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WO2024017293A1 - 盐酸米托蒽醌脂质体的用途 - Google Patents

盐酸米托蒽醌脂质体的用途 Download PDF

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Publication number
WO2024017293A1
WO2024017293A1 PCT/CN2023/108139 CN2023108139W WO2024017293A1 WO 2024017293 A1 WO2024017293 A1 WO 2024017293A1 CN 2023108139 W CN2023108139 W CN 2023108139W WO 2024017293 A1 WO2024017293 A1 WO 2024017293A1
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Prior art keywords
mitoxantrone hydrochloride
neuromyelitis optica
liposomes
optica spectrum
mitoxantrone
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PCT/CN2023/108139
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English (en)
French (fr)
Inventor
李春雷
刘佳琪
李彦辉
于玉楼
杨修诰
李萌萌
吴国华
杜艳玲
周蒙
王世霞
李超
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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Priority to CN202380053512.1A priority Critical patent/CN119562804A/zh
Priority to EP23842355.2A priority patent/EP4559455A1/en
Priority to JP2025502655A priority patent/JP2025523701A/ja
Publication of WO2024017293A1 publication Critical patent/WO2024017293A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers

Definitions

  • the present application relates to the field of medicine, and specifically to the use of mitoxantrone hydrochloride liposomes, for example, in the treatment of neuromyelitis optica spectrum diseases.
  • NMOSD Neuromyelitis optica spectrum disorder
  • AQP4 Protein 4 (aquaporin-4, AQP4) antibody-related, mediated by autoantibodies, dominated by humoral immunity, and participated by a variety of immune cells and factors.
  • NMOSD occurs in all age groups, mostly in young adults, with the average age of onset being about 40 years old, and most patients are serum AQP4-IgG positive.
  • AQP4-IgG positive patients the ratio of female to male is as high as (4.7-11):1.
  • NMOSD neurodegenerative disease originating from a central nervous system.
  • More than 90% of patients have a multi-temporal disease course, of which 40%-60% relapse within 1 year and about 90% relapse within 3 years.
  • About 50% of patients with the natural course of the disease have severe visual or motor dysfunction within 5-10 years (Neuroimmunology Branch of the Chinese Society of Immunology, Huang Dehui, Wu Weiping. Chinese Guidelines for the Diagnosis and Treatment of Neuromyelitis Optica Spectrum Diseases (2021 Edition) ). Chinese Journal of Neuroimmunology and Neurology, Volume 28, Issue 6, November 2021).
  • NMOSD multiple sclerosis
  • MS multiple sclerosis
  • Certain MS drugs may aggravate NMOSD.
  • the disease worsens (Ji Wei, Wang Limei, Tan Song. Progress in differential diagnosis and treatment of laboratory indicators of neuromyelitis optica and multiple sclerosis. Chinese Journal of Practical Neurological Diseases, June 2016, Volume 19, Issue 10).
  • NMOSD neurodegenerative disease 2019
  • sequential treatment relapse prevention treatment
  • symptomatic treatment rehabilitation treatment
  • the purpose of acute phase treatment is to reduce irreversible nerve damage, promote functional recovery, and reduce mortality.
  • High-dose hormone pulse therapy, plasma exchange or immunoadsorption, and intravenous injection of human immunoglobulin are often used; the main purpose of sequential treatment is It is to reduce the recurrence rate and reduce the severity of the patient's disability.
  • Commonly used clinical drugs include monoclonal antibodies and immunotherapy.
  • first-line drugs include satelizumab, inalizumab, rituximab, azathioprine, and mycophenolate mofetil; second-line drugs include tacrolimus, cyclosporine A , cyclophosphamide, methotrexate and mitoxantrone, etc.
  • second-line drugs include tacrolimus, cyclosporine A , cyclophosphamide, methotrexate and mitoxantrone, etc.
  • Mitoxantrone Hydrochloride is an anthraquinone chemotherapy drug.
  • the FDA-approved indications for Mitoxantrone Hydrochloride General Injection are multiple sclerosis, prostate cancer and acute myeloid leukemia; it is approved in China for lymphoma,
  • the recommended dose for adults is 12-14 mg/m 2 as a single drug, once every 3-4 weeks; or 4-8 mg/m 2 once a day, for 3-5 days, with an interval of 2-3 weeks ;
  • the combined dosage is 5-10 mg/m 2 once.
  • the main adverse reactions of mitoxantrone include cardiotoxicity, bone marrow suppression, and gastrointestinal reactions.
  • Doxil doxorubicin hydrochloride liposome
  • ovarian cancer the recommended dose is 50 mg/m 2 , intravenously administered once every 4 weeks;
  • Kaposi's sarcoma the recommended dose is 20 mg/m 2 , administered intravenously every 3 weeks;
  • Multiple myeloma the recommended dose is 30 mg/m 2 , administered intravenously on the fourth day after bortezomib administration .
  • Abraxane paclitaxel for injection [albumin-bound]
  • Metastatic breast cancer the recommended dose is 260 mg/m 2 , intravenously infused for 30 minutes, given every 3 weeks.
  • non-small cell lung cancer recommended dose 100 mg/m 2 , intravenous infusion for 30 minutes, a course of treatment every 21 days, administered on the 1st, 8th and 15th day; injection on the 1st day Carboplatin is given immediately after the administration of paclitaxel (albumin-bound), once every 21 days;
  • Pancreatic cancer the recommended dose is 125 mg/m 2 , intravenously infused for 30-40 minutes, with a cycle of 28 days , administered once on days 1, 8, and 15, and gemcitabine was administered immediately after each administration of paclitaxel for injection (albumin-bound).
  • AmBisome amphotericin B liposome for injection
  • empiric treatment recommended dose 3mg/kg/day
  • systemic fungal infection Aspergillus, Candida
  • Cryptococcus the recommended dose is 3 to 5 mg/kg/day
  • cryptococcal meningitis in HIV-infected patients the recommended dose is 6 mg/kg/day (days 1-5), 3 mg/kg/day (day 1-5) 4, 21 days)
  • Patients with visceral leishmaniasis with low immune function 4mg/kg/day (1st- 5 days), 4 mg/kg/day (days 10, 17, 24, 31, and 38); dosage and dosing data are personalized according to the patient's actual situation to achieve maximum efficacy and minimum toxicity or adverse reactions.
  • Dosage and administration data should be personalized according to the specific disease and the actual situation of the patient to achieve maximum efficacy and minimum toxicity or adverse reactions, and achieve safe and effective treatment of the disease.
  • a special dosage form that is different from ordinary injections, its absorption, distribution, and metabolism after entering the body are very complex.
  • the treatment of different indications, especially the treatment of different tumors, is also difficult. It is difficult to simply extrapolate from one indication to another.
  • the present application provides the use of mitoxantrone hydrochloride liposomes in the treatment of neuromyelitis optica spectrum diseases.
  • the inventor of the present application unexpectedly discovered during research that mitoxantrone hydrochloride liposomes have a good therapeutic effect on neuromyelitis optica spectrum diseases and can be used to prepare related drugs.
  • the present application provides the use of mitoxantrone hydrochloride liposomes in the preparation of drugs for treating neuromyelitis optica spectrum diseases.
  • the application provides a method of treating neuromyelitis optica spectrum disorder in an individual, comprising administering to the individual a therapeutically effective amount of mitoxantrone hydrochloride liposomes or comprising a therapeutically effective amount of mitoxantrone hydrochloride liposomes body pharmaceutical compositions.
