托蒽醌脂质体药物制剂，其中淋巴瘤优选非霍奇金淋巴瘤，进一步优选侵袭性非霍奇金淋巴瘤，更优选弥漫大B细胞淋巴瘤或外周T细胞淋巴瘤，更进一步优选复发难治性的弥漫大B细胞淋巴瘤或外周T细胞淋巴瘤。
根据上述治疗淋巴瘤的方法，其中施用所述米托蒽醌脂质体药物制剂作为单一抗肿瘤治疗剂，而不与其他抗肿瘤药物联合。
根据上述治疗淋巴瘤的方法，其中所述对象至少已经接受过一线治疗，例如所述对象患有弥漫大B细胞淋巴瘤并且至少已经接受过一线和/或二线治疗，或者例如所述对象患有外周T细胞淋巴瘤并且至少已经接受过一线治疗。
根据上述治疗淋巴瘤的方法，其中每1、2、3、4、5、6、7或8周施用一次所述脂质体药物制剂，优选每3-6周给药一次，进一步优选为每4周施用一次；和/或向所述对象施用1、2、3、4、5或6次所述米托蒽醌脂质体药物制剂，例如2、3、4或5次。
根据上述治疗淋巴瘤的方法，其中所述脂质体药物制剂的给药剂量为6-30mg/m 2，例如8、10、12、14、16、18、20、22、24、26、28或30mg/m 2，优选14-24mg/m 2。
根据上述治疗淋巴瘤的方法，其中以静脉滴注方式向所述对象施用所述脂质体药物制剂，并且滴注给药时间不少于30、40、45、50、60、70、75、80、90、100、110或120min，为30min-120min，优选40min-80min,60min-120min，进一步优选不少于60min，更优选为60min。
根据上述治疗淋巴瘤的方法，其中所述脂质体药物制剂给予每个对象(病人)的总剂量不超过200mg/m 2，优选不超过160mg/m 2，进一步优选不超过140mg/m 2。
根据上述治疗淋巴瘤的方法，其中给药途径可选自口服给药、注射给药和局部给药，优选注射给药；进一步地，注射给药可选自静脉注射、皮下注射、肌肉注射，优选静脉注射；进一步地，静脉注射可选静脉滴注和静脉推注，优选静脉滴注。
根据上述治疗淋巴瘤的方法，其中施用途径为静脉滴注，所述方法包括将所述脂质体稀释于氯化钠注射液或葡萄糖注射液中，优选稀释于葡萄糖注射液中；然后在施用给对象；其中所述氯化钠注射液的浓度为0.5％-1％，优选0.9％；葡萄糖注射液的浓度为1％-10％，优选5％。
根据上述治疗淋巴瘤的方法，包括将所述脂质体药物配制成可直接输注的溶液后再施用给所述对象，其中配制后的可直接输注的脂质体溶液的浓度为0.05mg/ml-0.5mg/ml，优选0.08mg/ml-0.4mg/ml，更优选0.1mg/ml-0.3mg/ml，更优选0.1mg/ml、0.15mg/ml、0.2mg/ml、0.25mg/ml或0.3mg/ml。
根据上述治疗淋巴瘤的方法，经过3个周期(每个周期即意味着施用所述脂质体药物制剂一次)以上的治疗后，其可达到比单用HDAC抑制剂更高的总缓解率(ORR)。
根据上述治疗淋巴瘤的方法，经过3个周期以上的治疗后，该方法的总缓解率(ORR)至少为30％，优选至少为40％；进一步地，所述总缓解率为30％-60％。
其中，病人前期经历过选自以下的一种、二种或更多种治疗：CHOP(环磷酰胺+多柔比星+长春新碱+泼尼松)、DICE(地塞米松+异环磷酰胺+卡铂+依托泊苷)、Gemox(吉西他滨+奥沙利铂)、R-CHOP(利妥昔单抗-环磷酰胺+多柔比星+长春新碱+泼尼松)、EP(足叶乙苷+顺铂)、etoposide(依托泊苷)、R-CHOP+ibrutinib(利妥昔单抗-环磷酰胺+多柔比星+长春新碱+泼尼松+依鲁替尼)、ICE(异环磷酰胺+卡铂+依托泊苷)、R-EPOCH(利妥昔单抗-依托泊苷+长春新碱+吡柔比星+环磷酰胺+强的松)、FC(氟尿嘧啶+卡铂)、GCP(吉西他滨+环磷酰胺+地塞米松)、CHOP+Mesna(环磷酰胺+多柔比星+长春新碱+泼尼松+美司钠)、R-MTX(利妥昔单抗-氨甲蝶呤)、GEMOX+TNF(吉西他滨+奥沙利铂+人肿瘤坏死因子)、ECOP(足叶乙甙、环磷酰胺、长春新碱、强的松)、CTP(环磷酰胺+沙利度胺+强的松)、EPP(依托泊苷+顺铂+地塞米松)、OB(博来霉素+长春新碱)、ABVD(阿霉素、博莱霉素、长春花碱、氮烯唑胺)、CDOP(环磷酰胺+多柔比星脂质体+长春新碱+泼尼松)、GDP(吉西他滨+顺铂+地塞米松)、DICE+Chidamide(地塞米松+异环磷酰胺+卡铂+依托泊苷+西达本胺)、R-DA-EPOCH(利妥 昔单抗-柔红霉素+阿糖胞苷-依托泊苷+长春新碱+吡柔比星+环磷酰胺+强的松)、GDE(吉西他滨+顺铂+依托泊苷)、R-GDP(利妥昔单抗-吉西他滨+顺铂+地塞米松)、R(利妥昔单抗)、R-GDE(利妥昔单抗-吉西他滨+顺铂+依托泊苷)。
