WO2016138790A1 - 变频交流电场辅助冻干药物脂质体粉的方法和设备 - Google Patents

变频交流电场辅助冻干药物脂质体粉的方法和设备 Download PDF

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Publication number
WO2016138790A1
WO2016138790A1 PCT/CN2015/099639 CN2015099639W WO2016138790A1 WO 2016138790 A1 WO2016138790 A1 WO 2016138790A1 CN 2015099639 W CN2015099639 W CN 2015099639W WO 2016138790 A1 WO2016138790 A1 WO 2016138790A1
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Prior art keywords
sample
freeze
drying
assisting
low temperature
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PCT/CN2015/099639
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English (en)
French (fr)
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孙大文
程丽娜
朱志伟
曾新安
王启军
张孜
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华南理工大学
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Priority to US15/548,054 priority Critical patent/US10415881B2/en
Priority to EP15883840.9A priority patent/EP3267134B1/en
Publication of WO2016138790A1 publication Critical patent/WO2016138790A1/zh

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Classifications

    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B7/00—Drying solid materials or objects by processes using a combination of processes not covered by a single one of groups F26B3/00 and F26B5/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes
    • 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
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B20/00—Combinations of machines or apparatus covered by two or more of groups F26B9/00 - F26B19/00
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B25/00—Details of general application not covered by group F26B21/00 or F26B23/00
    • F26B25/22—Controlling the drying process in dependence on liquid content of solid materials or objects
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B3/00—Drying solid materials or objects by processes involving the application of heat
    • F26B3/32—Drying solid materials or objects by processes involving the application of heat by development of heat within the materials or objects to be dried, e.g. by fermentation or other microbiological action
    • F26B3/34—Drying solid materials or objects by processes involving the application of heat by development of heat within the materials or objects to be dried, e.g. by fermentation or other microbiological action by using electrical effects
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B3/00—Drying solid materials or objects by processes involving the application of heat
    • F26B3/32—Drying solid materials or objects by processes involving the application of heat by development of heat within the materials or objects to be dried, e.g. by fermentation or other microbiological action
    • F26B3/34—Drying solid materials or objects by processes involving the application of heat by development of heat within the materials or objects to be dried, e.g. by fermentation or other microbiological action by using electrical effects
    • F26B3/347—Electromagnetic heating, e.g. induction heating or heating using microwave energy
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/041—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum for drying flowable materials, e.g. suspensions, bulk goods, in a continuous operation, e.g. with locks or other air tight arrangements for charging/discharging
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing

Definitions

  • the present invention relates to the field of lyophilization of pharmaceutical preparations, and more particularly to a method and apparatus for assisting lyophilization of pharmaceutical liposome powder by a variable frequency alternating electric field.
  • Vacuum freeze-drying also known as freeze-drying, referred to as freeze-drying, is to freeze the material below the eutectic point temperature, and at low pressure, remove the moisture from the material by sublimation.
  • a drying method particularly suitable for prolonging the shelf life of biological agents and improving quality, such as proteins, vaccines, microorganisms, and the like.
  • the general drying method is to convert the moisture in the material from a liquid state to a gas state
  • lyophilization is to convert the moisture in the material from a liquid state to a solid state and then from a solid state to a gaseous state.
  • the freezing of water is an exothermic process.
  • the sublimation of ice is an endothermic process. Therefore, the freeze-drying system mainly consists of three major operations: refrigeration, heat supply and vacuum.
  • Freezing is the shortest period of lyophilization, but it affects several key steps throughout the process: sublimation, analysis, and quality of freeze-dried products, such as cake shape, porosity, protein aggregation, etc. .
  • Drying is a long period of lyophilization, which is divided into two small stages: first drying (sublimation) and second drying (de-analysis).
  • the size of the ice crystals during the freezing process determines the size of the voids in the drying matrix, that is, the sublimation rate; however, the resolution rate is mainly determined by the size of the ice crystal specific surface area.
  • the larger the ice crystal the faster the evaporation heat transfer, so the shorter the sublimation is; the larger the specific surface area, the easier the unfrozen water to evaporate, that is, the shorter the resolution stage.
