WO2020216334A1 - Bpa冻干制剂及制备方法 - Google Patents

Bpa冻干制剂及制备方法 Download PDF

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WO2020216334A1
WO2020216334A1 PCT/CN2020/086745 CN2020086745W WO2020216334A1 WO 2020216334 A1 WO2020216334 A1 WO 2020216334A1 CN 2020086745 W CN2020086745 W CN 2020086745W WO 2020216334 A1 WO2020216334 A1 WO 2020216334A1
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bpa
freeze
solution
drying process
preparation
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PCT/CN2020/086745
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French (fr)
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刘渊豪
陈腊梅
吴晓明
季红峰
李亚璟
何静
王冬春
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南京中硼联康医疗科技有限公司
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Priority to EP20795662.4A priority Critical patent/EP3960204A4/en
Priority to JP2021545479A priority patent/JP7297077B2/ja
Publication of WO2020216334A1 publication Critical patent/WO2020216334A1/zh
Priority to US17/375,071 priority patent/US20210338588A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/009—Neutron capture therapy, e.g. using uranium or non-boron material
    • A61K41/0095—Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins
    • 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
    • A61K9/14—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

Definitions

  • the present invention relates to the field of medicine. Specifically, the present invention relates to a freeze-dried BPA preparation and a preparation method.
  • BNCT Boron Neutron Capture Therapy
  • 10 B boron-containing drugs
  • 10 B (n, ⁇ ) 7 Li neutron capture and nuclear fission reaction Two heavily charged particles of 4 He and 7 Li are produced.
  • the average energy of the two charged particles is about 2.33 MeV, which has the characteristics of high linear energy transfer (LET) and short range.
  • the linear energy transfer and range of ⁇ particles are 150keV/ ⁇ m and 8 ⁇ m, respectively, while the 7 Li heavy-charged particle It is 175keV/ ⁇ m and 5 ⁇ m.
  • the total range of the two particles is about the size of a cell. Therefore, the radiation damage caused by the organism can be limited to the cell level.
  • the boron-containing drug is selectively aggregated in the tumor cells, it is matched with the appropriate medium.
  • the sub-radiation source can achieve the purpose of killing tumor cells locally without causing too much damage to normal tissues.
  • BPA 4-Borate-phenylalanine
  • the purpose of the present invention is to provide a method for preparing a freeze-dried BPA preparation and a BPA preparation prepared by the method, the preparation prepared by the method has good stability and low impurity content.
  • a method for preparing a freeze-dried BPA preparation including a liquid preparation process and a freeze-drying process;
  • the liquid preparation process includes: (1) dissolving BPA and polyol in an aqueous solution by alkali to obtain a clear solution; (2) adjusting the clear solution to 7.5 ⁇ pH ⁇ 8.5 by acid to obtain a BPA solution;
  • the freeze-drying process includes: (3) Divide the BPA solution and freeze-dry under the condition of a vacuum of 10-20 Pa to obtain the freeze-dried preparation.
  • the temperature of the solution is controlled not to be higher than 60°C, preferably 18-50°C, more preferably 18-40°C.
  • the weight ratio of the BPA to the polyol is 1:1 to 1.3; preferably, 1:1.1 to 1.25.
  • the vacuum degree of the freeze-drying is 10-20 Pa, preferably 10-11 Pa.
  • the clear solution is adjusted back to a pH value of 7.6 to 8.1 to obtain a BPA solution.
  • the alkali includes: lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide.
  • the BPA and the polyol are dissolved in the aqueous solution by alkali to obtain a clear solution, and the pH of the clear solution is 8.5-9.5.
  • the polyol includes fructose, lactose, sorbitol, maltose, mannitol, xylitol, ribose, glucose, and sucrose.
  • a filtering step is further included after the liquid preparation process and before the freeze-drying process.
  • freeze-drying process time is 39-80 hours.
  • the vacuum degree in the freeze-drying process is 10-11 Pa.
  • the freeze-drying process further includes a pre-freezing process.
  • the temperature of the pre-freezing process is -20°C to -50°C.
  • the time of the pre-freezing process is 5-15 hours.
  • the freeze-drying process further includes a sublimation process.
  • the temperature of the sublimation process is -20°C to -35°C.
  • the vacuum degree of the sublimation process is 10-20Pa.
  • the time of the sublimation process is 30-55 hours.
