CN116650425A - 糖酯化合物或其盐在冷冻保护、冷冻干燥保护中的应用 - Google Patents
糖酯化合物或其盐在冷冻保护、冷冻干燥保护中的应用 Download PDFInfo
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- CN116650425A CN116650425A CN202310858523.9A CN202310858523A CN116650425A CN 116650425 A CN116650425 A CN 116650425A CN 202310858523 A CN202310858523 A CN 202310858523A CN 116650425 A CN116650425 A CN 116650425A
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- RYCLIXPGLDDLTM-UHFFFAOYSA-J tetrapotassium;phosphonato phosphate Chemical compound [K+].[K+].[K+].[K+].[O-]P([O-])(=O)OP([O-])([O-])=O RYCLIXPGLDDLTM-UHFFFAOYSA-J 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- LABSPYBHMPDTEL-JGZVXCDNSA-N trehalose-6-phosphate Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@@H]1O[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](COP(O)(O)=O)O1 LABSPYBHMPDTEL-JGZVXCDNSA-N 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
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Classifications
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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
- A61K9/14—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
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0205—Chemical aspects
- A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明提供了糖酯化合物或其盐在冷冻保护、冷冻干燥保护中的应用，属于医药技术领域。本发明将糖酯化合物或其盐用于冷冻干燥保护剂或冷冻保护剂，可以有效保证冷冻干燥后的脂质纳米颗粒完整性、包封药物活性、脂质纳米颗粒的粒度在可接受范围内，并且含有活性成分的脂质纳米颗粒冷冻干燥后冷冻干燥粉外观良好、容易复溶（约5‑10秒），且复溶后样品外观与冷冻干燥前无差异，可以在室温下长期储存，为低温储存的产品解决了运输和储存难题。本发明提出的含有糖酯化合物或其盐的用于冷冻保护或冷冻干燥保护的组合物，应用广泛，不仅可以作为脂质纳米颗粒的冷冻干燥/冷冻保护剂，也可用作细胞的冷冻/冻存保护。
Description
技术领域
本发明属于医药技术领域，尤其涉及糖酯化合物或其盐在冷冻保护、冷冻干燥保护中的应用。
背景技术