  • the present application provides mitoxantrone hydrochloride liposomes or pharmaceutical compositions comprising mitoxantrone hydrochloride liposomes for use in treating neuromyelitis optica spectrum disorders in an individual.
  • the neuromyelitis optica spectrum disease described in the first to third aspects above is a highly relapsing neuromyelitis optica spectrum disease.
  • the highly relapsing neuromyelitis optica spectrum disorder is a highly relapsing neuromyelitis optica spectrum disorder that has failed other medical treatments.
  • the other drugs are selected from first-line, second-line or above second-line drugs for neuromyelitis optica spectrum diseases, especially in China or abroad (such as the United States , European Union, Japan, South Korea, etc.) first-line, second-line or above second-line drugs approved by the drug regulatory authorities for the treatment of neuromyelitis optica spectrum diseases, including but not limited to: FDA-approved glucocorticoids, monoclonal antibody drugs and immunosuppressants wait.
  • mitoxantrone hydrochloride liposomes are used as the sole active ingredient for the treatment of neuromyelitis optica spectrum diseases or as the sole active ingredient for the preparation of a medicament or pharmaceutical composition for the treatment of neuromyelitis optica spectrum diseases.
  • the pharmaceutical composition or medicine containing mitoxantrone hydrochloride liposomes in the above first to third aspects is an injection form, including liquid injection, injection powder, injection tablet, etc. wait.
  • the pharmaceutical composition or medicine containing mitoxantrone hydrochloride liposome is a liquid injection.
  • the content of mitoxantrone in the drug or pharmaceutical composition is calculated as mitoxantrone. is 0.5-5mg/mL. In a preferred embodiment, the content of mitoxantrone in the drug is 1-2 mg/mL. In a more preferred embodiment, the content of mitoxantrone in the drug or pharmaceutical composition is 1 mg/mL.
  • the therapeutically effective amount in the above second aspect is 4-30 mg/m 2 based on mitoxantrone, such as 8-20 mg/m 2 or 12-30 mg/m 2 , or any 2 of the above Doses in a range between doses, for example, 8 mg/m 2 , 12 mg/m 2 , etc.
  • the mitoxantrone hydrochloride liposomes, pharmaceutical compositions or medicaments containing mitoxantrone hydrochloride liposomes of the present application are administered to the subject in need by intravenous administration.
  • the administration cycle of the mitoxantrone hydrochloride liposomes, pharmaceutical compositions or medicaments containing mitoxantrone hydrochloride liposomes of the present application is once every 12 weeks.
  • the liposomes are used alone to treat neuromyelitis optica spectrum disorders in an individual.
  • the therapeutically effective amount of the liposome (based on mitoxantrone) is 4-30 mg/m 2 , such as 8-20 mg/m 2 or 12-30 mg/m 2 , or any of the above A dose in the range between 2 doses, for example, 8 mg/m 2 or 12 mg/m 2 .
  • the liposomes are administered intravenously.
  • the liposomes are administered every 12 weeks.
  • the dosage stated is based on mitoxantrone unless otherwise stated.
  • the mitoxantrone hydrochloride liposomes can be prepared by methods known in the art, and can be mitoxantrone hydrochloride liposomes prepared by any method disclosed in the prior art, for example, using Prepared by the method disclosed in WO2008/080367A1.
  • the drug, mitoxantrone hydrochloride liposome, or pharmaceutical composition comprising the mitoxantrone hydrochloride liposome in the above-mentioned first to third aspects has one or more of the following Item 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.
  • Mitoxantrone hydrochloride liposomes are mitoxantrone hydrochloride liposomes with national drug approval number H20220001.
  • the mitoxantrone hydrochloride liposomes described herein have a particle size of about 30-80 nm, for example, any value between 30-80 nm. In some embodiments, the particle size is about 35-75 nm, preferably 40-70 nm, more preferably 40-60 nm, such as 60 nm.
  • the mitoxantrone hydrochloride liposomes described herein contain the active ingredient mitoxantrone and a phospholipid bilayer.
  • the active ingredient mitoxantrone can form an insoluble precipitate with multivalent counterions within the liposome.
  • the counterion is sulfate, citrate, or phosphate.
  • the phospholipid bilayer described above contains phospholipids with a phase transition temperature (Tm) higher than body temperature, such that the phase transition temperature of the liposome is higher than body temperature.
  • Tm phase transition temperature
  • the phospholipid with a Tm above body temperature is phosphatidylcholine, hydrogenated soy lecithin, hydrogenated egg yolk lecithin, dispalmitate lecithin, or distearate lecithin, or any combination thereof.
  • the phospholipid bilayer contains hydrogenated soy lecithin, cholesterol, and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine. In some embodiments, the mass ratio of hydrogenated soy lecithin, cholesterol and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine in the phospholipid bilayer is 3:1:1.
  • the mitoxantrone hydrochloride liposomes described herein have a particle size of about 60 nm, and the counterions within the liposomes are sulfate ions.
  • the phospholipid bilayer of the mitoxantrone hydrochloride liposomes described herein contains hydrogenated soy lecithin, cholesterol, and polyethylene glycol 2000-modified distearyl in a mass ratio of 3:1:1 Acyl phosphatidylethanolamine, the particle size of the liposome is about 40-60nm, and the counter ion in the liposome is sulfate ion.
  • the weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone in the mitoxantrone hydrochloride liposomes described herein is 9.58:3.19:3.19:1.
  • mitoxantrone liposomes are prepared as follows: HSPC (hydrogenated soy lecithin), Chol (cholesterol) and DSPE-PEG2000 (polyethylene glycol 2000 modified distearoyl phosphatidyl Ethanolamine) was weighed according to the mass ratio of (3:1:1) and dissolved in 95% ethanol to obtain a clear solution. Mix the ethanol solution of phospholipids with 300mM ammonium sulfate solution, and hydrate with shaking at 60-65°C for 1 hour to obtain uneven multi-lamellar liposomes. A microfluidic device was then used to reduce the particle size of the liposomes.
  • HSPC hydrogenated soy lecithin
  • Chol cholesterol
  • DSPE-PEG2000 polyethylene glycol 2000 modified distearoyl phosphatidyl Ethanolamine
  • the obtained sample was diluted 200 times with a NaCl solution with a concentration of 0.9%, and then tested with NanoZS.
  • the particles The average particle size is about 60nm, and the main peak is 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.
  • mitoxantrone hydrochloride solution (10 mg/mL)
  • the encapsulation efficiency was demonstrated to be approximately 100% using gel exclusion chromatography.
  • the weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone 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.
  • lipid-to-drug ratio parameters in preparing specific liposome drug preparations those skilled in the art can design, test and ultimately obtain a suitable lipid-to-drug ratio to maximize the drug loading capacity while reducing the amount of drug leakage.
  • a wide range of lipid-to-drug ratios can be used, for example, as low as 2:1 or as high as 30:1, 40:1 or 50:1.
  • a more 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.
  • mammals such as humans, but may also be other mammals, such as domestic animals or experimental animals.
  • treatment means the administration of mitoxantrone hydrochloride liposomes or formulations described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes: ( i) inhibit a disease or disease state, i.e. arrest its progression; (ii) alleviate a disease or disease state, i.e. i.e. regress the disease or disease state.