  • the freeze-drying process further includes an analytical drying process.
  • the temperature of the analytical drying process is 20°C-40°C.
  • the vacuum degree of the analytical drying process is 10-20 Pa, and preferably, the time of the analytical drying process is 4-10 hours.
  • the second aspect of the present invention provides a lyophilized BPA preparation prepared by the method of the first aspect of the present invention.
  • the third aspect of the present invention provides a composition comprising the BPA freeze-dried formulation as described in the second aspect.
  • the fourth aspect of the present invention provides a kit containing the BPA freeze-dried preparation as described in the second aspect.
  • Fig. 1 is a production process of a preferred BPA freeze-dried preparation of the present invention.
  • the "alkali” mentioned in the invention is mainly an inorganic base, including but not limited to: lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide.
  • the “acid” in the present invention includes inorganic acids and organic acids.
  • inorganic acids include, but are not limited to, perchloric acid, hydroiodic acid, sulfuric acid, hydrobromic acid, hydrochloric acid, nitric acid, iodic acid, oxalic acid (oxalic acid), sulfurous acid, phosphoric acid, pyruvic acid, carbonic acid, citric acid, hydrofluoric acid Acid, malic acid, gluconic acid, formic acid, lactic acid, benzoic acid, acrylic acid, acetic acid (acetic acid), propionic acid, stearic acid, hydrosulfuric acid, hypochlorous acid, boric acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, The preferred acid is hydrochloric acid.
  • the "BPA” in the present invention is 4-dihydroxyboryl phenylalanine, the chemical formula is Where B includes 10 B and 11 B.
  • B When B is 10 B, it can be used as a drug for boron neutron capture therapy (BNCT), which has two isomers, L type And type D Both configurations should be included in the protection scope of the present invention, and the BPA described in the present invention is preferably L-BPA (L-BPA).
  • the present invention provides a method for preparing a BPA freeze-dried preparation, including a liquid preparation process and a freeze-drying process: the liquid preparation process includes: (1) dissolving BPA and polyol in an aqueous solution by alkali to obtain a clear solution; (2) The BPA solution is obtained by adjusting the clear solution to 7.5 ⁇ pH ⁇ 8.5 by acid; the freeze-drying process includes: (3) The BPA solution is divided into aliquots and freeze-dried under the condition of a vacuum of 10-20 Pa to obtain the Lyophilized preparations.
  • the “solution” referred to here refers to any of the liquid preparation processes. "Solution”.
  • the temperature is 18-50°C, more preferably 18-40°C.
  • the weight ratio of BPA to polyol affects the dissolution of BPA, and the weight ratio is not particularly limited.
  • the weight ratio of the BPA to the polyol is 1:1 to 1.3; more preferably, it is 1:1.1 to 1.25.
  • the polyols include fructose, lactose, sorbitol, maltose, mannitol, xylitol, ribose, glucose, and sucrose.
  • the BPA and the polyol are dissolved in the aqueous solution by alkali to obtain a clear solution, and the pH of the clear solution is 8.5-9.5. Further, it is necessary to adjust the clear solution to a pH value of 7.6-8.1 by acid to obtain a BPA solution.
  • the vacuum degree of the freeze-drying is 10-20 Pa, preferably 10-11 Pa.
  • the freeze-drying process time is 39-80 hours. In actual operation, it can be determined according to the actual parameters in the liquid dispensing process, and there is no special restriction.
  • the freeze-drying process includes: a pre-freezing process, a sublimation process, and an analytical drying process.
  • the temperature, time, vacuum degree and other parameters in the three processes can be independently selected according to actual needs.
  • the BPA solution is freeze-dried under the following conditions to obtain a BPA freeze-dried preparation: pre-freezing process: the sample is cooled to -20°C to -60°C for 5-15 hours to completely freeze the sample.
  • Sublimation process increase the temperature to -15°C ⁇ -35°C, maintain the vacuum for 10-11pa, last for 30-55 hours.
  • Analytical drying process heating the separator, raising the temperature to 0°C-40°C, maintaining it for 4-10 hours, and maintaining a vacuum of 10-11pa throughout the analytical drying process.
  • the temperature can sometimes be adjusted multiple times according to actual needs, for example, the temperature is first reduced to -60°C for a period of time, and then the temperature is increased to -20 to -50°C.
