WO2019023873A1 - 一种用于治疗造血系统增殖性疾病的纳米脂质微粒组合物及药用组合物 - Google Patents

一种用于治疗造血系统增殖性疾病的纳米脂质微粒组合物及药用组合物 Download PDF

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WO2019023873A1
WO2019023873A1 PCT/CN2017/095241 CN2017095241W WO2019023873A1 WO 2019023873 A1 WO2019023873 A1 WO 2019023873A1 CN 2017095241 W CN2017095241 W CN 2017095241W WO 2019023873 A1 WO2019023873 A1 WO 2019023873A1
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nanolipid
lipid
nano
cytarabine
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PCT/CN2017/095241
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French (fr)
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冯皓
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江苏竞诺择生物医药科技有限公司
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Priority to PCT/CN2017/095241 priority Critical patent/WO2019023873A1/zh
Priority to US16/635,858 priority patent/US20200368170A1/en
Priority to PCT/CN2018/097770 priority patent/WO2019024841A1/zh
Publication of WO2019023873A1 publication Critical patent/WO2019023873A1/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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention relates to the technical field of pharmaceutical preparations, in particular to a nano-lipid microparticle composition and a pharmaceutical composition for treating a proliferative disease of a hematopoietic system.
  • Hematopoietic system proliferative diseases include leukemia, malignant lymphoma, multiple myeloma, and the like.
  • acute myelogenous leukemia AML
  • AML acute myelogenous leukemia
  • the current internationally recommended treatment guidelines are the combined "7+3" regimen: daunorubicin 90 mg/m 2 or 4-demethoxydaunorubicin 12 mg/m 2 in combination with a standard dose of cytarabine.
  • Cytarabine (Ara-C) is a cell-specific, specific anti-tumor inhibitor that significantly affects cells in the S phase of cell division.
  • cytarabine In the cell, cytarabine is converted to cytarabine-5'- Triphosphate (ara-CTP) acts as its active metabolite. It is currently believed that ara-CTP acts mainly by inhibiting DNA polymerase. Cytarabine has a cytotoxic effect on a variety of mammalian cells cultured in vitro.
  • the technical problem to be solved by the present invention is to provide a nano-lipid microparticle composition and a pharmaceutical composition for treating a proliferative disease of a hematopoietic system, which can maintain cytarabine and anthracycline antibiotics in the body for a long time.
  • the present invention provides a nano-lipid microparticle composition, wherein the nano-lipid microparticle composition is composed of cytarabine, an anthracycline antibiotic, and a nano-lipid microparticle, wherein cytarabine
  • the anthracycline antibiotic is co-encapsulated in the nanolipid microparticles, and the nanolipid microparticles comprise a charged lipid stabilizer having an effective average particle size of less than 400 nm.
  • anthracycline antibiotics are anamycin and 4-demethoxydaunorubicin.
  • cytarabine also contains a pharmaceutically acceptable salt thereof.
  • anthracyclines also include pharmaceutically acceptable salts thereof.
  • the molar ratio of cytarabine and anthracycline antibiotics is 2:1 to 50:1.
  • the molar ratio of cytarabine and anthracycline antibiotics is 5:1 to 40:1.
  • the molar ratio of cytarabine and anthracycline antibiotics is 10:1 to 30:1.
  • the nano-lipid microparticles have an effective average particle diameter of less than 200 nm.
  • composition of the nano-lipid microparticles comprises at least one phosphatidylcholine, a charged lipid stabilizer and a phospholipid membrane fluidity regulator.
  • the charged lipid stabilizer is selected from the group consisting of methoxy polyethylene glycol-distearoylphosphatidylethanolamine and phosphatidylglycerol.
  • the charged lipid stabilizer is selected from the group consisting of methoxypolyethylene glycol-distearoylphosphatidylethanolamine and cholesteryl sulfate.
  • the phosphatidylglycerol is selected from a mixture of any one or a combination of dimyristoyl phosphatidylglycerol, dipalmitoylphosphatidylglycerol, dioleoylphosphatidylglycerol, and distearoylphosphatidylglycerol.
  • the phosphatidylcholine is selected from the group consisting of egg yolk phosphatidylcholine, hydrogenated soybean phosphatidylcholine, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, dimyristoyl Any of phosphophosphatidylcholines.
  • the phospholipid membrane fluidity regulator is selected from the group consisting of cholesterol.
  • the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the nano-lipid microparticle composition and a pharmaceutically acceptable carrier thereof, the nano-lipid microparticle composition comprising by weight 1% to 7% of cytarabine, 0.1% to 3% by weight of anthracycline antibiotic, the carrier comprising 5% to 20% by weight of hydrogenated soybean phosphatidylcholine or distearoyl phospholipid Acetylcholine, 0.5% to 5% by weight of methoxypolyethylene glycol-distearoylphosphatidylethanolamine, 0.5% to 5% by weight of cholesterol, and 70% to 90% by weight of sucrose .