  • a large degree of subcooling that is, a large gap between the equilibrium freezing point temperature and the nucleation temperature value, will form a lot of ice crystals with small volume and large specific surface area, that is, the first drying stage is slow, and the second The drying stage is fast.
  • the smaller degree of subcooling that is, controlling the nucleation temperature close to the equilibrium freezing point temperature, will form many large ice crystals with small specific surface area, namely rapid sublimation and slow resolution.
  • Controlling the nucleation step removing the different sublimation and analytical kinetics caused by the random nucleation temperature, ensures the controllability of the drying process, and further ensures the quality of the lyophilized product.
  • the freezing phase affects the efficiency of the entire freeze-drying and the quality of the product, such as protein stability. [0005] Drying is one of the most energy-consuming units in the freeze-drying process.
  • the semiconductor Since there is no convection in the vacuum environment, the heat and mass transfer is slow, and the ordinary heating plate has a long heating cycle and high energy consumption.
  • the semiconductor is a special material. It uses a commutating circuit composed of relays.
  • the heating and cooling common terminal is a DC output of 12V.
  • the semiconductor is used for temperature rise and fall, and the speed is fast and the energy is saved.
  • Efficient and insoluble biopharmaceutical agents often use liposome as a carrier to increase the clinical use effect, and such agents often adopt freeze-drying method to obtain lyophilized powder which is resistant to storage, high activity and easy to transport. , freeze-dried needles, etc.
  • the commonly used auxiliary lyophilization method has a nucleating agent added in the freezing stage, and a new type of ultrasonic treatment is used to control the nucleation temperature and the degree of supercooling.
  • the shorter the freeze-drying treatment the better, and the lower the water content of the finished product, the finer and uniform the ice crystals formed. Therefore, prior art freeze-dried liposome agents have the following drawbacks:
  • the ordinary freeze-drying method cannot control the ice crystal growth in the freezing stage, that is, the nucleation randomness, the shape anisotropy, etc., and the size of the ice crystal further affects the daytime of the drying stage, and the larger ice crystals are in the freezing process. It is possible to puncture cells and cause loss of efficacy. Ice crystals of inconsistent size result in unsatisfactory quality uniformity.
  • the object of the present invention is to provide a method for assisting lyophilization of pharmaceutical liposome powder by a variable frequency alternating electric field, which not only greatly shortens the freezing and drying time, but also controls nucleation. The size of the ice crystals further ensures the quality of the lyophilized powder.
  • Another object of the present invention is to provide an apparatus for implementing the above-described variable frequency alternating electric field assisted freeze-dried pharmaceutical liposome powder method.
  • a method for assisting lyophilization of a pharmaceutical liposome powder by a variable frequency alternating electric field comprising the steps of:
  • Step (1) The drug-liposome suspension has a water content of 40 to 80%.
  • Step (2) the dehydration, specifically: dehydration to a sample moisture content of 18 to 35%.
  • Step (3) until the freezing is completed specifically: the sample core temperature reaches -20. C.
  • variable frequency alternating current electric field assisted freeze-dried drug liposome powder method of frequency conversion alternating electric field assisted freeze-drying drug liposome powder equipment including the connection tank, metering pump, dehydrator, high/low temperature treatment Room
  • an electrode plate is disposed on each of the upper and lower sides of the sample tank in the dehydrator; and an electrode plate is disposed on each of the upper and lower sides of the sample tank in the high/low temperature processing chamber; Connected to a high voltage variable frequency AC power control box;
  • the high/low temperature processing chamber is also connected to a vacuum pump;
  • the high/low temperature processing chamber is used to freeze dry and heat dry the sample.
  • a semiconductor refrigeration/heating sheet is disposed under the sample tank of the high/low temperature processing chamber, and a fan is disposed under the semiconductor refrigeration heating sheet/below; and a wireless thermocouple probe is disposed on the sample tank of the high/low temperature processing chamber.
  • the dehydrator is connected to the high/low temperature processing chamber by a screw pump. [0030] The dehydrator is also connected to a waste liquid tank.
  • the present invention is based on the freeze-dried pharmaceutical liposome preparation, assists in the high-pressure variable frequency alternating electric field for freezing, and applies different high-voltage alternating current treatments in the pre-freezing and freezing processes, thereby achieving the pre-freezing stage removal.