脂质纳米颗粒作为核酸治疗、小分子药物化合物治疗的递送载体在改善药物成药性和安全性方面发挥重要作用。例如在新冠核酸疫苗中有效改善了信使核酸的稳定性，提高了核酸的转染效率。但是脂质纳米颗粒递送技术本身仍存在稳定性问题，易发生颗粒聚集、氧化或水解降解等，不利于药物的贮存或使用。目前已上市的两款信使核酸疫苗：Moderna公司的mRNA疫苗 （商品名为Spikevax，代码：mRNA-1273）需要在-20℃条件下保存和运输，Pfizer/BioNTech公司的mRNA疫苗 （商品名：Comirnaty，代码：BNT162b2） 需要在-70℃条件下保存和运输，增加了疫苗的保存和运输的难度和成本，不利于疫苗向更多地区应用。因此脂质纳米颗粒制剂的储存稳定性问题急需解决。一种用于提高脂质纳米颗粒制剂的储存能力的解决方案是将脂质纳米颗粒制剂制造为冷冻干燥产品，该产品可以在施用之前复溶。冷冻干燥的脂质纳米颗粒组合物可以在适宜的温度下储存，更方便运输和临床用药。
冷冻干燥是将溶剂和/或混悬介质在低温条件下结晶，然后将其由固态直接升华为气态的一种干燥过程。冷冻干燥技术具有非常突出的优点，如保持样品活性、增强产品的稳定性和复溶性、简化无菌处理、剂量准确、延长制剂有效期、去除水的同时不过度加热产品等。冷冻干燥技术广泛应用于药品、生物制品和医疗产品，如蛋白质、激素、病毒、疫苗、细菌、酵母菌、抗生素、细胞抑制剂、脂质体、纳米颗粒、抗体、移植体、胶原蛋白等。但在冷冻干燥过程中存在很多问题，如脂质纳米颗粒在冷冻干燥过程中，纳米粒结构被不同程度破坏，发生纳米粒聚集或沉淀，导致复溶后脂质纳米粒粒径明显增大或药物泄露失活。常规的冷冻干燥保护剂如蔗糖或海藻糖等虽可发挥填充作用，减少冷冻干燥塌陷，改善冷冻干燥饼外观，但无法保护脂质纳米颗粒在冷冻干燥过程中的微观结构稳定。有研究报道，采用10%蔗糖为冷冻干燥保护剂的mRNA脂质纳米颗粒进行冷冷冻干燥燥，复溶后粒径显著增大，且粒度分布较差。因此，迫切需要针对脂质纳米颗粒质量稳定性问题，开发更好的冷冻干燥解决方案。
目前有研究尝试用糖、多元醇及其他水溶性高分子物质做为脂质纳米颗粒的冷冻干燥保护剂，虽在冷冻干燥制品外观等方面有部分改善，但仍未有效解决脂质纳米颗粒在冷冻干燥过程中的稳定性问题。
糖是常用的冷冻干燥赋形剂。在冷冻干燥过程中，常常采用低聚糖尤其是二糖作为冷冻干燥保护剂，这是因为二糖既能在冻结过程中起到低温保护作用剂的功能，又能在干燥脱水过程中起到脱水保护剂的作用。蔗糖和海藻糖是食品、药品以及生物体的冷冻干燥中最常用的冷冻干燥保护剂。通常在一定的浓度范围内，糖的保护作用随着浓度的升高而增大；当达到一定浓度时，保护作用达到最大值，此后再增加糖的浓度，保护效果反而会降低，且随着糖浓度的增加，冷冻干燥品的外观越来越差。
Tanaka等研究了山梨醇、肌醇和甘露醇等多元醇对脂质体的冷冻干燥保护作用，结果表明多元醇的冷冻干燥保护作用均比二糖差，冷冻干燥品均有明显的聚集现象，复溶后粒径显著增大，药物渗漏严重。
也有报道添加聚乙二醇、聚乙烯吡咯烷酮等聚合物，氯化钠、氯化钾等无机盐等组分作为冷冻干燥保护剂，但当聚合物聚合度过大时，会在冷冻过程中结晶，从而失去对样品的保护作用，而且聚合物浓度及分子量过大时会增加最终产品的水分，使得制品中样品变得更不稳定；无机盐在冷冻干燥过程中容易析出晶体，容易导致样品被破坏。
专利CN114557971A公布了“一种核酸-脂质纳米颗粒的冷冻干燥保护剂及其制备方法和应用”该专利选择蔗糖与海藻糖作为冷冻干燥保护剂，加入量为5-20%w/w。专利CN115624630A公布了“冻干保护组合物及其应用和基于该组合物的核酸脂质纳米颗粒冻存方法”提供了一种冻干保护组合物包含糖类和还原剂。其糖类包含单糖和二糖的组合，还原剂为枸橼酸、枸橼酸钾、枸橼酸钠、抗坏血酸、抗坏血酸钾和抗坏血酸钠组成的至少一种，以质量百分比计，所述冷冻干燥保护剂包含5-20%单糖、5-20%二糖和0.1-3%还原剂的PBS溶液，该专利还批露了该脂质纳米颗粒的冻存方法。专利CN114727964A公布了“脂质纳米粒子的冷冻干燥组合物”中公布了空白脂质纳米颗粒的冷冻干燥技术，将冷冻干燥后的脂质纳米颗粒与核酸溶液进行孵育载药，所用冷冻保护剂与总脂质的重量比为10：1-1000：1，冷冻保护剂的浓度为80-800mg/ml（以冷冻干燥前计），该冷冻保护剂为蔗糖。