在一个方面中，本发明提供一种脂质体药物制剂，其包含米托蒽醌脂质体，所述脂质体含有活性成分米托蒽醌，其中米托蒽醌和脂质体内的多价反离子形成难以溶解的沉淀，脂质体的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，从而使脂质体的相转变温度高于体温。
在一个实施方案中，所述脂质体的粒径为约30-80nm，例如约35-75nm，优选40-70nm，进一步优选40-60nm，特别优选60nm。
在另一个实施方案中，所述Tm高于体温的磷脂选自磷脂酰胆碱、氢化大豆卵磷脂、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂及其任何组合。
在另一个实施方案中，所述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，其质量比为3:1:1，所述反离子为硫酸根离子。
在另一方面中，本发明提供一种治疗淋巴瘤的方法，其包括向有此需要的对象施用米托蒽醌脂质体药物制剂，例如本发明上述方面中所述的脂质体药物制剂。
优选地所述淋巴瘤是非霍奇金淋巴瘤，进一步优选侵袭性非霍奇金淋巴瘤，更优选弥漫大B细胞淋巴瘤或外周T细胞淋巴瘤，更进一步优选复发难治性的弥漫大B细胞淋巴瘤或外周T细胞淋巴瘤，例如所述外周T细胞淋巴瘤选自非特指型外周T细胞淋巴瘤、血管免疫母T细胞淋巴瘤、ALK+系统性间变大T细胞淋巴瘤、ALK-系统性间变大T细胞淋巴瘤、结外NK/T细胞淋巴瘤，鼻型、肠病相关T细胞淋巴瘤、原发肝脾γδT细胞淋巴瘤和皮下脂膜炎样T细胞淋巴瘤。
在一个实施方案中，所述施用是施用所述米托蒽醌脂质体药物制剂作为单一抗肿瘤治疗剂，而不与其他抗肿瘤药物联合。
在另一个实施方案中，所述对象至少已经接受过一线治疗，例如所 述对象患有弥漫大B细胞淋巴瘤并且至少已经接受过一线和/或二线治疗，或者例如所述对象患有外周T细胞淋巴瘤并且至少已经接受过一线治疗。
在再一个实施方案中，所述对象前期经历过选自以下的一种、二种或更多种治疗：CHOP(环磷酰胺+多柔比星+长春新碱+泼尼松)、DICE(地塞米松+异环磷酰胺+卡铂+依托泊苷)、Gemox(吉西他滨+奥沙利铂)、R-CHOP(利妥昔单抗-环磷酰胺+多柔比星+长春新碱+泼尼松)、EP(足叶乙苷+顺铂)、etoposide(依托泊苷)、R-CHOP+ibrutinib(利妥昔单抗-环磷酰胺+多柔比星+长春新碱+泼尼松+依鲁替尼)、ICE(异环磷酰胺+卡铂+依托泊苷)、R-EPOCH(利妥昔单抗-依托泊苷+长春新碱+吡柔比星+环磷酰胺+强的松)、FC(氟尿嘧啶+卡铂)、GCP(吉西他滨+环磷酰胺+地塞米松)、CHOP+Mesna(环磷酰胺+多柔比星+长春新碱+泼尼松+美司钠)、R-MTX(利妥昔单抗-氨甲蝶呤)、GEMOX+TNF(吉西他滨+奥沙利铂+人肿瘤坏死因子)、ECOP(足叶乙甙、环磷酰胺、长春新碱、强的松)、CTP(环磷酰胺+沙利度胺+强的松)、EPP(依托泊苷+顺铂+地塞米松)、OB(博来霉素+长春新碱)、ABVD(阿霉素、博莱霉素、长春花碱、氮烯唑胺)、CDOP(环磷酰胺+多柔比星脂质体+长春新碱+泼尼松)、GDP(吉西他滨+顺铂+地塞米松)、DICE+Chidamide(地塞米松+异环磷酰胺+卡铂+依托泊苷+西达本胺)、R-DA-EPOCH(利妥昔单抗-柔红霉素+阿糖胞苷-依托泊苷+长春新碱+吡柔比星+环磷酰胺+强的松)、GDE(吉西他滨+顺铂+依托泊苷)、R-GDP(利妥昔单抗-吉西他滨+顺铂+地塞米松)、R(利妥昔单抗)、和R-GDE(利妥昔单抗-吉西他滨+顺铂+依托泊苷)。