  • Part of the water shortening the freezing and drying of the day; inhibiting nucleation during the freezing process, but the formation of ice crystals is small, avoiding the mechanical damage caused by freezing, and shortening the later dry day.
  • high-frequency high-voltage will generate part of the heat, the latent heat released during the freezing process is negligible compared with the effect of semiconductor refrigeration.
  • the condensation cycle can be connected with the dehydrator.
  • the machine controls the temperature; and the electric field has the bactericidal property, which can kill the microorganisms, further ensures the safety of the biological preparation, and avoids the sterilization treatment of the late freeze-dried powder.
  • the lyophilized sample does not need to undergo a pre-freezing pretreatment step of the ultra-low temperature freezer in the conventional lyophilization process.
  • the semiconductor is used as the refrigeration and heating system, which saves the working time of the system for providing refrigeration and heating by the condensing water heater and the heating plate, and the device is simplified.
  • the lyophilized powder does not need to be sterilized, and the principle and effect here are similar to those of pulsed electric field treatment.
  • FIG. 1 is a schematic view showing the composition of an apparatus for assisting lyophilization of a pharmaceutical liposome powder by a variable frequency alternating electric field according to an embodiment of the present invention.
  • FIG. 1 is a schematic view of an apparatus for assisting lyophilization of a pharmaceutical liposome powder by a variable frequency alternating electric field according to the present embodiment.
  • the mixing tank 1, the metering pump 2, the dehydrator 3, and the high/low temperature processing chamber 4 are sequentially connected; and an electrode plate 32 is disposed above and below the sample tank 31 in the dehydrator 3.
  • An electrode plate 42 is disposed above and below the sample tank 41 in the high/low temperature processing chamber 4; the electrode plate is connected to the high voltage variable frequency AC power control box 8; the high/low temperature processing chamber 4 is further The vacuum pump 5 is connected; the high/low temperature processing chamber is used for freeze drying and heat drying the sample.
  • the semiconductor cooling/heating sheet 43 is disposed under the sample tank 41 of the high/low temperature processing chamber 4, and the semiconductor refrigeration/force hot sheet 43 is connected to the semiconductor power supply control box 9; the semiconductor power control box 9 includes a refrigeration control system And the heating control system is connected to the refrigeration control system, and is connected to the heating control system; the semiconductor refrigeration/heating sheet 43 is provided with a fan 44; and the sample tank 41 is provided with a wireless thermocouple probe 45.
  • the dehydrator 3 is connected to the high/low temperature treatment chamber 4 via a screw pump 6, and a valve 61 is provided in the screw pump 6.
  • the dehydrator 3 is connected to the waste liquid tank 7.
  • the mixing tank, the dehydrator, and the high/low temperature processing outdoor wall are both double-layered and have an interlayer;
  • the electrode plate is a stainless steel plate electrode, and both of the sample tanks are vertically symmetric in the dehydrator and the freeze-drying chamber (electrodes) The distance between the two is close to the sample slot; the lyophilized indoor semiconductor refrigeration/heating sheet is in close contact with the lower electrode; after the power is applied, the processing chamber is a non-uniform electric field system; the dehydrator has a tempered glass window to facilitate the electric dehydration phenomenon.
  • sample tank size (length X width X height) using the dehydrator in the following examples is 40*15*10cm; high/low temperature processing chamber sample tank size (length X width X height) is 30 *15*10cm
  • the method for assisting lyophilization of a pharmaceutical liposome powder by the variable frequency alternating electric field of the embodiment comprises the following steps:
  • the metering pump flows into the sample tank of the dehydrator, it is treated with 8kV, 3kHz high-voltage alternating current for 15min (this ⁇ alternating pulse space is 35%), and the emulsion is dehydrated to 35% water content; in the preparation of quercetin liposome suspension
  • the semiconductor power control box is connected, and the cooling control system is connected, and the set temperature is -40.