综上所述，脂质纳米颗粒制剂在冷冻干燥复溶后经常会出现粒径、粒径分散性、包封率及纳米颗粒体内药物活性变差的问题，无法保持原有纳米颗粒的活性。目前常用的冷冻干燥保护剂主要为蔗糖、海藻糖、麦芽糖等二糖类化合物以及缓冲盐、表面活性剂、有机溶剂（甘油），不仅种类单一而且糖的用量很高，冷冻干燥保护作用有限，因此迫切需要开发一种新型冷冻干燥保护剂以提高冷冻干燥保护剂的保护效率，使冷冻干燥后所得产品保持冷冻干燥前的良好质量属性。
此外，冷冻做为冷冻干燥的组成步骤，同时也做为细胞或脂质纳米颗粒的低温保存方式。蔗糖、海藻糖等也是常用的细胞或脂质纳米粒的冷冻保护剂，在低温冷冻过程中同样存在与冷冻干燥相似的脂质膜损伤，引起膜融合或抑制酶的活性。因此，在低温冷冻技术领域，亦需要开发更安全有效的冷冻保护剂，以满足低温冷冻的需求。
发明内容
本发明针对现有技术存在的问题，提供了糖酯化合物或其盐在冷冻保护、冷冻干燥保护中的应用。本发明将糖酯化合物或其盐用于冷冻干燥保护剂或冷冻保护剂，可以有效保证冷冻干燥后的脂质纳米颗粒完整性、包封药物活性、脂质纳米颗粒的粒度在可接受范围内，并且含有活性成分的脂质纳米颗粒冷冻干燥后冷冻干燥粉外观良好、容易复溶（约5-10秒），且复溶后样品外观与冷冻干燥前无差异，可以在室温下长期储存，为低温储存的产品解决了运输和储存难题。本发明提出的含有糖酯化合物或其盐的用于冷冻保护或冷冻干燥保护的组合物，应用广泛，不仅可以作为脂质纳米颗粒的冷冻干燥/冷冻保护剂，也可用作细胞的冷冻/冻存保护剂。
为实现上述目的，第一方面，本发明提供了糖酯化合物或其盐在冷冻保护、冷冻干燥保护中的应用；所述糖酯化合物经糖与酸酯化得到；所述糖选自单糖和/或低聚糖；所述低聚糖由2-10个糖单元组成；所述酸为有机酸和/或无机酸。
本发明技术人员在研究过程中发现本发明中所述的糖酯化合物或其盐为两亲性分子，与所述的填充剂通过分子-分子相互作用，在冷冻和/或冷冻干燥过程中对纳米颗粒起到叠加的保护作用。
所述盐为母体化合物通过将现有的酸或碱部分转化为其盐形式(例如，通过使游离碱基与合适的有机酸反应)而被修饰得到。药学上可接受的盐的实例包括但不限于碱性残基如胺的无机酸盐或有机酸盐；酸性残基如羧酸的碱金属盐或有机盐。代表性的酸加成盐包括乙酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐, 氢溴酸盐、盐酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一烷酸盐、戊酸盐等。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁等，以及无毒的铵、季铵和胺阳离子，包括铵、四甲铵、四乙铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。本发明的药学上可接受的盐包括例如由无毒无机或有机酸形成的母体化合物的常规无毒盐。
在一项优选的实施方案中，所述酸选自硫酸、磷酸、磺酸、甲磺酸、羧酸。
在一项优选的实施方案中，所述单糖或所述低聚糖的糖单元碳原子数为4-7；更优选呋喃糖和/或吡喃糖。
在一项优选的实施方案中，所述的单糖或所述低聚糖的糖单元为阿拉伯糖、木糖、来苏糖、核糖、葡萄糖、甘露糖、阿洛糖、半乳糖、果糖、山梨糖、岩藻糖中的至少一种。
在一项优选的实施方案中，所述低聚糖选自2-8个糖单元组成的低聚糖。