  • terapéuticaally effective amount means a mitoxantrone hydrochloride lipid of the present application that (i) treats a specified disease, condition, or disorder, or (ii) reduces, ameliorates, or eliminates one or more symptoms of a specified disease, condition, or disorder.
  • the amount of mitoxantrone hydrochloride liposomes of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can routinely are determined by those skilled in the art based on their own knowledge and the disclosure herein.
  • mitoxantrone hydrochloride liposomes or pharmaceutical compositions comprising the mitoxantrone hydrochloride liposomes, such as mitoxantrone hydrochloride liposomes Quinone liposome injection has one or more of the following beneficial effects in the treatment of neuromyelitis optica spectrum diseases: safe tolerance, low toxic and side effects, improved treatment effectiveness, delaying the recurrence of neuromyelitis optica spectrum diseases, etc.
  • Figure 1 shows the body weight analysis of animals with neuromyelitis optica, data are expressed as Mean ⁇ SEM, ***P ⁇ 0.001.
  • Figure 2 shows a representative image of AQP4 immunofluorescence staining, Bar: 200 ⁇ m.
  • Figure 3 shows the statistics of the number of AQP4-positive cells. The data are expressed as Mean ⁇ SEM, *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
  • Example 1 The improving effect of mitoxantrone liposome on the NMOSD model induced by AQP4 antibody/complement combination in clinical patients
  • the NMOSD model can be induced by directly injecting AQP4 antibodies and human complement from clinically confirmed patients into the cerebral hemispheres or intraventricular ventricles of mice (Saadoun S, Waters P, Bell BA, et al. Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optical lesions in mice.Brain.2010,133:349-61). Therefore, in this example, the above modeling method was selected to study the therapeutic effect of mitoxantrone liposomes on NMOSD.
  • mice male CD-1 mice, 8 weeks old, purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd.
  • Test drug Mitoxantrone hydrochloride liposome injection 1.0 mg/ml (test product).
  • the blank group is the sham operation group.
  • the animal modeling process is the same as that of the model group and the test group, but no antibodies and complements are injected.
  • the animals in the test group were given a single intravenous injection of mitoxantrone hydrochloride liposome injection 15 mg/kg on the first day of modeling.
  • AQP4 purchased from Abclonal, item number: A2887, batch number: 0073660402;
  • GFAP purchased from Huaan Biotech, item number: EM140707, batch number: HO0604;
  • Goat Pab to Rabbit 594 purchased from abcam, item number: ab150080, batch number: GR3439696-1;
  • CD-1 mice were used to establish a neuromyelitis optica disease model by intracerebroventricular injection of AQP4 antibody/complement from clinically confirmed patients using stereotactic brain stereotaxic methods, and relevant histological tests were conducted to evaluate the effects of the compounds to be tested.
  • the number of AQP4-positive cells in the test group was higher than that in the model group on days 7-21, and the difference was statistically significant on day 21 (P ⁇ 0.001), suggesting that mitoxantrone hydrochloride liposome 15 mg/kg can play a role in the mechanism.
  • test results show that mitoxantrone hydrochloride liposome injection (15 mg/kg) can significantly inhibit the loss of AQP4 in mice and improve histopathological changes such as astrocytosis and myelin loss, indicating that mitoxantrone hydrochloride liposome injection Anthraquinone liposome injection can effectively improve the symptoms of NMOSD in mice and inhibit its occurrence and development.
  • This example is a randomized, double-blind, placebo-controlled phase II study.
  • the included subjects will receive mitoxantrone hydrochloride liposome injection treatment, aiming to evaluate the mitoxantrone hydrochloride liposome injection.
  • To study the safety and effectiveness of the injection in NMOSD subjects explore the reasonable dosage of mitoxantrone hydrochloride liposome injection in the treatment of neuromyelitis optica spectrum disorder (NMOSD), and provide a basis for later clinical development.
  • NMOSD neuromyelitis optica spectrum disorder
  • the entire study period is approximately 60 weeks, including a screening period (up to 4 weeks), a treatment period (48 weeks), and a safety follow-up period (8 weeks).
  • the investigator or designated person will contact all subjects by phone every 2 weeks after the start of the treatment period until the subject ends the trial (except when the time coincides with the study visit week). If the investigator suspects the onset or imminent onset of NMOSD, an evaluation visit will be scheduled within 72 hours.
  • Subjects diagnosed with NMOSD will be screened within 4 weeks (28 days) to determine their eligibility for study participation based on inclusion and exclusion criteria.
  • AQP4-IgG serostatus will be determined by a central laboratory. All subjects who met the eligibility criteria were then randomly assigned to study centers. Randomization (Day 1): Qualified subjects will be randomly assigned to trial group A (mitoxantrone hydrochloride liposome injection 8 mg/m 2 ) and trial group B in a ratio of 1:1:1 group (mitoxantrone hydrochloride liposome injection 12 mg/m 2 ) and placebo group. Successfully randomized subjects will receive liposomal mitoxantrone hydrochloride or placebo every 12 weeks.
  • Safety follow-up will begin after the subject terminates the trial prematurely or relapses or completes the treatment period at the end of the trial.
  • An 8-week safety follow-up is required (conducting scale assessment, laboratory tests and electrocardiogram tests, etc.) to monitor subjects' adverse events/serious adverse events and collect concomitant medications or treatments related to NMO/NMOSD. During this period, subjects may receive standard treatment for NMO/NMOSD at the discretion of the investigator.
  • This study includes a 4-week screening period, a treatment period of up to 48 weeks, and a safety follow-up period of 8 weeks, with an expected duration of approximately 60 weeks for each patient (excluding relapsed patients).
  • This study plans to enroll 45 subjects, and the entire study period is expected to be 24 months.
  • NOSD Neuromyelitis Optica Spectrum Disorders
  • Pregnant or lactating women for patients with childbearing potential, a positive serum pregnancy test result during screening, or unwillingness to take reliable contraceptive measures (physical barrier [patient or partner] and spermicides, birth control pills, patches agent, injection), intrauterine IUD or intrauterine system) and continue for at least 4 months after the last dose of study drug. Men of childbearing potential must sign the informed consent form and take effective contraceptive measures within 6 months after the last dose;
  • hepatitis B surface antigen HBsAg
  • hepatitis C antibody HCVAb
  • syphilis antibody syphilis antibody
  • HAV antibody human immunodeficiency virus
  • the subject has a history of severe drug allergy, or is allergic or intolerant to mitoxantrone and liposomes (shock, anaphylaxis);
  • glucocorticoid maintenance therapy such as rheumatoid arthritis, scleroderma, Sjogren's syndrome , ulcerative colitis, genetic immunodeficiency or drug-induced immunodeficiency; only patients with positive autoantibodies but no clinical manifestations can be enrolled in the trial;
  • satelizumab Use of any of the following within 3 months before randomization: satelizumab, tocilizumab, inelizumab, eculizumab, alemtuzumab, cyclosporine, thiazole Purine, methotrexate, cyclophosphamide, tacrolimus, mycophenolate mofetil. Any other treatment to prevent multiple sclerosis (MS) relapses (such as interferon, natalizumab, glatiramer acetate, fingolimod, Teriflunomide or dimethyl fumarate);
  • MS multiple sclerosis
  • IVIG intravenous immune globulin
  • PE plasma exchange treatment
  • the cardiac ejection fraction (EF) detected by echocardiography is lower than 50% or lower than the lower limit of the laboratory test value of the research center; those with a history of chronic congestive heart failure and cardiac function NYHA class III to IV;
  • AST Aspartate aminotransferase
  • UPN upper limit of normal
  • ALT alanine aminotransferase
  • total bilirubin 1.5 ⁇ ULN (unless due to Gilbert syndrome caused);
  • the researcher should arrange for the subject to terminate the study treatment early. After terminating the treatment, the subject should be followed up for 8 weeks and complete the end-of-study (EOS) visit assessment as much as possible.