  • the obtained quercetin liposome lyophilized powder has a water content of only 1%, a uniform particle diameter, and a pale yellow color; an encapsulation efficiency of 90%; hydration redispersion is easy; the surface area of the simulated biofilm is larger than ordinary Infusion; the effect of treatment on simulated mouse injury is significantly better than that of quercetin; microbial killing is reduced by 4 orders of magnitude compared with conventional freeze-drying, and is reduced by 3 orders of magnitude compared with new type of microwave freeze-drying.
  • the lyophilized day was shortened by 40 hours compared with the conventional freeze-dried sputum, and shortened by 25 hours compared with the new type of microwave lyophilization.
  • the method for assisting lyophilization of a pharmaceutical liposome powder by the variable frequency alternating electric field of the embodiment comprises the following steps:
  • the semiconductor power control box is connected to the cooling control system, and the set temperature is -25. C;
  • the dehydrated sample flows into the sample tank of the high/low temperature processing chamber through the pipeline pump (this sample height is about 3.5cm), close the pipeline, shut the vacuum pump, and give 15kHz, 0.2kV, to the completion of freezing , that is, the sample core temperature is -20.
  • C Do not open the semiconductor power control box, reverse the heating control system, set the temperature to 25. C, when the sample core temperature is 20. C ⁇ , indicating that the drying phase is completed; the equipment is turned off, and the breviscapine liposome lyophilized powder is taken out and placed in a sterile bottle.
  • the obtained breviscapine liposome lyophilized powder has a water content of only 0.8%, the particle diameter is uniform, and the color is pale yellow; the encapsulation efficiency is 88%, and the hydration redispersion is easy; the simulated biofilm surface dose is larger than ordinary Infusion; The therapeutic effect on simulated mouse injury is significantly better than that of breviscapine; microbial killing is reduced by 3 orders of magnitude compared with conventional freeze-drying, and the new type of microwave freeze-drying is reduced by 2 orders of magnitude, which is safe.
  • the lyophilized day was shortened by 20 hours compared with the conventional freeze-dried sputum, and shortened by 10 hours compared with the new type of microwave lyophilization.
  • the dehydrated sample flows into the sample tank of the high/low temperature processing chamber through the pipeline pump (this sample height is about 5cm), close the pipeline, shut the vacuum pump, and give 10kHz, 0.5kV, until the freezing is completed. That is, the sample core temperature is -20. C; Snoring the semiconductor power control box, reverse the heating control system, set the temperature to 30. C, when the sample core temperature is 20. C ⁇ , indicating that the drying phase is completed; the device is turned off, and the docetaxel liposome lyophilized powder is taken out and placed in a sterile bottle.
  • the obtained docetaxel liposome lyophilized powder has a water content of only 0.2%, the particle diameter is uniform, and the color is milky white; the encapsulation efficiency is 85%, hydration redispersion is easy; hydration redispersion is easy; in the simulated organism
  • the surface dose of the membrane is larger than that of the common infusion; the therapeutic effect on the simulated mouse injury is obviously better than that of the docetaxel; the microbial killing is 2.5 orders of magnitude lower than the conventional freeze-drying, and the new type of microwave is frozen.
  • the dryness is reduced by 1.5 orders of magnitude, which is within the safe range; the freeze-dried day is shortened by 30 hours compared with the conventional freeze-dried day, and the new type of microwave freeze-dried time is shortened by 15 hours.