在一项优选的实施方案中，所述低聚糖包括二糖、三糖、四糖、五糖、六糖、七糖、八糖、低分子量糖胺聚糖中的至少一种；所述二糖选自蔗糖、乳糖、麦芽糖、海藻糖、乳果糖、纤维二糖、黑曲霉糖、曲二糖、清酒二糖、异麦芽糖、槐糖、海带二糖、龙胆二糖、松二糖、麦芽酮糖、异麦芽酮糖、龙胆二酮糖、甘露二糖、蜜二糖和木二糖；所述三糖选自棉籽糖、麦芽三糖；所述四糖为水苏糖；所述五糖选自古罗糖醛酸五糖、戊聚糖；所述六糖为α-环糊精；所述七糖为β-环糊精；所述八糖为γ-环糊精；所述低分子量糖胺聚糖选自透明质酸、硫酸软骨素、硫酸皮肤素、硫酸角质素、硫酸乙酰肝素、肝素中的至少一种。
在一项优选的实施方案中，所述糖酯化合物或其盐包括二磷酸/硫酸果糖钠/钾、葡萄糖二磷酸/硫酸钾/钠、葡萄糖二磷酸/硫酸四（环己铵盐）、葡萄糖五硫酸/磷酸钾/钠盐、葡萄糖-6-磷酸-二钠/钾盐、6-磷酸葡萄糖酸三钠/钾盐、岩藻糖1-磷酸/硫酸双(环己基铵)盐、核糖磷酸/硫酸双(环己基铵)盐、半乳糖硫酸/磷酸钠/钾盐、半乳糖五乙酸钠/钾、半乳糖醛酸、半乳糖醛酸钠、半乳糖醛酸钾、甘露糖磷酸酯钠/钾、五乙酸甘露糖酯钠/钾、二磷酸吡喃甘露糖酯二钠/钾盐、阿拉伯糖-5-磷酸二钠/钾盐、蔗糖七硫酸钾/钠、蔗糖六硫酸钾/钠、蔗糖八硫酸盐三乙胺盐、蔗糖八硫酸酯钾/钠、蔗糖6，6’-二磷酸、蔗糖6’-单磷酸二钾盐、乳糖酸钾/钠、乳糖醛酸、β-麦芽糖七乙酸盐、麦芽糖酸、麦芽糖酸钠、麦芽糖酸钾、海藻糖-6-磷酸二钾/钠盐、藻酸钾、肝素二糖IS，钠盐、软骨素二糖ΔDI-6S钠盐、硫酸葡聚糖钠盐、硫酸戊聚糖钠、环糊精硫酸钠、β-环糊精磷酸钠盐、羧甲基-β-环糊精磷酸钠盐、N-乙酰基-O-硫酸化肝素(肝素IV-A)钠盐、透明质酸、透明质酸钠、硫酸软骨素、硫酸皮肤素、硫酸角质素、硫酸乙酰肝素中的至少一种。
第二方面，本发明提供了一种用于冷冻保护或冷冻干燥保护的组合物，所述组合物包含：
前述糖酯化合物或其盐，以及填充剂。
在一项优选的实施方案中，所述糖酯化合物或其盐与填充剂的质量比为1：500-3：1，更优选1：400-2：1。
在一项优选的实施方案中，所述填充剂为药学上可接受的赋形剂。
在一项优选的实施方案中，所述药学上可接受的赋形剂选自糖、多元醇、聚合物、盐、氨基酸中至少一种。
在一项优选的实施方案中，所述用于冷冻保护或冷冻干燥保护的组合物采用液体介质配制；所述液体介质选自水和/或pH6.0-8.5的缓冲盐体系。
第三方面，本发明提供了上述用于冷冻保护或冷冻干燥保护的组合物在脂质颗粒冷冻保护剂或冷冻干燥保护剂或细胞冷冻保护剂中的应用。
第四方面，本发明提供了一种冷冻干燥保护剂或冷冻保护剂，包含上述用于冷冻保护或冷冻干燥保护的组合物。
第五方面，本发明提供了一种含冷冻保护剂或冷冻干燥保护剂的脂质纳米颗粒组合物，包括上述冷冻保护剂或冷冻干燥保护剂，以及脂质纳米颗粒；冷冻保护剂或冷冻干燥保护剂与脂质纳米颗粒质量比为2：1-2000：1。
在一项优选的实施方案中，冷冻前或冷冻干燥前的含冷冻保护剂或冷冻干燥保护剂的脂质纳米颗粒组合物中，冷冻保护剂或冷冻干燥保护剂的浓度为50-400mg/ml，更优选为80-350mg/ml。
本发明将冷冻干燥保护剂添加到经预处理的脂质纳米颗粒液体中与冷冻干燥参数结合使用，以获得高质量的冷冻干燥脂质纳米颗粒产品。冷冻干燥产品易于复溶并易于作为药物制剂给药。
本发明所用术语“冷冻干燥保护剂”是指添加到组合物中以在冷冻干燥干燥阶段保护活性成分、帮助保存或稳定冷冻干燥产品的物质、化合物或赋形剂，和/或帮助使冷冻干燥产品更容易复原。如本发明所用，“冷冻保护剂”是指添加到生物或药物组合物中以保护其免受冷冻损伤的物质、化合物或赋形剂。
本发明使用的短语“药学上可接受的”是指在合理的医学判断范围内，适合与人类和动物的组织接触而不过量使用的那些化合物、材料、组合物和/或剂型。毒性、刺激、过敏反应或其他问题或并发症，与合理的收益/风险比相称。
如本发明所用，短语“药学上可接受的赋形剂”是指除本发明所述化合物之外的任何成分（例如，能够悬浮或溶解活性化合物的赋形剂）并具有在药物中基本上无毒和无炎症的性质。
通过使用所述用于冷冻保护或冷冻干燥保护的组合物可以在比脂质纳米颗粒液体更高的温度下稳定储存。通常，脂质纳米颗粒液体储存在-70°C，对于缺乏能够达到和维持该温度的设备的设施来说，这不是运输和储存的合适温度。冷冻干燥组合物可以在高于-20°C的温度下稳定储存。