  • the pharmaceutical composition comprises the nano-lipid microparticle composition and a pharmaceutically acceptable carrier thereof, the nano-lipid microparticle composition comprising by weight 1% to 7% of cytarabine, 0.1% to 3% by weight of anthracycline antibiotic, the carrier comprising 5% to 20% by weight of hydrogenated soybean phosphatidylcholine or distea
  • the nano-lipid microparticle composition comprises 2% to 5% by weight of cytarabine, 0.1% to 1.5% by weight of an anthracycline antibiotic, and the carrier comprises 6% to 12 by weight.
  • % hydrogenated soybean phosphatidylcholine or distearoylphosphatidylcholine 1% to 3% by weight of methoxypolyethylene glycol-distearoylphosphatidylethanolamine, 1% to 3 by weight % cholesterol and 75% to 85% by weight of sucrose.
  • the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the nano-lipid microparticle composition and a pharmaceutically acceptable carrier thereof, the nano-lipid microparticle composition comprising by weight 1% to 7% of cytarabine, 0.1% to 3% by weight of anthracycline antibiotic, 5% to 20% by weight of hydrogenated soybean phosphatidylcholine or distearoylphosphatidylcholine, From 0.5% to 10% by weight of distearoylphosphatidylglycerol, from 0.5% to 5% by weight of cholesterol and from 65% to 90% by weight of sucrose.
  • the pharmaceutical composition comprises the nano-lipid microparticle composition and a pharmaceutically acceptable carrier thereof, the nano-lipid microparticle composition comprising by weight 1% to 7% of cytarabine, 0.1% to 3% by weight of anthracycline antibiotic, 5% to 20% by weight of hydrogenated soybean phosphatidylcholine or distearoylphosphatidylcholine, From 0.5% to 10% by weight
  • the nano-lipid microparticle composition comprises 2% to 5% by weight of cytarabine, 0.1% to 1.5% by weight of an anthracycline antibiotic, and the carrier comprises 12% to 18% by weight.
  • % hydrogenated soybean phosphatidylcholine or distearoylphosphatidylcholine 2% to 5% by weight of distearoylphosphatidylglycerol, 0.5% to 2% by weight of cholesterol and 70 by weight % to 80% sucrose.
  • the effective average particle diameter of the nano-lipid microparticles is preferably less than 200 nm.
  • the nanolipid microparticles are in a liquid state or a freeze-dried state.
  • the beneficial effects of the invention are that the nano-lipid microparticles keep the ratio of cytarabine and anthracycline antibiotics in the body for a long time, can control the release rate of the encapsulated drug, and have a sustained release effect, and also It can reduce the toxicity of drugs and improve the efficacy of drugs.
  • nano-lipid particles can also provide protection for drugs.
  • Embodiment 1 of the present invention provides a nano-lipid microparticle composition, wherein the nano-lipid microparticle composition is composed of cytarabine, an anthracycline antibiotic and a nano-lipid microparticle, wherein cytarabine and anthracycline Antibiotics are co-encapsulated in nanolipid microparticles containing a charged lipid stabilizer having an effective average particle size of less than 400 nm.
  • the component-encapsulated nanolipid carrier refers to a nanolipid microparticle formed by encapsulating two or more drugs into a closed vesicle having a cell structure composed of a phospholipid bilayer.
  • the components constituting the lipid carrier include phosphatidylcholine, phosphatidylglycerol, cholesterol, and the like, and these lipid components are non-toxic, non-immunogenic, and have good biocompatibility.
  • the drug is encapsulated in nano-lipid microparticles with an average particle size of 50 nm to 1000 nm, and the in vivo half-life will be greatly extended.
  • the nano-lipid particles can control the release rate of the encapsulated drug, have a sustained release effect, and at the same time, can reduce the toxicity of the drug and improve the therapeutic effect of the drug.
  • nanolipid microparticles also provide protection against the drug.
  • the nanolipid carrier can encapsulate not only water-soluble drugs (in the inner aqueous phase) but also fat-soluble drugs (in the bilayer).
  • the half-life of the drug is synchronized with the nano-lipid particles, that is, after multiple drugs enter the body through the nano-lipid particle carrier. With a very close or even the same half-life for a certain period of time, the synergy of several drugs will be better utilized.
  • the nano-lipid microparticles have the ability to release drugs, and on the basis of reducing the toxicity of the drug, it is expected to achieve a better therapeutic effect at a higher dose in clinical practice, or achieve the same therapeutic effect at a lower dose.
  • the anthracycline antibiotic is preferably Annamycin and 4-demethoxyxaerythrin.
  • Cytarabine also comprises a pharmaceutically acceptable salt thereof, and an anthracycline antibiotic further comprises a pharmaceutically acceptable salt thereof.
  • the molar ratio of cytarabine and anthracycline antibiotic is 2:1 to 50:1; further, the molar ratio of cytarabine and anthracycline antibiotic is preferably 5:1 to 40:1; further, The molar ratio of cytarabine and anthracycline may preferably be from 10:1 to 30:1.
  • the nano-lipid microparticles have an effective average particle diameter of less than 200 nm.