  • the temperature in the analytical drying process, can be raised to a lower temperature first, and then gradually raised to a higher temperature, for example, the temperature is raised to 0°C for a period of time, and then the temperature is raised to 30 ⁇ 10°C.
  • the optimized process parameters are used to greatly avoid the adverse effects of unclean water removal and poor temperature control during the freeze-drying process on the product form, and control the product moisture to the lowest level; at the same time, temperature transmission Uniform, the product is loose and full, with uniform particles, and will not collapse, bubble, loose, shrink, etc.
  • the product has good resolubility, quick dissolution with water, high purity and good stability.
  • the product has no visible foreign matter, the content of related substances is low, and the impurity control effect is good.
  • BPA freeze-dried preparation and preparation method including a liquid preparation process and a freeze-drying process.
  • optimized process parameters are used, which greatly avoids freeze-drying.
  • water removal is not clean, and poor temperature control has an adverse effect on the product form.
  • the formulation has good stability and low impurity content.
  • Table 1 The 48-hour precipitation status of the solution under different pH conditions
  • the BPA solution was freeze-dried under the following conditions to obtain a BPA freeze-dried preparation:
  • Pre-freezing process cooling the sample to -20°C to -60°C for 5-15 hours to completely freeze the sample.
  • the production process of BPA freeze-dried preparations includes: 1 preparation process; 2 filling process; 3 freeze drying process; 4 unboxing and capping process; 5 packaging process.
  • the detailed process description is as follows:
  • the auxiliary material is the polyol according to the present invention.

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Abstract

一种制备BPA冻干制剂的方法，包括配液过程和冷冻干燥过程；其中配液过程包括：(1)通过碱使BPA和多元醇在水溶液中溶解得到澄清溶液；(2)通过酸回调所述澄清溶液至7.5＜pH≤8.5，得到BPA溶液；冷冻干燥过程包括：(3)将所述BPA溶液分装，在真空度为10～20Pa的条件下冷冻干燥，得到所述冻干制剂。所述方法制备的BPA冻干制剂稳定性好，杂质含量小。