在本发明的治疗方法中，例如可以如下实施所述治疗：
每1、2、3、4、5、6、7或8周施用一次所述米托蒽醌脂质体药物制剂，优选每3-6周施用一次，进一步优选每4周施用一次；和/或
向所述对象施用1、2、3、4、5或6次所述米托蒽醌脂质体药物制剂，例如2、3、4或5次；和/或
以6-30mg/m 2，例如8、10、12、14、16、18、20、22、24、26、28或30mg/m 2，优选14-24mg/m 2的剂量向所述对象施用所述米托蒽醌脂质体药物制剂。
在一个实施方案中，以静脉滴注方式向所述对象施用所述米托蒽醌脂质体药物制剂，并且滴注时间不少于30、40、45、50、60、70、75、80、90、100、110或120min，优选为40-80min，更优选为约60min。
在另一个实施方案中，向所述对象施用的所述脂质体药物制剂的总剂量不超过200mg/m 2，例如不超过120、140、160、180或200mg/m 2，优选不超过160mg/m 2，进一步优选不超过140mg/m 2。
在一个实施方案中，本发明的治疗方法包括向所述对象施用3次或更多次米托蒽醌脂质体药物制剂进行治疗，所述方法达到比单用HDAC抑制剂更高的总缓解率(ORR)。
在一个实施方案中，本发明的治疗方法包括向所述对象施用3次或更多次米托蒽醌脂质体药物制剂进行治疗，该方法的总缓解率(ORR)至少为30％，优选至少为40％；进一步地，所述总缓解率为30％-60％。
具体实施方式
实施例1 米托蒽醌脂质体的制备
将HSPC、Chol和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。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lh，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米托蒽醌盐酸盐溶液(10mg/mL)，在60-65℃进行载药。孵育约lh后，使用凝胶排阻色谱可证明包封效率约为100％。其中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。
实施例2 米托蒽醌脂质体稳定性考察
将上述方法制备的米托蒽醌脂质体分别以5％葡萄糖注射液、0.9％氯 化钠注射液(生理盐水)作为稀释剂，玻璃输液瓶为容器，配制浓度为0.1mg/ml和0.2mg/ml两种规格，分别考察在30℃、30℃避光、2-8℃冷藏条件下的0h、2h、4h、6h、8h、24h六个时间节点溶液的pH、脂质体的平均粒径、包封药物浓度、磷脂、溶血卵磷脂、有关物质、含量等参数，实验结果如下表1-4所示。
表1-使用5％的葡萄糖注射液稀释的米托蒽醌脂质体的稳定性，玻璃输液瓶，0.1mg/mL
Figure PCTCN2019095396-appb-000002
Figure PCTCN2019095396-appb-000003
N/A:不适用；ND:未检测
表2-使用0.9％的氯化钠注射液稀释的米托蒽醌脂质体的稳定性，玻璃输液瓶，0.1mg/mL
Figure PCTCN2019095396-appb-000004
Figure PCTCN2019095396-appb-000005
N/A:不适用；ND:未检测
表3-使用5％的葡萄糖注射液稀释的米托蒽醌脂质体的稳定性，玻璃输液瓶，0.2mg/mL
Figure PCTCN2019095396-appb-000006
Figure PCTCN2019095396-appb-000007
N/A:不适用；ND:未检测
表4-使用0.9％的氯化钠注射液稀释的米托蒽醌脂质体的稳定性，玻璃输液瓶，0.2mg/mL
Figure PCTCN2019095396-appb-000008
Figure PCTCN2019095396-appb-000009
N/A:不适用；ND:未检测