  • the components of the nanolipid microparticles comprise at least one phosphatidylcholine, a charged lipid stabilizer and a phospholipid membrane fluidity modifier.
  • phosphatidylcholine is selected from the group consisting of egg yolk phosphatidylcholine (EPC), hydrogenated soybean phosphatidylcholine (HSPC), distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC) Any one of them is preferably hydrogenated soybean phosphatidylcholine or distearoylphosphatidylcholine.
  • EPC egg yolk phosphatidylcholine
  • HSPC hydrogenated soybean phosphatidylcholine
  • DSPC distearoylphosphatidylcholine
  • DPPC dipalmitoylphosphatidylcholine
  • DOPC dioleoylphosphatidylcholine
  • DMPC dimyristoylphosphatidylcholine
  • the charged lipid stabilizer is selected from the group consisting of methoxy polyethylene glycol-distearoylphosphatidylethanolamine, phosphatidylglycerol or cholesteryl sulfate
  • phosphatidylglycerol is selected from the group consisting of dimyristoyl phosphatidylglycerol (DMPG), Any one or a mixture of palmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylglycerol (DOPG), distearoylphosphatidylglycerol (DSPG), preferably methoxypolyethylene glycol- Distearoylphosphatidylethanolamine and distearoylphosphatidylglycerol, or methoxypolyethylene glycol-distearoylphosphatidylethanolamine and cholesteryl sulfate.
  • DMPG dimyristoyl phosphatidylglycerol
  • DOPG
  • the phospholipid membrane fluidity regulator is preferably derived from cholesterol.
  • the nanolipid microparticle composition of the present embodiment can be prepared as a lyophilized preparation, and further includes a lyoprotectant selected from the group consisting of sucrose, trehalose or mannitol, preferably sucrose.
  • the nanolipid microparticles can be prepared by the following preparation methods:
  • the average particle size is reduced to about 100nm; ultra-filter to remove unencapsulated drug, and the replacement buffer is sucrose solution, adjust the pH to about 6.50, add anthracycline antibiotic solution, 60 ° C Keep it for more than 30 minutes. After aliquoting and lyophilization, the cytarabine/anthracycline antibiotic nanolipid particles are injected.
  • the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the nano-lipid microparticle composition and a pharmaceutically acceptable carrier thereof, the nano-lipid microparticle composition comprising by weight 1% to 7% of cytarabine, 0.1% to 3% by weight of anthracycline antibiotic, the carrier comprising 5% to 20% by weight of hydrogenated soybean phosphatidylcholine or distearoyl phospholipid Acetylcholine, 0.5% to 5% by weight of methoxypolyethylene glycol-distearoylphosphatidylethanolamine, 0.5% to 5% by weight of cholesterol, and 70% to 90% by weight of sucrose .
  • the pharmaceutical composition comprises the nano-lipid microparticle composition and a pharmaceutically acceptable carrier thereof, the nano-lipid microparticle composition comprising by weight 1% to 7% of cytarabine, 0.1% to 3% by weight of anthracycline antibiotic, the carrier comprising 5% to 20% by weight of hydrogenated soybean phosphatidylcholine or distea
  • the nano-lipid microparticle composition comprises 2% to 5% by weight of cytarabine, 0.1% to 1.5% by weight of an anthracycline antibiotic, and the carrier comprises 6% to 12 by weight.
  • the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the nano-lipid microparticle composition and a pharmaceutically acceptable carrier thereof, the nano-lipid microparticle composition comprising by weight 1% to 7% of cytarabine, 0.1% to 3% by weight of anthracycline antibiotic, 5% to 20% by weight of hydrogenated soybean phosphatidylcholine or distearoylphosphatidylcholine, From 0.5% to 10% by weight of distearoylphosphatidylglycerol, from 0.5% to 5% by weight of cholesterol and from 65% to 90% by weight of sucrose.
  • the pharmaceutical composition comprises the nano-lipid microparticle composition and a pharmaceutically acceptable carrier thereof, the nano-lipid microparticle composition comprising by weight 1% to 7% of cytarabine, 0.1% to 3% by weight of anthracycline antibiotic, 5% to 20% by weight of hydrogenated soybean phosphatidylcholine or distearoylphosphatidylcholine, From 0.5% to 10% by weight
  • the nano-lipid microparticle composition comprises 2% to 5% by weight of cytarabine, 0.1% to 1.5% by weight of an anthracycline antibiotic, and the carrier comprises 12% to 18% by weight.
  • % hydrogenated soybean phosphatidylcholine or distearoylphosphatidylcholine 2% to 5% by weight of distearoylphosphatidylglycerol, 0.5% to 2% by weight of cholesterol and 70 by weight % to 80% sucrose.
  • the effective average particle diameter of the nano-lipid microparticles is preferably less than 200 nm.
  • the nanolipid microparticles are in a liquid state or a freeze-dried state.
  • nanolipid microparticle compositions and pharmaceutical compositions of the present invention are useful in the treatment of hematopoietic proliferative diseases, particularly in the treatment of acute leukemia.
  • nanolipid microparticle composition of the present invention and a pharmaceutical composition will be described below by three examples.