Description

BPA冻干制剂及制备方法 技术领域
本发明属涉及医药领域，具体地，本发明涉及到BPA冻干制剂及制备方法。
背景技术
硼中子捕获治疗(Boron Neutron Capture Therapy,BNCT)是利用含硼( 10B)药物对热中子具有高捕获截面的特性，借由 10B(n,α) 7Li中子捕获及核分裂反应产生 4He和 7Li两个重荷电粒子。两荷电粒子的平均能量约为2.33MeV，具有高线性转移(Linear Energy Transfer,LET)、短射程特征，α粒子的线性能量转移与射程分别为150keV/μm、8μm，而 7Li重荷粒子则为175keV/μm、5μm，两粒子的总射程约相当于一个细胞大小，因此对于生物体造成的辐射伤害能局限在细胞层级，当含硼药物选择性地聚集在肿瘤细胞中，搭配适当的中子射源，便能在不对正常组织造成太大伤害的前提下，达到局部杀死肿瘤细胞的目的。
4-硼酸-苯丙氨酸(BPA)是目前研究比较多的一种含 10B的药物。由于BPA难溶于水，一般需要加入助溶剂，并在强酸或碱作用下将其溶解，再调至生理pH左右，经过除菌制成无菌注射液后，用于病人或者动物，该溶液需要现用现配。繁琐的配置过程造成该药物的在临床使用中极不方便，且无菌性不能得到保证，限制了其应用。专利CN103100094B公开了一种应用于L-BPA的冷冻干燥工艺，将L-BPA和助溶剂果糖混合后，将L-BPA溶解，于真空状态下冷冻干燥22-26小时。
发明内容
本发明的目的是提供一种制备BPA冻干制剂的方法和通过所述方法制备的BPA制剂，所述方法制备的制剂稳定性好，杂质含量小。
本发明第一方面，提供了一种制备BPA冻干制剂的方法，包括配液过程和冷冻干燥过程；其中
配液过程包括：(1)通过碱使BPA和多元醇在水溶液中溶解得到澄清溶液；(2)通过酸回调所述澄清溶液至7.5＜pH≤8.5，得到BPA溶液；
冷冻干燥过程包括：(3)将所述BPA溶液分装，在真空度为10～20Pa的条件下冷冻干燥，得到所述冻干制剂。
在另一优选例中，在配液过程中，控制所述溶液的温度不高于60℃，优选为18～50℃，更优选为18～40℃。
在另一优选例中，所述BPA与多元醇的重量份比为1:1～1.3；优选为1:1.1～1.25。
在另一优选例中，所述冷冻干燥的真空度为10～20Pa，优选为10～11Pa。
在另一优选例中，回调所述澄清溶液至pH值为7.6～8.1，得到BPA溶液。
在另一优选例中，所述碱包括：氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁。
在另一优选例中，所述配液过程中，通过碱使BPA和多元醇在水溶液中溶解得到澄清溶液，所述澄清溶液的pH值为8.5～9.5。
在另一优选例中，所述多元醇包括：果糖、乳糖、山梨醇、麦芽糖、甘露醇、木糖醇、核糖、葡萄糖、蔗糖。
在另一优选例中，在所述配液过程之后，冷冻干燥过程之前还包括过滤步骤。
在另一优选例中，所述冷冻干燥过程时间为39-80小时。
在另一优选例中，所述冷冻干燥过程中的真空度为10～11Pa。
在另一优选例中，所述冷冻干燥过程还包括预冻过程。优选地，所述预冻过程的温度为-20℃～-50℃。优选地，所述预冻过程的时间为5-15小时。
在另一优选例中，所述冷冻干燥过程还包括升华过程。优选地，所述升华过程的温度为-20℃～-35℃。优选地，所述升华过程的真空度为10～20Pa。优选地，所述升华过程的时间为30-55小时。
在另一优选例中，所述冷冻干燥过程还包括解析干燥过程。优选地，所述解析干燥过程的温度为20℃～40℃。优选地，所述解析干燥过程的真空度为10～20Pa条件，优选地，所述解析干燥过程的时间为4-10小时。
本发明第二方面，提供了一种如本发明第一方面所述方法制备的BPA冻干制剂。
本发明第三方面，提供了一种组合物，所述组合物包括如第二方面所述的BPA冻干制剂。
本发明第四方面，提供了一种试剂盒，，所述试剂盒含有如第二方面所述的BPA冻干制剂。
应理解，在本发明范围内，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为本发明的一种优选的BPA冻干制剂的生产工艺过程。
术语
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
发明所述的“碱”主要为无机碱，包括但不限于：氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙。本发明所述的“酸”包括无机酸和有机酸。无机酸例如包括但不限于高氯酸、氢碘酸、硫酸、氢溴酸、盐酸、硝酸、碘酸、草酸(乙二酸)、亚硫酸、磷酸、丙酮酸、碳酸、柠檬酸、氢氟酸、苹果酸、葡萄糖酸、甲酸、乳酸、苯甲酸、丙烯酸、乙酸(醋酸)、丙酸、硬脂酸，氢硫酸、次氯酸、硼酸、三氟乙酸、甲磺酸、苯磺酸，优选的酸为盐酸。