上述结果显示，在相同浓度、相同储存条件下，采用葡萄糖注射液和氯化钠注射液为稀释剂，所得溶液随时间变化的pH、包封药物浓度、磷脂、溶血卵磷脂、有关物质、含量等参数无显著差异，但米托蒽醌脂质体的平均粒径却有较大差异，以0.9％氯化钠注射剂为稀释剂时从0h至24h的米托蒽醌脂质体的平均粒径有明显的增大趋势，而以0.5％葡萄糖注射剂为稀释剂时，从0h至24h的脂质体药物平均粒度变化不大。
另外，在相同稀释剂、相同储存条件下，米托蒽醌脂质体药物浓度为0.1mg/ml与0.2mg/ml的溶液的随时间变化的pH、平均粒径、包封药物浓度、磷脂、溶血卵磷脂、有关物质、含量等参数无显著差异。
实施例3 给药方法示例
将上述得到的米托蒽醌脂质体(规格10mg/10ml/支)溶于250ml的5％葡萄糖注射液中，滴注时间为60分钟。由一侧前臂静脉滴注，给药时采取半卧位，静脉给药过程均有临床医生的监督。
实施例4 米托蒽醌脂质体单独使用治疗DLBCL
入选标准：
进行了一项米托蒽醌脂质体治疗DLBCL和外周T/NK细胞淋巴瘤的II期临床研究，此研究的入选标准如下：
1)志愿受试并签署知情同意书；
2)年龄18-75周岁，性别不限；
3)ECOG评分0-2级；
4)预期生存时间≥3个月；
5)组织病理学证实的弥漫大B细胞和外周T/NK细胞的非霍奇金淋巴瘤，且外周T/NK细胞淋巴瘤仅限以下几种类型：外周T细胞淋巴瘤(非特指型)、血管免疫母T细胞淋巴瘤、ALK+系统性间变大T细胞淋巴瘤、ALK-系统性间变大T细胞淋巴瘤、结外NK/T细胞淋巴瘤，鼻型、肠病相关T细胞淋巴瘤、原发肝脾γδT细胞淋巴瘤、皮下脂膜炎样T细胞淋巴瘤；
6)既往接受过至少一次系统性治疗失败或复发，且无条件行自体外周血造血干细胞移植患者；
7)至少有一个可测量病灶，单个可测量病灶长径≥1.5cm；
8)目标肿瘤距离上一次化疗、放疗、生物治疗、干细胞移植或其他试验性药物治疗后间隔至少4周；
9)育龄受试者同意在试验期间采取有效的避孕措施；女性血妊娠检查结果为阴性(绝经后或手术导致不育的除外)；
10)器官功能水平基本正常。
安全性评价：
安全性评估包括不良事件、体格检查和其它检查(血常规、尿常规、血生化、心电图、心脏彩超)，以及因安全性或耐受性原因而提前退出的情况。安全性评价标准：NCI-CTC4.0。
有效性评价：
疗效性评价的方法：患者在基线期进行一次肿瘤评估，以肿瘤部位CT扫描结果为准。根据恶性淋巴瘤国际工作组(IWC)标准(2007年)进行疗效评价。
有效性分析：
在此研究中，我们针对DLBCL患者进行分析，受试者平均接受3.0±2.0周期药物进行治疗米托蒽醌脂质体使用剂量为16mg/m 2或20mg/m 2，28天给药一次，19例可评价疗效的DLBCL患者中，10例达到了CR或PR，ORR为52.6％。
联合化疗方案的ORR约为60％-70％(ICE方案：异环磷酰胺、卡铂和依托泊苷三种药物联用的ORR为66％；利妥昔单抗、依托泊苷、甲泼尼松、阿糖胞苷和顺铂五种药物联用的ORR为73％)(Treatment challenges in the management of relapsed or refractory non-Hodgkin’s lymphoma–novel and emerging therapies,Journal of Cancer Management and Research,Mark P Chao et al.,2013,Vol.5,pp.251-269)，与本实施例中米托蒽醌脂质体单独使用的疗效相当，无统计学差异。
米托蒽醌脂质体临床单独使用治疗DLBCL的疗效详见下表5。
表5 米托蒽醌脂质体临床单独使用治疗DLBCL的疗效
Figure PCTCN2019095396-appb-000010
Figure PCTCN2019095396-appb-000011
Figure PCTCN2019095396-appb-000012
注：上述各缩写含义如下：
CR：完全缓解，定义为所有疾病证据消失。
PR：局部缓解，定义为可测量病灶缩小，且无新发病灶。
PD：疾病进展，定义为出现任何新发病灶，或原有病灶较最低点增大≥50％。
SD：疾病稳定，定义为不属于任何一种情况。
总缓解率(ORR)＝(CR+PR)/总的可评价病例数*100％