  • the nano-lipid particles are made up to 10 L;
  • the cytarabine/anadamycin nanolipid microparticle injection was obtained by filling 5 mL/branche into a 5 mL neutral borosilicate glass vial and stoppering the lid.
  • the replacement buffer is sucrose buffer and concentrated to 7L, adjust the pH to 6.50, add 4-demethoxydaunorubicin sucrose aqueous solution, heat at 60 ° C for 30 minutes;
  • the final nano-lipid particles are made up to 10L

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Abstract

一种纳米脂质微粒组合物，所述纳米脂质微粒组合物由阿糖胞苷、蒽环类抗生素和纳米脂质微粒组成，其中阿糖胞苷和蒽环类抗生素被共包封于纳米脂质微粒中，纳米脂质微粒包含一种带电荷的脂质稳定剂，其有效平均粒径小于400nm。

Description

一种用于治疗造血系统增殖性疾病的纳米脂质微粒组合物及药用组合物 技术领域
本发明涉及药物制剂技术领域，尤其涉及一种用于治疗造血系统增殖性疾病的纳米脂质微粒组合物及药用组合物。
背景技术
造血系统增殖性疾病包括白血病、恶性淋巴瘤、多发性骨髓瘤、等疾病。其中急性髓性白血病(acute myelogenous leukemia,AML)是造血系统增殖性疾病中较多见一类疾病。对于AML治疗，目前国际推荐的治疗指南为联合“7+3”方案：柔红霉素90mg/m2或4-去甲氧柔红霉素12mg/m2联合标准剂量阿糖胞苷。阿糖胞苷(Cytarabine，Ara-C)是细胞周期性特异抗肿瘤抑制剂，在细胞分裂的S期显著的影响细胞，在细胞内，阿糖胞苷转化为阿糖胞苷-5’-三磷酸酯(ara-CTP)作为其活性代谢物。目前认为ara-CTP主要通过抑制DNA聚合酶发挥作用。阿糖胞苷对于体外培养的多种哺乳动物细胞都具有细胞毒作用。
安那霉素(annamycin)是新一代蒽环类抗生素，与其他蒽环类药物相比，具有较低的心脏毒性，作为单用药物已用于急性髓性白血病治疗的临床研究。4-去甲氧柔红霉素(idarubicin，IDA)是蒽环类药物柔红霉素的衍生物，本品嵌入DNA双链的碱基对之间，抑制DNA链的延伸、复制和转录，最后导致细胞死亡。新近发现，本品还可影响拓扑异构酶Ⅱ(TopⅡ)的活性。TopⅡ在维持DNA的正常空间结构、保证DNA复制和转录中具有重要作用。
常规“7+3”联合疗法具有有限的疗效获益。其局限在于普通联合给药情况下，一种或多种药物在到达病灶位置之前被迅速清除；联合给药情况下，一种药物配迅速清除而另一种药物未被迅速清除，药物组合的比例失效，导致降低药物组合的治疗效果，同时引起毒性。同时7+3给药情况下，阿糖胞苷给药过程为每天1小时，连续7天。这种给药方式导致住院时间长、治疗支出增加、并发症增多等危险因素增多。
30年以来逐渐确定蒽环类和阿糖胞苷仍是急性髓性白血病的标准诱导治疗的基石疗法。因此有必要结合先进制剂技术开发新型药物组合，显著改善疾病总体存活，降低毒性，缩短给药过程，改善给药顺应性。
发明内容
本发明所要解决的技术问题在于，提供一种用于治疗造血系统增殖性疾病的纳米脂质微粒组合物及药用组合物，能使阿糖胞苷和蒽环类抗生素在体内长时间保持两者的比例，以发挥最大的药物协同作用。
为了解决上述技术问题，本发明提供一种纳米脂质微粒组合物，其中，所述纳米脂质微粒组合物由阿糖胞苷、蒽环类抗生素和纳米脂质微粒组成，其中阿糖胞苷和蒽环类抗生素被共包封于纳米脂质微粒中，纳米脂质微粒包含一种带电荷的脂质稳定剂，其有效平均粒径小于400nm。
其中，蒽环类抗生素为安那霉素和4-去甲氧柔红霉素。
其中，阿糖胞苷还包含其药学上可接受的盐。
其中，蒽环类抗生素还包含其药学上可接受的盐。
其中，阿糖胞苷和蒽环类抗生素的摩尔比例为2:1到50:1。
其中，阿糖胞苷和蒽环类抗生素的摩尔比例为5:1到40:1。
其中，阿糖胞苷和蒽环类抗生素的摩尔比例为10:1到30:1。
其中，所述纳米脂质微粒的有效平均粒径小于200nm。
其中，所述纳米脂质微粒的组分包括至少一种磷脂酰胆碱，一种带电荷的脂质稳定剂和一种磷脂膜流动性调节剂。
其中，带电荷的脂质稳定剂选自甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺和磷脂酰甘油。
其中，带电荷的脂质稳定剂选自甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺和硫酸胆固醇酯。
其中，磷脂酰甘油选自二肉豆蔻酰磷脂酰甘油、二棕榈酰磷脂酰甘油、二油酰磷脂酰甘油、二硬脂酰磷脂酰甘油中的任意一种或几种的混合物。