本发明所述的“BPA”为4-二羟基硼基苯丙氨酸，化学式为
Figure PCTCN2020086745-appb-000001
式中B包括 10B和 11B。当B为 10B时，可以作为药物用于硼中子捕获治疗(BNCT)，其具有两种异构体，分别为L型
Figure PCTCN2020086745-appb-000002
和D型
Figure PCTCN2020086745-appb-000003
两种构型均应包括在本发明的保护范围内，本发明所述的BPA优选地为L型BPA(L-BPA)。
制备BPA冻干制剂的方法
本发明提供了一种制备BPA冻干制剂的方法，包括配液过程和冷冻干燥过程：其中配液过程包括：(1)通过碱使BPA和多元醇在水溶液中溶解得到澄清溶液；(2)通过酸回调所述 澄清溶液至7.5＜pH≤8.5，得到BPA溶液；冷冻干燥过程包括：(3)将所述BPA溶液分装，在真空度为10～20Pa的条件下冷冻干燥，得到所述冻干制剂。为了保证溶液中各组分的化学性质不发生变化，在配液过程中，需要控制所述溶液的温度不高于60℃，这里所说的“溶液”指配液过程中任一所述的“溶液”。优选地，所述温度为18～50℃，更优选为18～40℃。
BPA与多元醇的重量份比影响BPA的溶解，其重量份比没有特别的限制。优选地，所述BPA与多元醇的重量份比为1:1～1.3；更优选为1:1.1～1.25。所述多元醇包括：果糖、乳糖、山梨醇、麦芽糖、甘露醇、木糖醇、核糖、葡萄糖、蔗糖。
所述配液过程中，通过碱使BPA和多元醇在水溶液中溶解得到澄清溶液，所述澄清溶液的pH值为8.5～9.5。进一步地，需要通过酸回调所述澄清溶液至pH值为7.6～8.1，得到BPA溶液。
在冷冻干燥过程中，所述冷冻干燥的真空度为10～20Pa，优选为10～11Pa。所述冷冻干燥过程时间为39-80小时。在实际操作中，可根据在配液过程中的实际参数来决定，没有特别的限制。所述冷冻干燥过程包括：预冻过程、升华过程和解析干燥过程，三个过程中的温度、时间、真空度等参数可根据实际需要独立选择。作为一种优选地方案，将BPA溶液按如下条件冷冻干燥，得到BPA冻干制剂：预冻过程：使样品降温至-20℃～-60℃，持续5-15小时，使样品完全冻结。升华过程：升温至-15℃～-35℃，维持真空10-11pa，持续30-55小时。解析干燥过程：对隔板加热，升温至0℃～40℃，维持4-10小时，整个解析干燥过程维持真空10-11pa。作为一种优选的方案，在预冻过程中，根据实际需要有时可以多次调整温度，比如先降温至-60℃持续一段时间后，再升温到-20～-50℃。作为一种优选的方案，在解析干燥过程中，可以先升温至一个较低的温度，再逐步上升到较高的温度，比如先升温至0℃保持一段时间，再升温至30±10℃。
本发明的主要优点包括：
1.在冻干过程中，采用优化的工艺参数，极大程度避免了冻干过程中水分去除不干净及温度控制不好对产品形态的不良影响，将产品水分控制在最低水平；同时温度传递均匀，产品疏松饱满、颗粒均匀，不会出现塌陷、气泡、松散、萎缩等现象。
2.产品复溶性好，加水速溶，纯度高，稳定性好。
3.产品无可见异物，有关物质含量低，杂质控制效果好。
具体实施方式
本发明人经过广泛而深入地研究，开发了一种BPA冻干制剂及制备方法，包括配液过程和冷冻干燥过程，在冻干过程中，采用优化的工艺参数，极大程度避免了冻干过程中水分去除不干净，及温度控制不好对产品形态的不良影响，制剂稳定性好，杂质含量小。在此基础上，完成了本发明。
以下结合具体实施例，进一步说明本发明。需理解，以下的描述仅为本发明的最优选实施方式，而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上，下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件，本领域技术人员可以对本发明的技术方案作出非本质的改动，这样的改动应当被视为包括于本发明的保护范围之中的。除非另外说明，否则百分比和份数是重量百分比和重量份数。
实施例1
BPA溶液的配制：
(1)在配液罐中加入1.0kgBPA，1.1-1.3kg果糖和适量的注射用水，水清洗装BPA和果糖的容器3次，并将清洗的水转移至配液罐中，搅拌10min；
(2)向配液罐中加入氢氧化钠溶液使BPA溶解，搅拌至溶液澄清；
(3)加入盐酸溶液，将溶液的pH值调至7.6。
考察使用盐酸进行回调配置后的溶液是否稳定，加入的盐酸调至接近生理pH值的不同的pH值，观察pH＝7.3-8.5条件下溶液48小时是否有沉淀生成的实验结果如表1所示。另外，分别在pH＝7.6、8.0、8.5条件下的pH值，如表2所示，溶液的pH值在24小时内没有明显变化。
表1不同pH条件下溶液的48小时沉淀状况
pH值 溶液48h是否有沉淀
8.5 无