相对于现有技术，本发明具有以下有益效果：
1、本发明提出了糖酯化合物或其盐的新用途，即在冷冻干燥和/或冷冻中的应用。
2、本发明首次使用糖酯化合物或其盐作为冷冻干燥和/或冷冻保护剂的组分，并提供了一种新的用于冷冻保护或冷冻干燥保护的组合物，用于脂质纳米颗粒冷冻或冷冻干燥和/或细胞的冻存。
3、本发明提出的含有糖酯化合物或其盐的用于冷冻保护或冷冻干燥保护的组合物，可以很好的保证脂质纳米颗粒在冷冻或冷冻干燥过程中的结构稳定性；
4、采用本发明提出的含有糖酯化合物或其盐的用于冷冻保护或冷冻干燥保护的组合物作为冷冻干燥保护剂，含有活性成分的脂质纳米颗粒冷冻干燥后冷冻干燥粉外观良好，无塌陷、收缩、裂化、结膜、喷瓶等现象；
5、采用本发明提出的含有糖酯化合物或其盐的用于冷冻保护或冷冻干燥保护的组合物作为冷冻干燥保护剂，含有活性成分的脂质纳米颗粒较容易复溶（约5-10秒），且复溶后样品外观与冷冻干燥前无差异；
6、采用本发明提出的含有糖酯化合物或其盐的用于冷冻保护或冷冻干燥保护的组合物作为冷冻干燥保护剂，含有活性成分的脂质纳米颗粒在冷冻干燥前和冷冻干燥复溶后，粒径、电位、包封率等药学指标均与冷冻干燥前保持一致，且冷冻干燥复溶后脂质纳米颗粒粒径分布良好。
7、采用本发明提出的含有糖酯化合物或其盐的用于冷冻保护或冷冻干燥保护的组合物作为冷冻干燥保护剂或冷冻保护剂，含有活性成分的脂质纳米颗粒在冷冻干燥前和冷冻干燥复溶后或冷冻前和冷冻解冻后，体内/外测试均显示出良好的活性。
8、采用本发明提出的含有糖酯化合物或其盐的用于冷冻保护或冷冻干燥保护的组合物作为冷冻干燥保护剂，含有活性成分的脂质纳米颗粒可以在室温下长期储存，为低温储存的产品解决了运输和储存难题。
9、本发明提出的含有糖酯化合物或其盐的用于冷冻保护或冷冻干燥保护的组合物，应用广泛，不仅可以作为脂质纳米颗粒的冷冻干燥/冻存保护剂，也可用作细胞的冷冻干燥/冻存保护剂。
附图说明
图1 实施例19的冷冻干燥样品及复溶样品的图片，左：冷冻干燥前照片；中：冷冻干燥后照片；右：冻干复溶后照片；
图2 实施例9冷冻干燥前/冷冻干燥复溶后样品粒度分布图；
图3实施例19冷冻干燥前/冷冻干燥复溶后样品粒度分布图；
图4实施例15的冷冻干燥样品的扫描电镜照片；
图5实施例18的冷冻干燥样品的扫描电镜照片；
图6实施例20的冷冻干燥样品的扫描电镜照片；
图7实施例9冷冻前/冷冻解冻后样品的体外细胞转染效果图；
图8 实施例11冷冻干燥前/冷冻干燥复溶后样品的体外细胞转染效果图；
图9实施例26和30冷冻干燥前/冷冻干燥复溶样品给药后小鼠肿瘤体积随时间变化曲线图。
具体实施方式
下面结合具体实施例，对本发明作进一步详细的阐述，下述实施例不用于限制本发明，仅用于说明本发明。以下实施例中所使用的实验方法如无特殊说明，实施例中未注明具体条件的实验方法，通常按照常规条件，下述实施例中所使用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下面结合实施例进一步说明本发明的技术方案和有益效果。
实施例和对比例 含冷冻干燥保护剂的脂质纳米颗粒组合物
脂质颗粒：将荧光素酶mRNA(Luc mRNA)制备成脂质纳米颗粒作为模型样品1；将多西他赛制备成脂质体作为模型样品2。
冷冻干燥保护剂：按配方称取原料，采用无菌水溶解即得。
（1）基于模型样品1的含冷冻保护剂/冷冻干燥保护剂的脂质纳米颗粒组合物制备：
将荧光素酶mRNA稀释于10-100mMpH4.0枸橼酸钠缓冲溶液中，mRNA溶液浓度为135μg/ml；按ALC-0315：DSPC：胆固醇：ALC-0159摩尔比47.3：9.6：41.4：1.7比例配制脂质混合乙醇溶液（ALC-0315为商业化产品Comirnaty的阳离子脂质）；将mRNA溶液与脂质混合溶液以3：1体积比例在纳米药物制备设备混合后，经超滤过滤，收集样品，保存于4℃。