其中，磷脂酰胆碱选自蛋黄磷脂酰胆碱、氢化大豆磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二油酰磷脂酰胆碱、二肉豆蔻酰磷磷脂酰胆碱中的任意一种。
其中，磷脂膜流动性调节剂选自胆固醇。
本发明还提供一种药用组合物，其中，所述药用组合物包含所述的纳米脂质微粒组合物和其药学上可接受的载体，所述纳米脂质微粒组合物包含以重量计1％～7％的阿糖胞苷、以重量计0.1％～3％的蒽环类抗生素，所述载体包含以重量计5％～20％的氢化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱、以重量计0.5％～5％的甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺、以重量计0.5％～5％的胆固醇和以重量计70％～90％的蔗糖。
其中，所述纳米脂质微粒组合物包含以重量计2％～5％的阿糖胞苷、以重量计0.1％～1.5％的蒽环类抗生素，所述载体包含以重量计6％～12％的氢化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱、以重量计1％～3％的甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺、以重量计1％～3％的胆固醇和以重量计75％～85％的蔗糖。
本发明还提供一种药用组合物，其中，所述药用组合物包含所述的纳米脂质微粒组合物和其药学上可接受的载体，所述纳米脂质微粒组合物包含以重量计1％～7％的阿糖胞苷、以重量计0.1％～3％的蒽环类抗生素、以重量计5％～20％的氢化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱、以重量计0.5％～10％的二硬脂酰磷脂酰甘油、以重量计0.5％～5％的胆固醇和以重量计65％～90％的蔗糖。
其中，所述纳米脂质微粒组合物包含以重量计2％～5％的阿糖胞苷、以重量计0.1％～1.5％的蒽环类抗生素，所述载体包含以重量计12％～18％的氢化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱、以重量计2％～5％的二硬脂酰磷脂酰甘油、以重量计0.5％～2％的胆固醇和以重量计70％～80％的蔗糖。
其中，所述纳米脂质微粒的有效平均粒径优选小于200nm。
其中，纳米脂质微粒为液体状态或冷冻干燥状态。
本发明带来的有益效果在于，纳米脂质微粒使阿糖胞苷和蒽环类抗生素在体内长时间保持两者的比例，能够控制被包封药物的释放速度，具有缓释作用，同时还能降低药物的毒性，提高药物的疗效，对于体内易被酶解的药物，纳米脂质微粒还能提供对药物的保护作用。
具体实施方式
本发明实施例一提供一种纳米脂质微粒组合物，其中，所述纳米脂质微粒组合物由阿糖胞苷、蒽环类抗生素和纳米脂质微粒组成，其中阿糖胞苷和蒽环类抗生素被共包封于纳米脂质微粒中，纳米脂质微粒包含一种带电荷的脂质稳定剂，其有效平均粒径小于400nm。
具体地，组分包封纳米脂质载体是指将两种或两种以上的药物包封至由磷脂双分子层构成的具有类似细胞结构的封闭囊泡中所形成的纳米脂质微粒。构成脂质载体的成分包括磷脂酰胆碱、磷脂酰甘油和胆固醇等，这些脂质成分无毒、无免疫原性，生物相容性好。药物被包封在平均粒径为50nm-1000nm的纳米脂质微粒中，体内半衰期将被大大延长。因此纳米脂质微粒能够控制被包封药物的释放速度，具有缓释作用，同时还能降低药物的毒性，提高药物的疗效。对于体内易被酶解的药物，纳米脂质微粒还能提供对药物的保护作用。纳米脂质载体不但可以包封水溶性药物(内水相中)，也可以包封脂溶性药物(双分子层中)。
不同的药物在体内往往具有不同的半衰期，当被多组分包封至纳米脂质微粒中后，药物的半衰期与纳米脂质微粒同步，即多个药物通过纳米脂质微粒载体进入体内后，在一定时间内拥有非常接近甚至相同的半衰期，将更好地发挥几种药物的协同作用。同时纳米脂质微粒具有缓释药物的能力，在降低药物毒性的基础上，有望在临床上实现以更高的剂量达到更好的疗效，或者更低的剂量实现相同的疗效。
本实施例中，蒽环类抗生素优选为安那霉素(Annamycin)和4-去甲氧柔红霉素(idarubicin)。
阿糖胞苷还包含其药学上可接受的盐，蒽环类抗生素还包含其药学上可接受的盐。阿糖胞苷和蒽环类抗生素的摩尔比例为2:1到50:1；进一步地，阿糖胞苷和蒽环类抗生素的摩尔比例优选为5:1到40:1；再进一步地，阿糖胞苷和蒽环类抗生素的摩尔比例可以优选为10:1到30:1。
本实施例中，纳米脂质微粒的有效平均粒径小于200nm。
本实施例中，纳米脂质微粒的组分包括至少一种磷脂酰胆碱，一种带电荷的脂质稳定剂和一种磷脂膜流动性调节剂。
其中，磷脂酰胆碱选自蛋黄磷脂酰胆碱(EPC)、氢化大豆磷脂酰胆碱 (HSPC)、二硬脂酰磷脂酰胆碱(DSPC)、二棕榈酰磷脂酰胆碱(DPPC)、二油酰磷脂酰胆碱(DOPC)、二肉豆蔻酰磷磷脂酰胆碱(DMPC)中的任意一种，优选为氢化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱。