8.4 无
8.3 无
8.2 无
8.1 无
8.0 无
7.9 无
7.8 无
7.7 无
7.6 无
7.5 无
7.4 有
7.30 有
表2不同pH条件下溶液24小时内的pH值变化
Figure PCTCN2020086745-appb-000004
实施例2
将BPA溶液按如下条件冷冻干燥，得到BPA冻干制剂：
(1)预冻过程：使样品降温至-20℃～-60℃，持续5-15小时，使样品完全冻结。
(2)升华过程：升温至-15℃～-35℃，维持真空10-11pa，持续30-55小时。
(3)解析干燥过程：对隔板加热，升温至0℃～40℃，维持4-10小时，整个解析干燥过程维持真空10-11pa。
如表3所示，将冻干样品加水复溶配制溶液室温放置24小时内，pH、澄清度、透光率、含量测定结果均未发生明显变化，本品配制后室温放置24h溶液稳定性良好。
表3冻干样品复溶后溶液的稳定性
Figure PCTCN2020086745-appb-000005
Figure PCTCN2020086745-appb-000006
实施例3
如图1所示，BPA冻干制剂的生产工艺过程包括：①配制工序；②灌装工序；③冷冻干燥工序；④出箱、轧盖工序；⑤包装工序。详细工艺描述如下：
①配制工序
液罐中加入注射用水，加入处方量的BPA、辅料，加入氢氧化钠溶液，分别用的注射用水荡洗装辅料和氢氧化钠溶液的容器并转移至配液罐。搅拌至溶液澄清。调节pH，加入剩余的注射用水，搅匀，检测中间体，过滤。所述辅料为本发明所述的多元醇。
②灌装工序
根据中间体含量调节装量，灌装，半加塞，进冻干箱。
③冷冻干燥工序
包括：预冻阶段、升华阶段和解析干燥阶段。
④出箱、轧盖工序
出箱：半成品于百级层流保护下，提出缺塞、压塞移位、瓶破裂等不合格品，做报废处理。轧盖：在生产的前、中、后取样检测其外观。
⑤包装工序
贴签、装盒、装箱，入库。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种制备BPA冻干制剂的方法，其特征在于，包括配液过程和冷冻干燥过程；其中
    配液过程包括：(1)通过碱使BPA和多元醇在水溶液中溶解得到澄清溶液；(2)通过酸回调所述澄清溶液至7.5＜pH≤8.5，得到BPA溶液；
    冷冻干燥过程包括：(3)将所述BPA溶液分装，在真空度为10～20Pa的条件下冷冻干燥，得到所述冻干制剂。
  2. 如权利要求1所述的方法，其特征在于，控制所述配液过程中任一所述“溶液”的温度不高于60℃。
  3. 如权利要求1所述的方法，其特征在于，所述BPA与多元醇的重量份比为1:1～1.3。
  4. 如权利要求1所述的方法，其特征在于，所述碱包括：氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁。
  5. 如权利要求1所述的方法，其特征在于，所述配液过程中，通过碱使BPA和多元醇在水溶液中溶解得到澄清溶液，所述澄清溶液的pH值为8.5～9.5。
  6. 如权利要求1、3、5任一所述的方法，其特征在于，所述多元醇包括：果糖、乳糖、山梨醇、麦芽糖、甘露醇、木糖醇、核糖、葡萄糖、蔗糖。
  7. 如权利要求1所述的方法，其特征在于，在所述配液过程之后，冷冻干燥过程之前还包括过滤步骤。
  8. 如权利要求1所述的方法，其特征在于，所述冷冻干燥过程时间为39-80小时。
  9. 如权利要求1所述的方法，其特征在于，所述冷冻干燥的真空度为10～11Pa。
  10. 如权利要求1所述的方法，其特征在于，所述冷冻干燥过程还包括：
    预冻过程，所述预冻过程的温度为-20℃～-60℃；和/或
    升华过程，所述升华过程的温度为-15℃～-35℃；和/或
    解析干燥过程，所述解析干燥过程的温度为0℃～40℃。
  11. 如权利要求1所述的方法，其特征在于，所述冷冻干燥过程还包括：
    预冻过程，所述预冻过程的时间为5-15小时；和/或
    升华过程，所述升华过程的时间为30-55小时；和/或
    解析干燥过程，所述解析干燥过程的时间为4-10小时。
  12. 如权利要求1所述的方法，其特征在于，所述BPA化学式为
    Figure PCTCN2020086745-appb-100001
    式中B为 10B。
  13. 一种如权利要求1所述方法制备的BPA冻干制剂。
  14. 一种组合物，其特征在于，所述组合物包括如权利要求13所述的BPA冻干制剂。
  15. 一种试剂盒，其特征在于，所述试剂盒含有如权利要求13所述的BPA冻干制剂。
PCT/CN2020/086745 2019-04-26 2020-04-24 Bpa冻干制剂及制备方法 WO2020216334A1 (zh)

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