按照表1实施例1-23及对比例1-6所列处方组成及用量制备含冷冻干燥保护剂的脂质纳米颗粒组合物。将冷冻干燥保护剂加入模型样品中混合均匀后，分装至西林瓶中，冷冻干燥。冷冻干燥后样品采用无菌水进行复溶。
按照表1实施例1-10所列处方组成及用量制备含冷冻保护剂的脂质纳米颗粒组合物，将保护剂加入模型样品中混合均匀后，分装至西林瓶中，置于-80℃冷冻保存，一个月后取出样品，于2-8℃进行解冻。
（2）基于模型样品2的含冷冻保护剂/冷冻干燥保护剂的脂质纳米颗粒组合物制备：
以DSPC：胆固醇摩尔比为2：1为脂质膜材，药物脂质质量比为1：15，利用薄膜分散法制备多西他赛脂质体，收集样品。
按照表1实施例24-33所列处方组成及用量制备含冷冻干燥保护剂的脂质纳米颗粒组合物。将冷冻干燥保护剂加入模型样品中混合均匀后，分装至西林瓶中，冷冻干燥。冷冻干燥后样品采用无菌水进行复溶。
表1
应用例
1、冷冻干燥复溶样品质量属性和稳定性（粒径、PDI、电位和包封率）以及冷冻样品解冻后样品质量属性。
1）粒径和PDI：采用Malvern ZetaSizer Nano ZS90通过动态光散射测定实施例中样品溶液的平均粒径及多分散指数PDI。测量角为90°，分散剂折射率为1.330，测试温度为25℃。
2）Zeta电位：采用Malvern ZetaSizer Nano ZS90，基于电泳光散射技术（ELS）测定实施例中样品溶液的Zeta电位。分散剂折射率：1.330，测试温度：25℃。
3）包封率：按照制造商的说明，使用Quant-it Ribogreen RNA定量测定试剂盒（ThermoFisher Scientific, UK），测定计算模型样品1中mRNA的包封率。采用HPLC法测定模型2样品的包封率，具体色谱条件为以乙腈：水（50:50）为流动相，流速为1.0ml/min，进样体积为20μl，检测波长为232nm。
模型样品1-2、以及实施例和对比例的含冷冻保护剂/冷冻干燥保护剂的脂质纳米颗粒组合物冷冻干燥复溶的粒径、PDI、电位和包封率结果见表2、实施例1-10冷冻保护组合物冷冻解冻的粒径、PDI、电位和包封率结果见表3，冷冻干燥样品放置稳定性见表4，实施例19的冷冻干燥样品及复溶样品的图片（左：冷冻干燥前照片；中：冷冻干燥后照片；右：冻干复溶后照片）见附图1，实施例9及实施例19冷冻干燥前/冷冻干燥复溶后样品粒度分布图见附图2-3。
表2冷冻干燥复溶样品质量属性数据
表3 冷冻解冻样品质量属性数据
表4冷冻干燥样品放置稳定性数据
可以看出，实施例的样品冷冻干燥前和冷冻干燥复溶后粒径、PDI、电位和包封率等关键参数变化很小，并且与模型样品的关键质量参数无明显变化。而对比例1-6冷冻干燥复溶后与模型样品的的关键质量参数差异很大（表2-3）。
尤其从表4可以看出，实施例1、实施例3、实施例9、实施例12、实施例19、实施例23、实施例26以及实施例30的含冷冻保护剂/冷冻干燥保护剂的脂质纳米颗粒组合物在放置12月以后复溶，与未经放置直接复溶时相比，粒径、PDI、电位和包封率等关键参数变化很小，并且与模型样品的关键质量参数无明显变化。而对比例1、对比例4和对比例6放置1月后复溶，与未经放置直接复溶时相比，粒径、PDI等关键参数有一定程度的变化，并且与模型样品的关键质量参数差异很大。由此可见，本发明限定范围内的保护剂，可以保证冻干复溶后的样品与模型样品的关键质量参数无明显变化，长时间放置后亦无显著变化。
2、扫描电镜形态观察
取实施例15、18、20冷冻干燥粉末，利用放大200倍的扫描电镜观察冷冻干燥样品的形态，结果见附图4-6。可以看出，实施例15/18/20冷冻干燥样品为均匀疏松粉末，无分层，无塌陷。
3、细胞实验