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Abstract

一种变频交流电场辅助冻干药物脂质体粉的方法及设备，其中方法包括以下步骤：(1)制备药物-脂质体混悬液样品；(2)在给予1～10kHz、3～10kV的高压交流电处理的条件下，对样品进行脱水；(3)在-20～-40℃、给予10～25kHz，0.2～1kV高压交流电处理，对经步骤(2)处理后的样品进行冷冻干燥，直至冷冻完成；(4)在真空条件下对样品进行加热干燥，直至升华及解析完成，获得药物脂质体冻干粉。该设备包括依次连接的调配罐（1）、计量泵（2）、脱水器（3）、高/低温处理室（4）；脱水器（3）中的样品槽（31）的上、下方设有各设一个电极板（32）；高/低温处理室（4）中的样品槽（41）的上、下方设有各设一个电极板（42）；电极板（32、42）与高压变频交流电源控制箱（8）连接；高/低温处理室（4）还与真空泵（5）连接；高/低温处理室（4）用于对样品进行冷冻干燥和加热干燥。该装置应用该方法后，不仅大大缩短冷冻及干燥时间，而且控制成核、冰晶的大小，进一步保证了冻干粉的品质。

Description

说明书 发明名称：变频交流电场辅助冻干药物脂质体粉的方法和设备 技术领域
[0001] 本发明涉及医药制剂冻干技术领域， 特别涉及一种变频交流电场辅助冻干药物 脂质体粉的方法和设备。
背景技术
[0002] 真空冷冻干燥 (vacuum freeze-drying) , 也称作冷冻干燥 (freeze-drying) , 简称冻 干， 是将物料冻结到共晶点温度以下， 在低压状态下， 通过升华除去物料中水 分的一种干燥方法； 特别适用于生物制剂的货架期的延长及品质的改善， 例如 蛋白质、 疫苗、 微生物等。 一般的干燥方法是将物料中的水分由液态转变为气 态， 而冷冻干燥是将物料中的水分先由液态转变为固态再由固态转变为气态。 水的冻结是一个放热的过程， 冰的升华是一个吸热过程， 所以冻干系统主要由 制冷、 供热、 真空三大操作组成。
[0003] 冷冻是冻干过程中耗吋最短的一阶段， 但其影响着整个过程的几个关键步骤： 升华、 解析及冻干制品的品质， 例如蛋糕的形状、 孔隙度、 蛋白质的聚合等。 干燥是冻干中耗吋较长的阶段， 分为第一干燥 （升华） 及第二干燥 （去解析） 两个小阶段。
[0004] 冷冻过程中冰晶的大小决定着干燥矩阵中空隙的大小， 即影响升华速率； 然而 解析的速率又主要由冰晶比表面积的大小决定。 冰晶越大， 蒸发传热越快， 所 以升华吋间越短； 比表面积越大， 未冻结水蒸发越容易， 即解析阶段越短。 一 般来说， 较大的过冷度， 即平衡冰点温度与成核温度值之间存在较大的差距， 将会形成很多体积小， 比表面积大的冰晶， 即第一干燥阶段慢， 第二干燥阶段 快。 然而， 较小的过冷度， 即控制成核温度接近于平衡冰点温度， 将会形成很 多体积大， 比表面积小的冰晶， 即快速升华， 慢速解析。 控制成核步骤， 去除 随机的成核温度导致的不同的升华及解析动力学表现， 即保证了干燥过程的可 控性， 亦进一步保证了冻干制品的品质。 简言之， 冷冻阶段影响整个冻干的效 率及产品的品质， 例如蛋白的稳定性等。 [0005] 干燥是冻干过程能耗最多的一个单元， 由于真空环境中没有对流， 传热传质缓 慢， 普通的加热板加热周期长， 能耗高。 半导体是一种特殊材料， 采用继电器 构成的换向电路， 加热制冷公共端为 12V的直流输出， 采用半导体进行升降温， 速度快， 节吋节能。
[0006] 高效的难溶的生物类制药剂， 常以脂质体为载体， 增加其临床使用的效果， 而 此类药剂常采用冷冻干燥法获得耐储存、 活性高、 易运输的冻干粉、 冻干针等 。 目前常用的辅助冻干方法有在冷冻阶段加成核试剂， 另有新型的以超声处理 进行控制成核温度及过冷度。 要想生物类药剂活性高， 则冻干处理吋间越短越 好， 且成品含水量越低越好， 形成的冰晶越细小、 均匀越好。 故现有技术冻干 脂质体药剂存在以下缺陷：