带电荷的脂质稳定剂选自甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺，磷脂酰甘油或硫酸胆固醇酯，磷脂酰甘油选自二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酰甘油(DPPG)、二油酰磷脂酰甘油(DOPG)、二硬脂酰磷脂酰甘油(DSPG)中的任意一种或几种的混合物，优选为甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺和二硬脂酰磷脂酰甘油，或者甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺和硫酸胆固醇酯。
磷脂膜流动性调节剂优选自胆固醇。
本实施例的纳米脂质微粒组合物可制备成冻干制剂，还包括冻干保护剂，所述的冻干保护剂选自蔗糖、海藻糖或甘露醇，优选为蔗糖。
纳米脂质微粒可采用如下制备方法制备：
将过量阿糖胞苷溶解于适量硫酸铵溶液中；磷脂酰胆碱、带电荷的脂质和脂质膜流动性调节剂溶解于适量无水乙醇或95％乙醇中；两者混匀后，采用高速剪切机以9000rpm以上的速度混合，获得脂质微粒粗品；将脂质微粒粗品通过以500bar以上的压力通过高压均质机若干个循环，保持物料温度在60℃左右，再高压挤过100nm聚碳酸脂膜若干次，使平均粒径减少至100nm左右；超滤除去未包封的药物，并置换缓冲液为蔗糖溶液，调节pH值至6.50左右，加入蒽环类抗生素水溶液，60℃保持30min以上。分装后冷冻干燥，即得注射用阿糖胞苷/蒽环类抗生素纳米脂质微粒。
本发明还提供一种药用组合物，其中，所述药用组合物包含所述的纳米脂质微粒组合物和其药学上可接受的载体，所述纳米脂质微粒组合物包含以重量计1％～7％的阿糖胞苷、以重量计0.1％～3％的蒽环类抗生素，所述载体包含以重量计5％～20％的氢化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱、以重量计0.5％～5％的甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺、以重量计0.5％～5％的胆固醇和以重量计70％～90％的蔗糖。
其中，所述纳米脂质微粒组合物包含以重量计2％～5％的阿糖胞苷、以重量计0.1％～1.5％的蒽环类抗生素，所述载体包含以重量计6％～12％的氢 化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱、以重量计1％～3％的甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺、以重量计1％～3％的胆固醇和以重量计75％～85％的蔗糖。
本发明还提供一种药用组合物，其中，所述药用组合物包含所述的纳米脂质微粒组合物和其药学上可接受的载体，所述纳米脂质微粒组合物包含以重量计1％～7％的阿糖胞苷、以重量计0.1％～3％的蒽环类抗生素、以重量计5％～20％的氢化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱、以重量计0.5％～10％的二硬脂酰磷脂酰甘油、以重量计0.5％～5％的胆固醇和以重量计65％～90％的蔗糖。
其中，所述纳米脂质微粒组合物包含以重量计2％～5％的阿糖胞苷、以重量计0.1％～1.5％的蒽环类抗生素，所述载体包含以重量计12％～18％的氢化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱、以重量计2％～5％的二硬脂酰磷脂酰甘油、以重量计0.5％～2％的胆固醇和以重量计70％～80％的蔗糖。。
其中，所述纳米脂质微粒的有效平均粒径优选小于200nm。
其中，纳米脂质微粒为液体状态或冷冻干燥状态。
本发明的纳米脂质微粒组合物及药用组合物用于造血系统增殖性疾病，尤其用于急性白血病的治疗。
以下再通过三个实施例来说明将本发明的纳米脂质微粒组合物及药用组合物的具体应用。
实施例1：阿糖胞苷/Annamycin纳米脂质微粒注射液
处方：
阿糖胞苷  50g
安那霉素(Annamycin)  2g
二硬脂酰磷脂酰胆碱  220g
二硬脂酰磷脂酰甘油  60g
胆固醇  20g
蔗糖  1.26kg
注射用水  10L
制备工艺：
(1)将过量阿糖胞苷溶解于硫酸铵溶液中；
(2)将二硬脂酰磷脂酰胆碱、二硬脂酰磷脂酰甘油、胆固醇和安那霉素溶于60℃无水乙醇中；
(3)将(2)旋转蒸发除去无水乙醇，加入(1)于60℃水化1h，形成脂质微粒粗品；
(4)将脂质微粒粗品通过以700bar通过高压均质机3个循环，高压挤过100nm聚碳酸脂膜1次，保持物料温度在60℃左右，平均粒径减少至约100nm；
(5)超滤除去未包封的药物，并置换缓冲液为蔗糖溶液；
(6)将纳米脂质微粒定容至10L；
以5mL/支灌装至5mL中性硼硅玻璃西林瓶中，加塞轧盖，即得阿糖胞苷/安那霉素纳米脂质微粒注射液。
实施例2：阿糖胞苷/4-去甲氧柔红霉素纳米脂质微粒注射液
处方：
阿糖胞苷  50g
4-去甲氧柔红霉素(以游离碱计)  3.5g
氢化大豆磷脂酰胆碱  100g
甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺  30g