采用HEK-293 细胞进行实施例9的脂质纳米颗粒组合物冷冻前和冷冻解冻后以及实施例11的脂质纳米颗粒组合物冷冻干燥前后体外转染效率评价。将HEK293细胞用DMEM+10%FBS培养基进行常规培养，确保细胞处于对数生长期；转染前一天，以合适的细胞密度接种到96孔培养板上，生长过夜。转染时，细胞要达到70-90%的融合；用DMEM分别将冷冻前和冷冻解冻后的实施例9的脂质纳米颗粒组合物以及冷冻干燥前和复溶的实施例11的脂质纳米颗粒组合物分别稀释成4个不同剂量浓度，加入96孔细胞培养板中，使每孔浓度分别达到400ng、200ng、100ng和50ng，用Lipofectamine 2000转染Luciferase质粒为阳性参照（PC）。在37℃，5%的CO2培养箱中孵育24h后，向孔中加入底物，用酶标仪测定荧光强度，结果见附图7-8。可见，实施例9冷冻前和冷冻解冻后以及实施例11冷冻干燥前样品以及冷冻干燥复溶样品对体外转染效果相当。
4、动物实验
采用6-8周龄CB17 Scid 雌性小鼠，将人脑星形胶质母细胞瘤细胞（U87）株接种于小鼠皮下，细胞接种量为5*106cells/0.2 mL DPBS with matrigel(1:1)，建立小鼠U87肿瘤模型。
实施例26及实施例30冷冻干燥前样品以及冷冻干燥复溶样品均按10mg/kg剂量静脉注射给药；记录给药后肿瘤体积随时间的变化，评估样品的抗肿瘤活性，结果见附图9。可以看出，实施例26及实施例30冷冻干燥前样品以及冷冻干燥复溶样品对U87肿瘤的抑制效果相当，冷冻干燥前后具有良好的抗肿瘤活性。
最后应当说明的是，以上内容仅用以说明本发明的技术方案，而非对本发明保护范围的限制，本领域的普通技术人员对本发明的技术方案进行的简单修改或者等同替换，均不脱离本发明技术方案的实质和范围。
Claims (20)
1.糖酯化合物或其盐在冷冻保护、冷冻干燥保护中的应用，其特征在于：所述糖酯化合物经糖与酸酯化得到；所述糖选自单糖和/或低聚糖；所述低聚糖由2-10个糖单元组成；所述酸为有机酸和/或无机酸。
2.如权利要求1所述的应用，其特征在于：所述酸选自硫酸、磷酸、磺酸、甲磺酸、羧酸。
3.如权利要求1所述的应用，其特征在于：所述单糖或所述低聚糖的糖单元碳原子数为4-7。
4.如权利要求3所述的应用，其特征在于：所述单糖或所述低聚糖的糖单元选自呋喃糖和/或吡喃糖。
5.如权利要求4所述的应用，所述单糖或所述低聚糖的糖单元为阿拉伯糖、木糖、来苏糖、核糖、葡萄糖、甘露糖、阿洛糖、半乳糖、果糖、山梨糖、岩藻糖中的至少一种。
6.如权利要求1所述的应用，其特征在于：所述低聚糖选自2-8个糖单元组成的低聚糖。
7.如权利要求6所述的应用，其特征在于：所述低聚糖包括二糖、三糖、四糖、五糖、六糖、七糖、八糖、低分子量糖胺聚糖中的至少一种；所述二糖选自蔗糖、乳糖、麦芽糖、海藻糖、乳果糖、纤维二糖、黑曲霉糖、曲二糖、清酒二糖、异麦芽糖、槐糖、海带二糖、龙胆二糖、松二糖、麦芽酮糖、异麦芽酮糖、龙胆二酮糖、甘露二糖、蜜二糖和木二糖；所述三糖选自棉籽糖、麦芽三糖；所述四糖为水苏糖；所述五糖选自古罗糖醛酸五糖、戊聚糖；所述六糖为α-环糊精；所述七糖为β-环糊精；所述八糖为γ-环糊精；所述低分子量糖胺聚糖选自透明质酸、硫酸软骨素、硫酸皮肤素、硫酸角质素、硫酸乙酰肝素、肝素中的至少一种。
8.一种用于冷冻保护或冷冻干燥保护的组合物，其特征在于：所述组合物包含权利要求1-7任一项所述的糖酯化合物或其盐，以及填充剂。
9.如权利要求8所述的组合物，其特征在于：所述糖酯化合物或其盐与填充剂的质量比为1：500-3：1。
10.如权利要求9所述的组合物，其特征在于：所述糖酯化合物或其盐与填充剂的质量比为1：400-2：1。
11.如权利要求8所述的组合物，其特征在于：所述填充剂为药学上可接受的赋形剂。
12.如权利要求11所述的组合物，其特征在于：所述药学上可接受的赋形剂选自糖、多元醇、聚合物、盐、氨基酸中至少一种。
13.如权利要求8所述的组合物，其特征在于：所述用于冷冻保护或冷冻干燥保护的组合物采用液体介质配制。
14.如权利要求13所述的组合物，其特征在于：所述液体介质选自水和/或pH6.0-8.5的缓冲盐体系。