[0007] (1) 普通冻干方法无法控制冷冻阶段的冰晶生长， 即出现成核随机性、 形状 个异性等， 且冰晶的大小进一步影响了干燥阶段的吋间， 较大冰晶在冷冻过程 中有可能刺破细胞， 导致药效流失。 大小不一致的冰晶导致品质均匀性得不到 保证。
[0008] (2) 添加成核试剂的冻干方法， 额外添加的成核试剂， 参数复杂， 操作不易
， 成本高。
[0009] (3) 新兴的超声辅助冻干技术， 则易出现由于超声带来的瞬吋大量潜热对药 效的伤害； 且有超声媒介存在的情况下超声功能才能得到发挥， 而这种媒介的 存在则会大大影响超声-冻干一体机的设计， 带来极大不便； 另超声带来的噪声 亦极其刺耳。
[0010] (4) 常规的补水器冷凝制冷系统， 传热慢， 冷冻吋间长； 常规的普通加热板 构成的加热系统， 干燥吋间长， 耗能， 对成品品质产生一定影响。
[0011] (5) 无论是普通的还是新型的冻干方式， 都无法在冻干体系内改变样品内的 含水量， 从而减少冷冻及干燥吋间， 亦更加进一步控制成核及成品品质。
技术问题
[0012] 为了克服现有技术的上述缺点与不足， 本发明的目的在于提供一种变频交流电 场辅助冻干药物脂质体粉的方法， 不仅大大缩短冷冻及干燥吋间， 而且控制成 核， 冰晶的大小， 进而进一步保证了冻干粉的品质。 [0013] 本发明的另一目的在于提供实现上述的变频交流电场辅助冻干药物脂质体粉方 法的设备。
问题的解决方案
技术解决方案
[0014] 本发明的目的通过以下技术方案实现：
[0015] 变频交流电场辅助冻干药物脂质体粉的方法， 包括以下步骤：
[0016] (1) 制备药物-脂质体混悬液样品；
[0017] (2) 在给予 l~10kHz、 3~10kV的高压交流电处理的条件下， 对样品进行脱水
[0018] (3) 在 -20〜- 40。C、 给予 10~25kHz， 0.2~lkV高压交流电处理， 对经步骤 （2) 处理后的样品进行冷冻干燥， 直至冷冻完成；
[0019] (4) 在真空条件下对样品进行加热干燥， 直至升华及解析完成， 获得药物脂 质体冻干粉。
[0020] 步骤 （1) 所述药物 -脂质体混悬液的含水率为 40~80%。
[0021] 步骤 （2) 所述脱水， 具体为： 脱水至样品含水率为 18~35%。
[0022] 步骤 （3) 所述直至冷冻完成， 具体为： 样品核心温度达到 -20。C。
[0023] 步骤 （4) 所述直至升华及解析完成， 具体为： 样品核心温度达到 20。C。
[0024] 实现上述的变频交流电场辅助冻干药物脂质体粉方法的变频交流电场辅助冻干 药物脂质体粉的设备， 包括依次连接的调配罐、 计量泵、 脱水器、 高 /低温处理 室；
[0025] 所述脱水器中的样品槽的上、 下方设有各设一个电极板； 所述高 /低温处理室 中的样品槽的上、 下方设有各设一个电极板； 所述电极板与高压变频交流电源 控制箱连接；
[0026] 所述高 /低温处理室还与真空泵连接；
[0027] 所述高 /低温处理室用于对样品进行冷冻干燥和加热干燥。
[0028] 所述高 /低温处理室的样品槽下设有半导体制冷 /加热片， 半导体制冷加热片 /下 设有风机； 所述高 /低温处理室的样品槽上设有无线热电偶探头。
[0029] 所述脱水器通过螺旋泵与高 /低温处理室连接。 [0030] 所述脱水器还与废液罐连接。