胆固醇  30g
蔗糖  1kg
注射用水  10L
制备工艺：
(1)将过量阿糖胞苷溶解于4L硫酸铵溶液中；
(2)将氢化大豆磷脂酰胆碱，甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺和胆固醇溶于601L60℃无水乙醇中；
(3)两者混匀后，用IKA高速剪切机以10000rpm混匀，加入6L硫酸铵溶液，以6000rpm混匀；
(4)以上脂质微粒粗品混悬液通过以700bar通过高压均质机2个循环，高 压挤过100nm聚碳酸脂膜3次，保持物料温度在60℃左右，使平均粒径减少至约100nm；
(5)超滤除去未包封的药物并浓缩至7L，调节pH值至6.50，加入4-去甲氧柔红霉素蔗糖水溶液，60℃保温30分钟；
(6)将纳米脂质微粒定容至10L
(7)以5mL/支灌装至5mL中性硼硅玻璃西林瓶中，加塞轧盖，即得阿糖胞苷/4-去甲氧柔红霉素纳米脂质微粒注射液。
实施例3：注射用阿糖胞苷/4-去甲氧柔红霉素纳米脂质微粒
处方：
阿糖胞苷  50g
4-去甲氧柔红霉素(以游离碱计)  3.5g
二硬脂酰磷脂酰胆碱  230g
二硬脂酰磷脂酰甘油  70g
胆固醇  15g
蔗糖  1.26kg
注射用水  10L
制备工艺：
(1)将过量阿糖胞苷溶解于10L硫酸铵溶液中；
(2)将二硬脂酰磷脂酰胆碱，二硬脂酰磷脂酰甘油和胆固醇溶于60℃无水乙醇中；
(3)两者混匀后，用IKA高速剪切机以9000rpm混匀；
(4)将以上脂质微粒粗品混悬液通过以2000bar通过微射流均质机1个循环，并高压挤过100nm聚碳酸脂膜3次，保持物料温度在60℃左右，使平均粒径减少至约100nm；
(5)超滤除去未包封的药物，置换缓冲液为蔗糖缓冲液并浓缩至7L，调节pH值至6.50，加入4-去甲氧柔红霉素蔗糖水溶液，60℃保温30分钟；
(6)将最终纳米脂质微粒定容至10L
(7)以5mL/支灌装至20mL中性硼硅玻璃西林瓶中，冷冻干燥后，即得注 射用阿糖胞苷/4-去甲氧柔红霉素纳米脂质微粒。
以上所揭露的仅为本发明较佳实施例而已，当然不能以此来限定本发明之权利范围，因此依本发明权利要求所作的等同变化，仍属本发明所涵盖的范围。

Claims (20)

  1. 一种纳米脂质微粒组合物，其中，所述纳米脂质微粒组合物由阿糖胞苷、蒽环类抗生素和纳米脂质微粒组成，其中阿糖胞苷和蒽环类抗生素被共包封于纳米脂质微粒中，纳米脂质微粒包含一种带电荷的脂质稳定剂，其有效平均粒径小于400nm。
  2. 根据权利要求1所述的纳米脂质微粒组合物，其中，蒽环类抗生素为安那霉素和4-去甲氧柔红霉素。
  3. 根据权利要求1所述的纳米脂质微粒组合物，其中，阿糖胞苷还包含其药学上可接受的盐。
  4. 根据权利要求2所述的纳米脂质微粒组合物，其中，蒽环类抗生素还包含其药学上可接受的盐。
  5. 根据权利要求1所述的纳米脂质微粒组合物，其中，阿糖胞苷和蒽环类抗生素的摩尔比例为2:1到50:1。
  6. 根据权利要求5所述的纳米脂质微粒组合物，其中，阿糖胞苷和蒽环类抗生素的摩尔比例为5:1到40:1。
  7. 根据权利要求6所述的纳米脂质微粒组合物，其中，阿糖胞苷和蒽环类抗生素的摩尔比例为10:1到30:1。
  8. 根据权利要求1所述的纳米脂质微粒组合物，其中，所述纳米脂质微粒的有效平均粒径小于200nm。
  9. 根据权利要求1所述的纳米脂质微粒组合物，其中，所述纳米脂质微粒的组分包括至少一种磷脂酰胆碱，一种带电荷的脂质稳定剂和一种磷脂膜流动性调节剂。
  10. 根据权利要求9所述的纳米脂质微粒组合物，其中，带电荷的脂质稳定剂选自甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺和磷脂酰甘油。
  11. 根据权利要求9所述的纳米脂质微粒组合物，其中，带电荷的脂质稳定剂选自甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺和硫酸胆固醇酯。
  12. 根据权利要求10所述的纳米脂质微粒组合物，其中，磷脂酰甘油选自二肉豆蔻酰磷脂酰甘油、二棕榈酰磷脂酰甘油、二油酰磷脂酰甘油、二硬脂酰磷脂酰甘油中的任意一种或几种的混合物。
  13. 根据权利要求9所述的纳米脂质微粒组合物，其中，磷脂酰胆碱选自蛋黄磷脂酰胆碱、氢化大豆磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二油酰磷脂酰胆碱、二肉豆蔻酰磷磷脂酰胆碱中的任意一种。
  14. 根据权利要求9所述的组合物，其中，磷脂膜流动性调节剂选自胆固醇。
  15. 一种药用组合物，其中，所述药用组合物包含如权利要求1所述的纳米脂质微粒组合物和其药学上可接受的载体，所述纳米脂质微粒组合物包含以重量计1％～7％的阿糖胞苷、以重量计0.1％～3％的蒽环类抗生素，所述载体包含以重量计5％～20％的氢化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱、以重量计0.5％～5％的甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺、以重量计0.5％～5％的胆固醇和以重量计70％～90％的蔗糖。