15.如权利要求8-14任一项所述的用于冷冻保护或冷冻干燥保护的组合物在脂质颗粒冷冻保护剂或冷冻干燥保护剂或细胞冷冻保护剂中的应用。
16.一种冷冻保护剂或冷冻干燥保护剂，其特征在于：包含权利要求8-14任一项所述的用于冷冻保护或冷冻干燥保护的组合物。
17.一种含冷冻保护剂或冷冻干燥保护剂的脂质纳米颗粒组合物，其特征在于：包括权利要求16所述的冷冻保护剂或冷冻干燥保护剂，以及脂质纳米颗粒。
18.如权利要求17所述的脂质纳米颗粒组合物，其特征在于：所述冷冻保护剂或冷冻干燥保护剂与脂质纳米颗粒质量比为2：1-2000：1。
19.如权利要求17所述的脂质纳米颗粒组合物，其特征在于：冷冻前或冷冻干燥前的含冷冻保护剂或冷冻干燥保护剂的脂质纳米颗粒组合物中，冷冻保护剂或冷冻干燥保护剂的浓度为50-400mg/ml。
20.如权利要求19所述的脂质纳米颗粒组合物，其特征在于：冷冻前或冷冻干燥前的含冷冻保护剂或冷冻干燥保护剂的脂质纳米颗粒组合物中，冷冻保护剂或冷冻干燥保护剂的浓度为80-350mg/ml。
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| CN117618531A (zh) * | 2023-11-14 | 2024-03-01 | 晟迪生物医药(苏州)有限公司 | 抗菌药物组合物、被界面膜包围的胶体颗粒、其制备方法和应用 |
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| US20150320031A1 (en) * | 2012-11-30 | 2015-11-12 | Pharmacosmos A/S | Cryoprotecting agent, cryoprotecting and cryopreserved compositions, uses thereof, and methods of cryopreservation |
| US20160235687A1 (en) * | 2015-02-13 | 2016-08-18 | St. John's University | Sugar ester nanoparticle stabilizers |
| CN115624630A (zh) * | 2022-12-19 | 2023-01-20 | 北京荷牧生物科技有限公司 | 冻干保护组合物及其应用和基于该组合物的核酸脂质纳米颗粒冻存方法 |
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| US20110015266A1 (en) * | 2008-03-20 | 2011-01-20 | Meck Patent Gesellschaft | Lyophilized nanoemulsion |
| US20150320031A1 (en) * | 2012-11-30 | 2015-11-12 | Pharmacosmos A/S | Cryoprotecting agent, cryoprotecting and cryopreserved compositions, uses thereof, and methods of cryopreservation |
| US20160235687A1 (en) * | 2015-02-13 | 2016-08-18 | St. John's University | Sugar ester nanoparticle stabilizers |
| CN115624630A (zh) * | 2022-12-19 | 2023-01-20 | 北京荷牧生物科技有限公司 | 冻干保护组合物及其应用和基于该组合物的核酸脂质纳米颗粒冻存方法 |
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