[0031] 本发明在冻干药物脂质体制剂的基础上， 辅助以高压变频交流电电场来进行冷 冻， 在冷冻前期及冷冻过程中分别给予不同的高电压交流电的处理， 从而达到 冷冻前期脱除部分水， 缩短冷冻及干燥的吋间； 冷冻过程中抑制成核， 但形成 的冰晶细小， 避免了由冷冻所造成机械损伤， 且缩短了后期的干燥吋间。 虽然 高频高压会产生部分热量， 但是在冷冻过程中与半导体制冷的效果相比， 其释 放的潜热可忽略不计； 在脱水过程中若药物对温度有严格要求， 可与脱水机配 套连接冷凝循环机， 以控制温度； 而且电场具有杀菌的特性， 能够杀灭微生物 ， 进一步保证了生物制剂的安全性， 避免了后期冻干粉的灭菌处理工作。
发明的有益效果
有益效果
[0032] 与现有技术相比， 本发明具有以下优点和有益效果：
[0033] ( 1) 采用本发明的方法， 冻干样品无需经过常规冻干过程中的超低温冰箱的 预冻前处理步骤。
[0034] (2) 采用本发明的方法， 在冷冻前期给予高频交流电处理， 极强的破乳现象 的发生， 大大减少了样品的含水量， 使得随之冷冻结晶吋间得到大大减少， 即 后期的干燥升华阶段亦会随之相应得到大大减短。
[0035] (3) 采用本发明的方法， 在冷冻过程中给予低频交流电处理， 推迟了成核现 象的发生， 但正是这种抑制水分子之间氢键的结合， 使得形成的冰晶数量多， 颗粒小。 较大的比表面积， 促进了干燥过程中的解析阶段的发生， 缩短了干燥 吋间。
[0036] (3) 采用本发明的方法， 以半导体作为制冷及加热系统， 节省了以冷凝补水 器及加热板分别提供制冷、 加热作用的系统的工作吋间， 且设备简单化。
[0037] (4) 采用本发明的方法， 冻干粉无需经过杀菌处理， 此处的原理及效果与脉 冲电场处理杀菌相似
[0038] (5) 采用本发明的方法， 冻干处理吋间得到大大缩短， 一定程度上避免了过 长冻干处理吋间导致生物药剂活性的损失的问题， 进一步保证了生物制剂的功 效及品质。 对附图的简要说明
附图说明
[0039] 图 1为本发明的实施例的变频交流电场辅助冻干药物脂质体粉的设备的组成示 意图。
实施该发明的最佳实施例
本发明的最佳实施方式
[0040] 下面结合实施例， 对本发明作进一步地详细说明， 但本发明的实施方式不限于 此。
[0041] 实施例 1
[0042] 图 1为本实施例的变频交流电场辅助冻干药物脂质体粉的设备的示意图。 图 1所 示， 包括依次连接的调配罐 1、 计量泵 2、 脱水器 3、 高 /低温处理室 4; 所述脱水 器 3中的样品槽 31的上、 下方设有各设一个电极板 32; 所述高 /低温处理室 4中的 样品槽 41的上、 下方设有各设一个电极板 42; 所述电极板与高压变频交流电源 控制箱 8连接； 所述高 /低温处理室 4还与真空泵 5连接； 所述高 /低温处理室用于 对样品进行冷冻干燥和加热干燥。
[0043] 所述高 /低温处理室 4的样品槽 41下设有半导体制冷 /加热片 43， 半导体制冷 /力口 热片 43与半导体电源控制箱 9连接； 半导体电源控制箱 9包含制冷控制系统和加 热控制系统， 正接为制冷控制系统， 反接为加热控制系统； 半导体制冷 /加热片 4 3下设有风机 44; 样品槽 41上设有无线热电偶探头 45。 所述脱水器 3通过螺旋泵 6 与高 /低温处理室 4连接， 所述螺旋泵 6中设有阀门 61。 所述脱水器 3与废液罐 7连 接。
[0044] 调配罐、 脱水器、 高 /低温处理室外壁均为双层设置， 具有夹层； 电极板为不 锈钢平板电极， 在脱水器、 冻干室内为皆为样品槽上下对称的两块 （电极间距 离约为 11cm) 紧贴着样品槽； 冻干室内半导体制冷 /加热片紧贴着下方电极； 通 电后， 处理室内是个非均匀的电场体系； 脱水器有钢化玻璃窗， 便于对电脱水 现象进行观察， 从而适吋取样通过水分测试仪测量试样的含水率； 无线热电偶 探头用于测量样品温度变化， 即判断冷冻及加热的吋间； 半导体制冷 /加热片用 于分别在冷冻、 加热阶段降低、 增加样品槽温度。 另高 /低温处理室样品槽的大 小可根据实际需要自由更改， 以下实施例中采用脱水器的样品槽大小 （长 X宽 X 高） 为 40*15*10cm; 高 /低温处理室内样品槽大小 （长 X宽 X高） 为 30*15*10cm