  16. 根据权利要求15所述药用组合物，其中，纳米脂质微粒为液体状态或冷冻干燥状态。
  17. 根据权利要求15所述药用组合物，其中，所述纳米脂质微粒组合物包含以重量计2％～5％的阿糖胞苷、以重量计0.1％～1.5％的蒽环类抗生素，所述载体包含以重量计6％～12％的氢化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱、以重量计1％～3％的甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺、以重量计1％～3％的胆固醇和以重量计75％～85％的蔗糖。
  18. 一种药用组合物，其中，所述药用组合物包含如权利要求1所述的纳米脂质微粒组合物和其药学上可接受的载体，所述纳米脂质微粒组合物包含以重量计1％～7％的阿糖胞苷、以重量计0.1％～3％的蒽环类抗生素、以重量计5％～20％的氢化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱、以重量计0.5％～10％的二硬脂酰磷脂酰甘油、以重量计0.5％～5％的胆固醇和以重量计65％～90％的蔗糖。
  19. 根据权利要求18所述药用组合物，其中，所述纳米脂质微粒组合物包含以重量计2％～5％的阿糖胞苷、以重量计0.1％～1.5％的蒽环类抗生素，所述载体包含以重量计12％～18％的氢化大豆磷脂酰胆碱或二硬脂酰磷脂酰胆碱、以重量计2％～5％的二硬脂酰磷脂酰甘油、以重量计0.5％～2％的胆固醇和以重量计70％～80％的蔗糖。
  20. 根据权利要求18所述药用组合物，其中，所述纳米脂质微粒的有效平均粒径优选小于200nm。
PCT/CN2017/095241 2017-07-31 2017-07-31 一种用于治疗造血系统增殖性疾病的纳米脂质微粒组合物及药用组合物 WO2019023873A1 (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114728101A (zh) * 2019-06-28 2022-07-08 德州大学系统董事会 重构脂质体安那霉素的方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102037354B1 (ko) * 2018-12-07 2019-10-28 (주) 바이노텍 생리활성물질 봉입을 위한 나노지질전달체 및 이의 제조방법

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1849143A (zh) * 2002-12-19 2006-10-18 阿尔扎公司 治疗血管源性组织生长的方法
CN101856359A (zh) * 2010-05-14 2010-10-13 山东大学 一种抗急性髓系白血病的药物组合物
CN105998046A (zh) * 2007-02-16 2016-10-12 切拉托尔制药公司 用于治疗造血性癌症和增殖性病症的固定药物比例
CN107569508A (zh) * 2016-07-05 2018-01-12 江苏竞诺择生物医药科技有限公司 一种治疗造血系统增殖性疾病的药用组合物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9693958B2 (en) * 2013-03-15 2017-07-04 Cureport, Inc. Methods and devices for preparation of lipid nanoparticles
CN104906586A (zh) * 2014-03-10 2015-09-16 中国科学院上海药物研究所 一种盐酸伊立替康复合磷脂组合物、制备方法及其应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1849143A (zh) * 2002-12-19 2006-10-18 阿尔扎公司 治疗血管源性组织生长的方法
CN105998046A (zh) * 2007-02-16 2016-10-12 切拉托尔制药公司 用于治疗造血性癌症和增殖性病症的固定药物比例
CN101856359A (zh) * 2010-05-14 2010-10-13 山东大学 一种抗急性髓系白血病的药物组合物
CN107569508A (zh) * 2016-07-05 2018-01-12 江苏竞诺择生物医药科技有限公司 一种治疗造血系统增殖性疾病的药用组合物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114728101A (zh) * 2019-06-28 2022-07-08 德州大学系统董事会 重构脂质体安那霉素的方法
CN114728101B (zh) * 2019-06-28 2023-07-14 德州大学系统董事会 重构脂质体安那霉素的方法

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