实施例5 米托蒽醌脂质体单独使用治疗DLBCL的不良反应分析：
安全性分析：
对上述DLBCL受试者发生的不良反应进行分析，不良反应发生率最高的为血液学毒性。
在血液学毒性中，31.4％受试者发生3级以上白细胞计数降低，28.6％受试者发生3级中性以上粒细胞降低，5.7％受试者发生3级以上血小板降低。这远低于背景技术中分析的文献(Phase II study of the irinotecan(CPT-11),mitoxantrone and dexamethasone regimen in elderly patients with relapsed or refractory peripheral T-cell lymphoma,Journal of Cancer Sci,Nozomi Niitsu et al.,2007,Vol.98,pp.109-112)中记载的血液学毒性(在该研究中，18例(60％)发生了3-4级血液学毒性。8例(27％)尽管使用了升高白血胞的药物(G-CSF)仍发生了4级中性粒细胞降低。5例(16.7％)发生了3-4级血小板降低)。
在非血液学毒性中，5.7％受试者发生了3级以上低白蛋白血症，5.7％受试者发生了3级以上肺部感染，2.9％受试者发生了3级以上肠梗阻，2.9％受试者发生了3级食欲减退。
实施例6 米托蒽醌脂质体单独使用治疗PTCL
入选标准、给药方法、安全性及疗效评价同实施例1。
我公司研制的米托蒽醌脂质体在治疗PTCL的定位为二线治疗，本品在临床研究中的ORR为52.9％，与目前二线推荐的HDAC抑制剂包括普拉曲沙、罗米地辛、贝林司他及西达本胺等相比(HDAC抑制剂为口服制剂，每天给药1次，ORR均低于30％)，远高于HDAC抑制剂。短期内达到缓解的患者，可以及时进行骨髓移植。
米托蒽醌脂质体为注射剂，使用剂量为14、16、20mg/m 2或24mg/m 2，28天给药1次。本次研究的受试者平均接受3.6±1.8周期的治疗。
米托蒽醌脂质体临床单独使用治疗PTCL的疗效详见下表6。
表6 米托蒽醌脂质体临床单独使用治疗PTCL的疗效
Figure PCTCN2019095396-appb-000013
Figure PCTCN2019095396-appb-000014
注：其中，CR、PR、PD、SD、ORR、疗效性评价的方法和疗效评估标准等含义如表5“注”部分所述。
实施例7 米托蒽醌脂质体单独使用治疗PTCL的不良反应分析：
对15例PTCL患者发生的不良反应进行分析，不良反应发生率最高的为血液学毒性。
在血液学毒性中，9例(60.0％)受试者发生3级白细胞计数降低，3例(20％)受试者发生4级白细胞计数降低；7例(46.7％)受试者发生3级中性粒细胞降低，1例(6.7％)受试者发生4级中性粒细胞降低；1例受试者发生3级血小板降低；1例受试者发生3级血红蛋白降低；1例受试者发生3级红细胞计数降低。
在非血液学毒性中，无3级以上毒性发生。
通过对比，尽管3-4级血液学毒性发生率相近，但4级中性粒细胞降低及3-4级血小板降低的发生率均低于前面文献报道的CMD方案。

Claims (13)

  1. 一种治疗淋巴瘤的方法，包括向有此需要的对象施用米托蒽醌脂质体药物制剂，其中：所述米托蒽醌脂质体药物制剂包含米托蒽醌脂质体，
    所述米托蒽醌脂质体的粒径为约30-80nm，并且含有活性成分米托蒽醌，其中米托蒽醌和脂质体内的多价反离子形成难以溶解的沉淀，脂质体的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，从而使脂质体的相转变温度高于体温；
    所述淋巴瘤优选非霍奇金淋巴瘤，进一步优选侵袭性非霍奇金淋巴瘤，更优选弥漫大B细胞淋巴瘤或外周T细胞淋巴瘤，更进一步优选复发难治性的弥漫大B细胞淋巴瘤或外周T细胞淋巴瘤；例如所述外周T细胞淋巴瘤选自非特指型外周T细胞淋巴瘤、血管免疫母T细胞淋巴瘤、ALK+系统性间变大T细胞淋巴瘤、ALK-系统性间变大T细胞淋巴瘤、结外NK/T细胞淋巴瘤，鼻型、肠病相关T细胞淋巴瘤、原发肝脾γδT细胞淋巴瘤和皮下脂膜炎样T细胞淋巴瘤。