  • EOS end-of-study
  • ALT or AST>5 ⁇ ULN persist for more than 2 weeks (without elevated bilirubin and/or fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia ( >5%);
  • d.ALT or AST>3 ⁇ ULN accompanied by fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%);
  • Time to first relapse refers to the time from subject randomization to the first onset of NMOSD.
  • NMOSD relapse was defined as the presence of new symptoms or worsening of existing symptoms related to NMOSD that met at least one of the NMOSD episode criteria for the protocol relapse definition.
  • ARR Annualized relapse rate
  • sGFAP serum glial fibrillary acid protein
  • NfL serum neurofilament light chain protein

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Abstract

本申请提供了盐酸米托蒽醌脂质体用于治疗视神经脊髓炎谱系疾病的用途，本申请还提供一种治疗个体的视神经脊髓炎谱系疾病的方法，所述方法包括给予所述个体治疗有效量的盐酸米托蒽醌脂质体或包含盐酸米托蒽醌脂质体的药物组合物。动物和临床试验结果表明，盐酸米托蒽醌脂质体对视神经脊髓炎谱系疾病安全有效。

Description

盐酸米托蒽醌脂质体的用途
相关申请
本申请要求于2022年7月20日提交的中国专利申请202210856534.9以及于2022年8月2日提交的中国专利申请202210924224.6的优先权，通过引用的方式将上述申请的全部内容整体并入本文，用于所有目的。
技术领域
本申请涉及医药领域，具体涉及盐酸米托蒽醌脂质体的用途，例如在治疗视神经脊髓炎谱系疾病中的用途。
背景技术
视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorder，NMOSD)是一种自身免疫介导的以视神经和脊髓同时或相继受累为主要表现的中枢神经系统炎性脱髓鞘疾病，其发病机制主要与水通道蛋白4(aquaporin-4，AQP4)抗体相关，由自身抗体介导、体液免疫主导、多种免疫细胞和因子共同参与。)NMOSD见于各年龄阶段，以青壮年居多，平均发病年龄约40岁，多数患者血清AQP4-IgG阳性。AQP4-IgG阳性患者中，女男患病比例高达(4.7～11)：1。临床上多以严重的视神经炎和纵向延伸的长节段横贯性脊髓炎为主要临床特征，常伴有NMO特征性脑部病灶(下丘脑、胼胝体、脑室旁或脑干)或系统性自身免疫性疾病。NMOSD为高复发性、高致残性疾病，90％以上患者为多时相病程，其中40％-60％在1年内复发，约90％在3年内复发。自然病程患者中，约50％在5-10年内遗留有严重的视觉功能或运动功能障碍(中国免疫学会神经免疫分会，黄德晖，吴卫平等.中国视神经脊髓炎谱系疾病诊断与治疗指南(2021版).中国神经免疫学和神经病学杂志，2021年11月第28卷第6期)。
发病机制、影像及临床表现等方面的证据表明NMOSD是一种不同于多发性硬化症(multiple sclerosis，MS)的独立疾病实体，其治疗方案也与MS不同，某些治疗MS药物可能会加剧NMOSD病症恶化(冀炜，王莉梅，谈颂.视神经脊髓炎与多发性硬化实验室指标鉴别诊断及治疗进展.中国实用神经疾病杂志，2016年6月第19卷第10期)。
目前临床常用的NMOSD治疗分为急性发作期治疗、序贯治疗(预防复发治疗)、对症治疗和康复治疗。急性期治疗的目的为减少神经不可逆性损伤，促进其功能恢复，降低病死率，常采用大剂量激素冲击疗法、血浆置换或免疫吸附，以及静脉注射人免疫球蛋白等；序贯治疗的目的主要是降低复发率，减轻患者伤残严重程度，临床常用药物包括单克隆抗体及免疫 抑制剂，一线药物有萨特利珠单抗、伊纳利珠单抗、利妥昔单抗、硫唑嘌呤和吗替麦考酚酯等；二线药物包括他克莫司、环孢素A、环磷酰胺、甲氨蝶呤及米托蒽醌等(中国免疫学会神经免疫分会，黄德晖，吴卫平等.中国视神经脊髓炎谱系疾病诊断与治疗指南(2021版).中国神经免疫学和神经病学杂志，2021年11月第28卷第6期)。
鉴于NMOSD呈高复发性、高致残性特点，大量NMOSD患者仍不能得到有效治疗，病情未得到有效控制，遗留严重的身体功能残疾，并对家庭及社会造成沉重疾病负担，因此亟需对本病进行早期诊断、以及有效地治疗NMOSD与预防NMOSD复发的药物。
盐酸米托蒽醌是一种蒽醌类化疗药物，FDA批准盐酸米托蒽醌普通注射液的适应症为多发性硬化症、前列腺癌和急性髓性白血病；在我国获批适用于淋巴瘤、白血病和乳腺癌等患者，推荐剂量为单药成人12-14mg/m2，每3-4周一次；或4-8mg/m2，一日一次，连用3-5日，间隔2-3周；联合使用剂量为5-10mg/m2一次。米托蒽醌作为蒽环类药物，主要的不良反应主要表现为心脏毒性、骨髓抑制和胃肠道反应等。
其中，骨髓抑制和胃肠道反应可通过给予适宜的药物来解决，但是心脏毒性往往会带来严重后果，是蒽环类药物最为严重的不良反应，临床研究和实践观察均显示蒽环类药物导致的心脏毒性多数呈进展性和不可逆性，特别是初次使用蒽环类药物就易造成心脏损伤。慢性剂量累积限制性毒性-心脏毒性是临床医生普遍关注的问题。因此，虽然乳腺癌这一适应症被批准，但是米托蒽醌并未被权威的临床用药指南推荐为乳腺癌的治疗手段。
不同肿瘤的药物敏感性不同。已有的研究显示，同一药物在治疗不同适应症时，其给药方案有可能是不同的。例如Doxil(盐酸多柔比星脂质体)在FDA批准了三个适应症，分别为：(1)卵巢癌，推荐剂量为50mg/m2，每4周一次静脉内给药；(2)卡波氏肉瘤，推荐剂量为20mg/m2，每3周一次静脉内给药；(3)多发性骨髓瘤，推荐剂量为30mg/m2，硼替佐米给药后第四天静脉给药。又如Abraxane(注射用紫杉醇[白蛋白结合型])在FDA获批的也是三个适应症，(1)转移性乳腺癌：推荐剂量260mg/m2，静脉滴注30分钟，每3周给药一次；(2)非小细胞肺癌：推荐剂量100mg/m2，静脉滴注30分钟，每21天一个疗程，分别在第1天、第8天和15天给药；第1天注射用紫杉醇(白蛋白结合型)给药后立即给予卡铂，每21天给药一次；(3)胰腺癌：建议使用剂量125mg/m2，静脉滴注30-40分钟，以28天为一个周期，第1、8、15天各给药一次，注射用紫杉醇(白蛋白结合型)每次给药后立即给予吉西他滨。再如AmBisome(注射用两性霉素B脂质体)治疗以下适应症的起始剂量为：(1)经验治疗：推荐剂量3mg/kg/天；(2)系统真菌感染(曲霉菌，念珠菌，隐球菌)：推荐剂量3～5mg/kg/天；(3)HIV感染者的隐球菌性脑膜炎：推荐剂量6mg/kg/天(第1-5天)，3mg/kg/天(第4、21天)；(4)免疫功能低下的内脏利什曼病患者：4mg/kg/天(第1- 5天)，4mg/kg/天(第10、17、24、31、38天)；剂量和给药数据根据患者实际情况个性化制定，以达到最大药效和最小毒性或不良反应。可见，同一种药物治疗不同适应症的安全有效剂量存在差异。剂量和给药数据应根据具体病种和患者实际情况个性化制定，以达到最大药效和最小毒性或不良反应，取得安全有效治疗疾病的效果。对于米托蒽醌脂质体这一不同于普通注射剂的特殊剂型，其在进入体内后的吸收、分布、代谢情况十分复杂，对于不同适应症的治疗，特别是在不同肿瘤的治疗上，也很难由一种适应症简单推导到另一种适应症。
发明内容
本申请提供了盐酸米托蒽醌脂质体在治疗视神经脊髓炎谱系疾病中的应用。本申请的发明人在研究中意外地发现，盐酸米托蒽醌脂质体对视神经脊髓炎谱系疾病具有很好的治疗效果，可用于制备相关药物。
第一方面，本申请提供了盐酸米托蒽醌脂质体在制备治疗视神经脊髓炎谱系疾病的药物中的用途。
第二方面，本申请提供了治疗个体的视神经脊髓炎谱系疾病的方法，其包括给予所述个体治疗有效量的盐酸米托蒽醌脂质体或包含治疗有效量的盐酸米托蒽醌脂质体的药物组合物。
第三方面，本申请提供了盐酸米托蒽醌脂质体或包含盐酸米托蒽醌脂质体的药物组合物，其用于治疗个体的视神经脊髓炎谱系疾病。
在一些实施方案中，上述第一方面至第三方面中所述的视神经脊髓炎谱系疾病为高度复发性视神经脊髓炎谱系疾病。在一些实施方案中，所述高度复发性视神经脊髓炎谱系疾病为经其他药物治疗失败的高度复发性视神经脊髓炎谱系疾病。
在一些实施方案中，对于经其他药物治疗失败的高度复发性视神经脊髓炎谱系疾病，所述其他药物选自视神经脊髓炎谱系疾病的一线、二线或二线以上药物，特别是中国或国外(例如美国、欧盟、日本、韩国等等)药物管理部门批准用于视神经脊髓炎谱系疾病治疗的一线、二线或二线以上药物，包括但不仅限于：FDA批准的糖皮质激素、单克隆抗体药物及免疫抑制剂等。
在一些实施方案中，盐酸米托蒽醌脂质体作为唯一活性成分用于治疗视神经脊髓炎谱系疾病或作为唯一活性成分用于制备治疗视神经脊髓炎谱系疾病的药物或药物组合物。
在一些实施方案中，上述第一方面至第三方面中的所述包含盐酸米托蒽醌脂质体的药物组合物或药物为注射剂型，包括液体注射剂、注射用粉剂、注射用片剂等等。在优选的实施 方案中，所述包含盐酸米托蒽醌脂质体的药物组合物或药物为液体注射剂。
在一些实施方案中，当所述包含盐酸米托蒽醌脂质体的药物组合物或药物为液体注射剂时，以米托蒽醌计，所述药物或药物组合物中米托蒽醌的含量为0.5-5mg/mL。在优选的实施方案中，所述药物中米托蒽醌的含量为1-2mg/mL。在更优选的实施方案中，所述药物或药物组合物中米托蒽醌的含量为1mg/mL。
在一些实施方案中，上述第二方面中的治疗有效量以米托蒽醌计为4-30mg/m2，例如为8-20mg/m2或者12-30mg/m2，或者上述任意2个剂量之间的范围内的剂量，例如，8mg/m2、12mg/m2等等。
在一些实施方案中，本申请的盐酸米托蒽醌脂质体、包含盐酸米托蒽醌脂质体的药物组合物或药物给予所需个体的方式为静脉给药。
在一些实施方案中，本申请的盐酸米托蒽醌脂质体、包含盐酸米托蒽醌脂质体的药物组合物或药物的给药周期为每12周给药一次。
在一些实施方案中，所述脂质体单独用于治疗个体的视神经脊髓炎谱系疾病。在一些实施方案中，所述脂质体的治疗有效量(以米托蒽醌计)为4-30mg/m2，例如8-20mg/m2或者12-30mg/m2，或者为上述任意2个剂量之间的范围内的剂量，例如，8mg/m2或12mg/m2。在一些实施方案中，所述脂质体的给药方式为静脉给药。
在一些实施方案中，所述脂质体的给药周期为每12周给药一次。
在本申请的上下文中，所述的剂量如无特别说明，则以米托蒽醌计。
在本申请的上下文中，所述的盐酸米托蒽醌脂质体可以采用本领域已知方法制备，可以是现有技术公开任意一种方法制备的盐酸米托蒽醌脂质体，例如采用WO2008/080367A1公开的方法制备。
在一些实施方案中，上述第一方面至第三方面中的所述药物、盐酸米托蒽醌脂质体或包含所述盐酸米托蒽醌脂质体的药物组合物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)。
(iiv)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。
(iiiv)盐酸米托蒽醌脂质体为国药准字H20220001的盐酸米托蒽醌脂质体。
在一些实施方案中，本文所述的盐酸米托蒽醌脂质体的粒径为约30-80nm，例如为30-80nm之间的任一数值。在一些实施方案中，所述粒径为约35-75nm，优选为40-70nm，更优选为40-60nm，例如为60nm。
在一些实施方案中，本文所述的盐酸米托蒽醌脂质体含有活性成分米托蒽醌和磷脂双分子层。
在一些实施方案中，活性成分米托蒽醌可以和脂质体内的多价反离子形成难以溶解的沉淀。在一些实施方案中，所述反离子为硫酸根、柠檬酸根或磷酸根。
在一些实施方案中，上述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。在一些实施方案中，所述Tm高于体温的磷脂为磷脂酰胆碱、氢化大豆卵磷脂、氢化蛋黄卵磷脂、双软脂酸卵磷脂或双硬脂酸卵磷脂或者其任何组合。
在一些实施方案中，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。在一些实施方案中，所述磷脂双分子层中的氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺的质量比为3:1:1。
在一些实施方案中，本文所述的盐酸米托蒽醌脂质体的粒径为约60nm，脂质体内的反离子为硫酸根离子。
在一些实施方案中，本文所述的盐酸米托蒽醌脂质体的磷脂双分子层含有质量比为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，脂质体的粒径为约40-60nm，脂质体内的反离子为硫酸根离子。在一些实施方案中，本文所述的盐酸米托蒽醌脂质体中HSPC：Chol：DSPE-PEG2000：米托蒽醌的重量比为9.58:3.19:3.19:1。