  2. 如权利要求1所述的方法，其中所述Tm高于体温的磷脂选自磷脂酰胆碱、氢化大豆卵磷脂、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂及其任何组合；和/或所述脂质体粒径为约35-75nm，优选40-70nm，进一步优选40-60nm，特别优选60nm。
  3. 如权利要求1或2所述的方法，其中所述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，其质量比为3:1:1，和/或所述脂质体粒径为约60nm，和/或所述反离子为硫酸根离子。
  4. 如权利要1至3中任一项所述的方法，其中施用所述米托蒽醌脂质体药物制剂作为单一抗肿瘤治疗剂，而不与其他抗肿瘤药物联合。
  5. 如权利要求1至4中任一项所述的方法，其中所述对象至少已经接受过一线治疗，例如所述对象患有弥漫大B细胞淋巴瘤并且至少已经接受过一线和/或二线治疗，或者例如所述对象患有外周T细胞淋巴瘤并且至少已经接受过一线治疗。
  6. 如权利要求1至5中任一项所述的方法，其中每1、2、3、4、5、6、7或8周施用一次所述米托蒽醌脂质体药物制剂，优选每3-6周施用一次，进一步优选每4周施用一次；和/或
    向所述对象施用1、2、3、4、5或6次所述米托蒽醌脂质体药物制剂，例如2、3、4或5次；和/或以6-30mg/m 2，例如8、10、12、14、16、18、20、22、24、26、28或30mg/m 2，优选14-24mg/m 2的剂量向所述对象施用所述米托蒽醌脂质体药物制剂。
  7. 如权利要求1至6中任一项所述的方法，其中以静脉滴注方式向所述对象施用所述脂质体药物制剂，并且滴注给药时间不少于30、40、45、50、60、70、75、80、90、100、110或120min，优选40-80min，更优选为60min。
  8. 如权利要求1至7中任一项所述的方法，其中向所述对象施用的所述脂质体药物制剂的总剂量不超过200mg/m 2，例如不超过120、140、160、180或200mg/m 2，优选不超过160mg/m 2，进一步优选不超过140mg/m 2。
  9. 如权利要求1至8中任一项所述的方法，其中施用途径选自口服施用、注射施用和局部施用，优选注射施用；进一步地，注射施用选自静脉注射、皮下注射和肌肉注射，优选静脉注射；进一步地，静脉注射选自静脉滴注和静脉推注，优选静脉滴注。
  10. 如权利要求1至9中任一项所述的方法，其中施用途径为静脉滴注，所述方法包括将所述米托蒽醌脂质体溶于氯化钠注射液或葡萄糖注射液中，优选溶于葡萄糖注射液中，然后再施用给所述对象；其中所述氯化钠注射液的浓度为0.5％-1％，优选0.9％；所述葡萄糖注射液的浓度为1％-10％，优选5％。
  11. 如权利要求1至10中任一项所述的方法，包括将所述米托蒽醌脂质体配制成可直接输注的溶液后再施用给所述对象，其中配制后的可直接输注的脂质体溶液的浓度为0.05mg/ml-0.5mg/ml，优选0.08mg/ml-0.4mg/ml，更优选0.1mg/ml-0.3mg/ml，更优选0.1mg/ml、0.15mg/ml、0.2mg/ml、0.25mg/ml或0.3mg/ml。
  12. 如权利要求1至11中任一项所述的方法，包括向所述对象施用3次或 更多次米托蒽醌脂质体药物制剂进行治疗，所述方法达到比单用HDAC抑制剂更高的总缓解率(ORR)。
  13. 如权利要求12所述的方法，包括向所述对象施用3次或更多次米托蒽醌脂质体药物制剂进行治疗，该方法的总缓解率(ORR)至少为30％，优选至少为40％；进一步地，所述总缓解率为30％-60％。
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CN117940164A (zh) * 2022-04-26 2024-04-26 石药集团中奇制药技术（石家庄）有限公司 米托蒽醌脂质体联合抗血管生成靶向药治疗卵巢癌的用途

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