在本申请的上下文中，米托蒽醌脂质体的制备方法如下：将HSPC(氢化大豆卵磷脂)、Chol(胆固醇)和DSPE-PEG2000(聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺)按照(3:1:1)的质量比称重，溶解于95％乙醇中，得到澄清溶液。将磷脂的乙醇溶液与300mM的硫酸铵溶液混合，在60-65℃下震荡水化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米托蒽醌盐酸盐溶液(10mg/mL)，在60-65℃下进行载药。孵育约1h后，使用凝胶排阻色谱可证明包封效率约为100％。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。
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整和确定。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都是可以的，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。
本文所使用的术语“个体”是指哺乳动物，如人类，但也可以是其它哺乳动物，如家畜或实验动物等。
本文所使用的术语“治疗”意为将本申请所述盐酸米托蒽醌脂质体或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：(i)抑制疾病或疾病状态，即遏制其发展；(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“治疗有效量”意指(i)治疗特定疾病、病况或障碍，或(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状的本申请盐酸米托蒽醌脂质体的用量。构成“治疗有效量”的本申请盐酸米托蒽醌脂质体的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本文公开内容而确定。
在一些实施方案中，上述第一方面至第三方面中的所述药物、盐酸米托蒽醌脂质体或包含所述盐酸米托蒽醌脂质体的药物组合物，例如盐酸米托蒽醌脂质体注射液在治疗视神经脊髓炎谱系疾病中具有以下一项或多项有益效果：安全耐受、毒副作用小，提高了治疗有效性，延缓视神经脊髓炎谱系疾病复发等。
附图说明
图1显示了患有视神经脊髓炎的动物的体重分析，数据以Mean±SEM表示，***P<0.001。
图2显示了AQP4免疫荧光染色代表图，Bar:200μm。
图3显示了AQP4阳性细胞数统计，数据以Mean±SEM表示，*P<0.05，**P<0.01，***P<0.001。
具体实施方式
下文将结合具体实施例对本申请的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本申请，而不应被解释为对本申请保护范围的限制。凡基于本申请上述内容所实现的技术均涵盖在本申请旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1米托蒽醌脂质体对临床患者AQP4抗体/补体联合诱导的NMOSD模型的改善作用
据文献报道，将临床确诊患者AQP4抗体及人补体直接注射入小鼠大脑半球或脑室内可诱导NMOSD模型(Saadoun S,Waters P,Bell BA,et al.Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice.Brain.2010,133:349-61)。因此，本实施例中选择上述造模方式来研究米托蒽醌脂质体对NMOSD的治疗作用。
试验动物：雄性CD-1小鼠，8周龄，购于济南朋悦实验动物繁育有限公司。
试验药物：盐酸米托蒽醌脂质体注射液1.0mg/ml(供试品)。
试验方法：首先进行临床病人血样AQP4-IgG抗体及正常人补体血清的提取、纯化和验证，此后选用27只8周龄CD-1雄性小鼠，在适应一周后，根据体重随机分为3组，分别为空白组、模型组和供试品组(米托蒽醌脂质体15mg/kg)，每组9只动物。
模型组和供试品组每只小鼠的侧脑室于第1、3、5天以0.3μl/min的速率注射2μl APQ4抗体(浓度18mg/ml)加上1μl人补体血清进行NMOSD模型诱导。
空白组为假手术组，动物的造模过程同模型组和供试品组，但不注射任何抗体及补体。
供试品组动物于造模第1天单次静脉注射盐酸米托蒽醌脂质体注射液15mg/kg。
在试验过程中监测动物健康状态，记录动物体重。在造模完成后Day 7、Day 11和Day21每次每组取3只动物经二氧化碳安乐死后，收集脑组织并通过AQP4、GFAP和LFB染色 评估小鼠脑组织的病理学变化。病理采集部位：染色区域为以注射位点为中央共切片30片以进一步探究病变范围。
免疫组化过程所需步骤以及抗体信息如下所述：
1.灌流-固定-沉糖-切片
1)小鼠进行异氟烷呼吸麻醉。
2)直剪剪开腹腔及胸腔，暴露心脏，先用生理盐水灌流冲尽血液，再用多聚甲醛进行灌流初固定。
3)剪下头部，镊子小心拨开脑壳，取出脑组织并放在多聚甲醛溶液中固定24h。
4)第二天取出放入20％蔗糖溶液24h。
5)第三天取出放入30％蔗糖溶液24h。
6)第四天取出放入35％蔗糖溶液24h。(根据脑组织沉糖情况适当增加时间或浓度)
7)取出脑组织，用OCT包埋剂包埋，冰冻切片机切16μm脑片。
2.免疫荧光染色(AQP4、GFAP)
1)切片复温30min；
2)封闭：10％血清+0.3％TritonX-100【每张片约50μl】，室温1h；
3)甩片，加一抗(PBS稀释)，4℃过夜；
4)复温30min；
5)洗一抗(PBS)，5min×3次；
6)背光加二抗(PBS稀释)，室温2h；
7)洗二抗(PBS)，5min×3次；
8)加DAPI，室温10min；
9)洗DAPI，5min×3次；
10)70％甘油封片，避免气泡。
3.抗体信息：
3.1.一抗
1)AQP4：购自Abclonal，货号：A2887，批号：0073660402；
2)GFAP：购自华安生物，货号：EM140707，批号：HO0604；
3.2.二抗
1)Goat Pab to Rabbit 594：购自abcam，货号：ab150080，批号：GR3439696-1；
2)Goat Pab to mouse 488：购自abcam，货号：ab150077，批号：GR3403178-2
4.Luxol fast blue stain(LFB)染色
购自Solarbio，货号：G3242，批号：20220422。按照试剂盒说明书操作。
试验结果：
该研究选用CD-1小鼠，通过脑立体定位的方式侧脑室内注射临床确诊患者AQP4抗体/补体建立视神经脊髓炎疾病模型，并开展相关的组织学检测以评估待测化合物作用效果。
动物体重分析结果如图1和表1。与模型组相比，供试品组自造模给药后第7天至第21天出现体重降低，动物状态良好，无药物毒性所致动物死亡。
表1

注：Mean±SEM，n＝3～9；与模型组比较：*p<0.05,**p<0.01,***p<0.001。
AQP4免疫荧光染色代表图及阳性细胞数统计结果见图2-3和表2。建模后第7天，与空白组和供试品组相比，模型组动物脑纹状体内AQP4阳性细胞数显著降低，并且这种降低随时间延长逐渐显著，说明通过脑立体定位的方式侧脑室内注射临床确诊患者AQP4抗体/补体成功建立了NMOSD疾病模型。供试品组AQP4阳性细胞数于7-21天高于模型组，并于第21天差异有统计学意义(P<0.001)，提示盐酸米托蒽醌脂质体15mg/kg可在机制上显著抑制NMOSD的AQP4缺失，有效改善小鼠NMOSD的病症。
表2

注：Mean±SEM，n＝3；与模型组比较：*p<0.05,**p<0.01,***p<0.001。
试验结果表明，盐酸米托蒽醌脂质体注射液(15mg/kg)能够显著抑制小鼠AQP4的缺失，改善星形胶质细胞病变和髓鞘脱失等组织病理学变化，说明盐酸米托蒽醌脂质体注射液能够有效改善小鼠NMOSD的病症，抑制其发生和发展。
实施例2盐酸米托蒽醌脂质体注射液治疗视神经脊髓炎谱系疾病(NMOSD)的有效性及安全性II期临床研究
本实施例是一项随机、双盲、安慰剂平行对照的Ⅱ期研究，纳入的受试者将接受盐酸米托蒽醌脂质体注射液治疗，旨在评价盐酸米托蒽醌脂质体注射液在NMOSD受试者中的安全性和有效性，探索盐酸米托蒽醌脂质体注射液治疗视神经脊髓炎谱系疾病(NMOSD)的合理剂量，为后期临床开发提供依据。
一、试验设计
1.试验流程
整个研究周期约60周，包括筛选期(最长4周)、治疗期(48周)和安全随访期(8周)。研究者或指定人员将从治疗期开始后每2周通过电话联系所有受试者，直至受试者结束试验(时间与研究访视周重合的情况除外)。如果研究者怀疑NMOSD发作或即将发作，将在72小时内安排评估访视。
诊断NMOSD的受试者将在4周(28天)内进行筛选，以根据入选和排除标准确定其参加研究的资格。AQP4-IgG血清状态将由中心实验室确定。然后将符合合格标准的所有受试者随机分配至研究中心。随机化(第1天)：筛选合格的受试者将按照1:1:1的比例被随机分配至试验A组(盐酸米托蒽醌脂质体注射液8mg/m2)、试验组B组(盐酸米托蒽醌脂质体注射液12mg/m2)和安慰剂组。随机成功的受试者将接受盐酸米托蒽醌脂质体或安慰剂治疗(每12周用药一次)。当末例入组患者随机分组后48周或复发，治疗期结束，进入安全随访期。安全随访将在受试者提前终止试验或复发后或完成治疗期试验结束时开始。需进行8周的安全性随访(进行量表评估、实验室检查和心电图检查等)，监测受试者的不良事件/严重不良事件及收集与NMO/NMOSD有关的合并用药或治疗。在该期间，根据研究者的判断，受试者可接受NMO/NMOSD的标准治疗。
2.研究持续时间
本研究包括筛选期4周，治疗期最多48周，安全随访期8周，预计每位患者持续时间约60周(除外复发患者)。
本研究计划入组45例受试者，本研究整个周期预计24个月。
二、试验人群：
符合下列全部入选标准并且没有任一排除标准的受试者才可入选本项临床研究。
(一)入选标准：
受试者必须符合以下所有标准：
1)签署知情同意书时年龄为18-60岁(含上下限)，男女均可；
2)符合2015年的视神经脊髓炎谱系疾病(NMOSD)国际共识诊断标准，且AQP4-IgG阳性或阴性(签署知情同意书前24周内检测结果均可接受)的患者；
3)筛选前2年内至少经历过2次发作和/或在筛选前12个月内有至少一次已记录复发(包括首次发作)的临床证据；
4)筛选和基线复测时EDSS≤7.5分；
5)受试者自愿签署知情同意书，且自愿按照方案要求完成试验
(二)排除标准：
1、一般安全性的排除：
1)妊娠期或哺乳期女性；对于有生育能力的患者，筛选时血清妊娠试验结果呈阳性，或不愿意采取可靠的避孕措施(物理屏障[患者或伴侣]以及杀精剂、避孕药、贴剂、注射剂)，宫内 节育器或宫内节育系统)，并持续至研究药物末次给药后至少4个月。有生育能力的男性在签署知情同意书至末次给药后6个月内采取有效避孕措施；
2)随机前4周内接受过任何手术操作有其他脱髓鞘疾病或进行性多灶性白质脑病(PML)的证据；
3)随机前4周内已知活动性感染(不包括甲床真菌感染或龋齿)；
4)筛选期传染病筛查，乙肝表面抗原(HBsAg)、丙型肝炎抗体(HCVAb)、梅毒抗体、人类免疫缺陷病毒(HIV抗体)阳性；
5)随机前1年内有药物或酒精滥用史(即每周饮酒超过14个标准单位(1单位＝360ml啤酒或45ml酒精量为40％的烈酒或150ml葡萄酒))或精神障碍者；
6)活动性结核病的证据(TB；不包括接受药物预防潜伏性TB感染的患者)；
7)活动性间质性肺病的证据；
8)随机前6周内接受过任何活疫苗或减毒活疫苗；
9)过去5年内有恶性肿瘤史，包括实体瘤、血液恶性肿瘤和原位癌(已完全切除并治愈的皮肤基底细胞癌和鳞状细胞癌或宫颈原位癌除外)；
10)受试者存在严重药物过敏史，或对米托蒽醌及脂质体过敏或不耐受者(休克、过敏反应)；
11)存在除NMOSD外的其他慢性活动性免疫系统病或病情稳定但需要大剂量(剂量与研究者确定)糖皮质激素维持治疗者：如类风湿关节炎、硬皮病、肖格伦综合征、溃疡性结肠炎、遗传免疫缺陷或药物引起的免疫缺陷；仅自身抗体阳性但没有临床表现的患者可以入组试验；
12)经研究者判定，受试者存在其他不适合参加本研究的疾病等。
2、与既往或合并治疗相关的排除标准：
13)随机前3个月内接受过任何研究型制剂治疗，或参加过医疗器械临床研究并经研究者判断可能对本试验结果有影响者；
14)既往NMOSD治疗史存在以下任意一项者：
a.既往接受过米托蒽醌或蒽环类药物治疗，全身照射或任何时间骨髓移植治疗；
b.随机前6个月内接受利妥昔单抗或任何实验性B细胞消耗剂，除非中心实验室认为受试者的B细胞计数高于LLN；
c.随机前3个月内使用以下任何一项：萨特利珠单抗、托珠单抗、伊奈利珠单抗、依库珠单抗、阿伦单抗、环孢菌素、硫唑嘌呤、氨甲蝶呤、环磷酰胺、他克莫司、吗替麦考酚酯。任何其他预防多发性硬化(MS)复发的治疗(如干扰素、那他珠单抗、醋酸格拉替雷、芬戈莫德、 特立氟胺或富马酸二甲酯)；
d.随机前1个月内接受静脉注射免疫球蛋白(IVIG)治疗、血浆置换治疗(PE)；
e.正在受泼尼松龙转换中剂量高于30mg/天的口服皮质类固醇药物治疗的患者；
f.随机前2年内使用过抗CD4、克拉屈滨。
3、实验室检查相关的排除标准：
15)存在以下有临床意义的疾病：
a.超声心动图检测心脏射血分数(EF)低于50％或低于研究中心实验室检查值下限；具有慢性充血性心力衰竭病史，心功能NYHA分级III～IV级者；
b.随机前3个月内出现以下任何事件：心肌梗死、急性冠脉综合征、病毒性心肌炎、肺栓塞者、脑卒中；6个月内行冠状动脉血运重建术者；
c.筛选期心电图检查提示QTc间期＞480ms(根据Fridericia校正公式，其中QTc＝QT/RR^0.33)，或有严重的QTc间期延长病史者。
16)筛选期实验室检查值存在以下异常者：
a.天门冬氨酸氨基转移酶(AST)>3×正常值上限(ULN)、丙氨酸氨基转移酶(ALT)>3×ULN、总胆红素>1.5×ULN(除非因Gilbert综合征所致)；
b.血小板计数<50,000/μL(或<50×109/L)、血红蛋白<9g/dL(或<90g/L)、白细胞<2.0×103/μL、中性粒细胞绝对计数<1.0×103/μL；
c.肌酐清除率(CLcr)<60mL/min(使用Cockcroft-Gault公式计算：[140-年龄(岁)]×[体重(kg)]×(0.85，如为女性)/[72×血肌酐(mg/dL)])或在筛选期间接受透析。
(三)退出/终止标准
如受试者在研究过程中任何时间均可决定提前终止研究治疗，并将不会影响其继续接受适当的临床诊疗。受试者应归还所有研究药物。受试者退出治疗的决定必须记录在源文件中。在撤回知情同意后，将不会因任何原因对患者进行随访。退出研究的患者将不予替换。
如发生以下情况之一，研究者应安排受试者提前终止研究治疗，终止治疗后应随访8周并尽可能完成研究结束(EOS)访视评估。
1)受试者要求退出试验或受试者失访；
2)受试者怀孕；
3)受试者出现严重不良事件或较大风险隐患的不良事件，研究者或申办者出于安全性考虑判定应该退出治疗；
4)受试者出现以下任何肝功能异常：
a.ALT或AST>8×ULN
b.ALT或AST>5×ULN且持续2周以上(无胆红素升高和/或出现的疲乏、恶心、呕吐、右上腹疼痛或压痛、发热、皮疹和/或嗜酸性粒细胞增多(>5％)；)
c.ALT或AST>3×ULN且总胆红素>2×ULN或国际标准化比值[INR]>1.5，未发现胆汁淤积因素；
d.ALT或AST>3×ULN并伴有疲乏、恶心、呕吐、右上腹疼痛或压痛、发热、皮疹和/或嗜酸性粒细胞增多(>5％)；
5)研究过程中，根据方案定义的标准确诊为NMOSD复发的受试者，或出现心脏毒性(LVEF低于下限或临床显著下降)者，研究者判断需终止研究治疗并退出研究。
6)受试者延迟用药超过14天，或出现重大方案违背，研究者出于依从性或获益考虑判定应该退出治疗；
7)其他研究者认为患者不适合继续参加本试验的情况。
三、疗效评价指标
主要终点：至首次复发时间；
首次复发时间指从受试者随机到首次出现NMOSD发作的时间。NMOSD复发的定义是存在与NMOSD相关的新症状或现有症状恶化，符合方案复发定义的NMOSD发作标准中的至少一个。
次要终点：
●年复发率(annualized relapse rate，ARR)：第48周的ARR计算为所有参与者确认复发次数之和除以所有参与者治疗时间之和(以年为单位)的比值。
●扩展残疾状态量表(expanded disability status scale，EDSS)评分相对于基线的变化
●改良Rankin Scale(mRS)评分相对于基线的变化
●T25FW评分相对于基线的变化
●EQ-5D评分相对于基线的变化
●低对比度视力评分(LCVA)相对于基线的变化
●5个部位的疼痛NRS评分相比基线的变化
●血清胶质纤维酸蛋白(sGFAP)和血清神经丝轻链蛋白NfL水平相比基线的变化
●血清AQP4滴度
四、研究结果
对于视神经脊髓炎谱系疾病患者，经盐酸米托蒽醌脂质体注射液治疗后，安全耐受、毒副作用小，提高了治疗有效性，延缓视神经脊髓炎谱系疾病复发。
以上对本申请技术方案的实施方式进行了示例性的说明。应当理解，本申请的保护范围不应该被不适当地局限于这些具体实施方案。凡在本申请的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。

Claims (11)

  1. 盐酸米托蒽醌脂质体在制备用于治疗视神经脊髓炎谱系疾病的药物中的用途；优选地，所述视神经脊髓炎谱系疾病为高度复发性视神经脊髓炎谱系疾病，更优选地，所述高度复发性视神经脊髓炎谱系疾病为经其他药物治疗失败的高度复发性视神经脊髓炎谱系疾病。
  2. 治疗个体的视神经脊髓炎谱系疾病的方法，其包括给予所述个体治疗有效量的盐酸米托蒽醌脂质体或包含治疗有效量的盐酸米托蒽醌脂质体的药物组合物；优选地，所述视神经脊髓炎谱系疾病为高度复发性视神经脊髓炎谱系疾病，更优选地，所述高度复发性视神经脊髓炎谱系疾病为经其他药物治疗失败的高度复发性视神经脊髓炎谱系疾病。
  3. 盐酸米托蒽醌脂质体或包含盐酸米托蒽醌脂质体的药物组合物，其用于治疗视神经脊髓炎谱系疾病；优选地，所述视神经脊髓炎谱系疾病为高度复发性视神经脊髓炎谱系疾病，更优选地，所述高度复发性视神经脊髓炎谱系疾病为经其他药物治疗失败的高度复发性视神经脊髓炎谱系疾病。
  4. 如权利要求1所述的用途、权利要求2所述的方法，或者权利要求3所述的盐酸米托蒽醌脂质体或包含盐酸米托蒽醌脂质体的药物组合物，其中盐酸米托蒽醌脂质体作为用于治疗视神经脊髓炎谱系疾病的唯一活性成分，或者所述盐酸米托蒽醌脂质体单独用于治疗视神经脊髓炎谱系疾病。
  5. 如权利要求1所述的用途、权利要求2所述的方法，或者权利要求3所述的盐酸米托蒽醌脂质体或包含盐酸米托蒽醌脂质体的药物组合物，其中所述药物或药物组合物为注射剂型，优选为液体注射剂、注射用粉剂、或注射用片剂；更优选地，所述药物或药物组合物为液体注射剂。
  6. 如权利要求1所述的用途、权利要求2所述的方法，或者权利要求3所述的盐酸米托蒽醌脂质体或包含盐酸米托蒽醌脂质体的药物组合物，其中以米托蒽醌计，所述药物或药物组合物的活性成分含量为0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
  7. 如权利要求1所述的用途、权利要求2所述的方法，或者权利要求3所述的盐酸米托 蒽醌脂质体或包含盐酸米托蒽醌脂质体的药物组合物，其中所述盐酸米托蒽醌脂质体粒径为约30-80nm，例如为约35-75nm，优选约40-70nm，更优选约40-60nm，例如约60nm。
  8. 如权利要求1所述的用途、权利要求2所述的方法，或者权利要求3所述的盐酸米托蒽醌脂质体或包含盐酸米托蒽醌脂质体的药物组合物，其中所述盐酸米托蒽醌脂质体中的活性成分米托蒽醌与脂质体内的多价反离子形成难以溶解的沉淀，所述多价反离子例如为硫酸根、柠檬酸根或磷酸根。
  9. 如权利要求1所述的用途、权利要求2所述的方法，或者权利要求3所述的盐酸米托蒽醌脂质体或包含盐酸米托蒽醌脂质体的药物组合物，其中所述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。
  10. 如权利要求1所述的用途、权利要求2所述的方法，或者权利要求3所述的盐酸米托蒽醌脂质体或包含盐酸米托蒽醌脂质体的药物组合物，其中所述氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺的质量比为3:1:1；和/或
    优选地，其中所述氢化大豆卵磷脂、胆固醇、聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺和米托蒽醌的重量比为9.58:3.19:3.19:1；和/或
    优选地，其中所述粒径为约60nm；和/或
    优选地，其中所述反离子为硫酸根离子。
  11. 如权利要求2所述的方法，其中以米托蒽醌计，所述治疗有效量为4-30mg/m2，优选为8-20mg/m2或者12-30mg/m2，例如为8mg/m2或12mg/m2；和/或
    所述给予方式为静脉给药；和/或
    给药周期为每12周给药一次。
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