。 以下实施例中不需要在脱水机外连接冷凝循环机， 实际可按需要判断外接与 否。
[0045] 本实施例的变频交流电场辅助冻干药物脂质体粉的方法， 包括以下步骤：
[0046] 称取适量的泊洛沙姆 188和聚乙二醇 -二硬脂酰磷脂酰乙醇胺， 加入适量吐温 -80 oC构成水相， 水浴加热至（70±5)。C， 构成水相。 山嵛酸甘油酯和胆固醇 75°C水 浴熔融； 精确称取适量槲皮素和大豆卵磷脂， 共溶于适量丙酮： 乙醇（1: 1)溶剂 中， 混合后成油相。 将制得的水相与油相 （V:V=1.5:1) 至于配料罐进行搅拌混合 ， 形成一个油包水的乳化液体系 （含水量为 75%) ， 总体积为 5L。 经计量泵流入 脱水器的样品槽内， 给予 8kV， 3kHz的高压交流电处理 15min (此吋交流脉冲空 占 35%) ， 破乳脱水至含水量 35%; 在制备槲皮素脂质体悬混液的同吋， 打幵半 导体电源控制箱， 正接制冷控制系统， 设定温度为 -40。C; 脱水后的样品经管道 输送泵流入高 /低温处理室的样品槽内 （此吋样品高度约为 5cm) ， 关闭管道幵 关， 打幵真空泵， 并给予 25kHz， lkV (此吋交流脉冲空占 45%) ， 至冷冻完成 ， 即样品核心温度为 -20。C; 打幵半导体电源控制箱， 反接加热控制系统， 设置 温度为 30。C， 当样品核心温度为 20。C吋， 表示干燥阶段完成； 关闭设备， 取出 槲皮素脂质体冻干粉， 装于无菌瓶中。 所得的槲皮素脂质体冻干粉含水量仅为 1 %, 颗粒直径均匀， 色呈淡黄色； 包封率为 90%; 水化再分散容易； 在模拟的生 物膜表面药量大于普通输液； 在模拟的小鼠损伤上治疗效果明显优于槲皮素原 药； 微生物杀灭方面， 较常规冻干降低了 4个数量级， 较新型的微波冻干降低了 3个数量级， 属于安全范围内； 冻干吋间较常规冷冻干燥吋间缩短 40h， 较新型 的微波冻干吋间缩短 25h。
[0047] 实施例 2
[0048] 本实施例的变频交流电场辅助冻干药物脂质体粉的方法， 包括以下步骤：
[0049] 称取一定量的灯盏花素， 蛋黄卵磷脂、 胆固醇、 表面活性剂、 稳定剂各适量， 加入少量乙醇超声至溶解， 减压旋转蒸发至乙醇挥干， 用含甘露醇和抗氧剂的 水合介质水合， 即得到灯盏花素脂质体混悬液 （含水量为 55%) ， 总体积为 3L。 经计量泵流入脱水器的样品槽内， 给予 4kV， 1kHz的高压交流电处理 8min (此吋 交流脉冲空占 40%) ， 破乳脱水至含水量 25%; 在制备灯盏花素脂质体悬混液的 同吋， 打半导体电源控制箱， 正接制冷控制系统， 设定温度为 -25。C; 脱水后的 样品经管道输送泵流入高 /低温处理室的样品槽内 （此吋样品高度约为 3.5cm) ， 关闭管道幵关， 打幵真空泵， 并给予 15kHz， 0.2kV， 至冷冻完成， 即样品核心 温度为 -20。C; 打幵半导体电源控制箱， 反接加热控制系统， 设置温度为 25。C， 当样品核心温度为 20。C吋， 表示干燥阶段完成； 关闭设备， 取出灯盏花素脂质 体冻干粉， 装于无菌瓶中。 所得的灯盏花素脂质体冻干粉含水量仅为 0.8%， 颗 粒直径均匀， 色呈淡黄色； 包封率为 88%， 水化再分散容易； 在模拟的生物膜表 面药量大于普通输液； 在模拟的小鼠损伤上治疗效果明显优于灯盏花素原药； 微生物杀灭方面， 较常规冻干降低了 3个数量级， 较新型的微波冻干降低了 2个 数量级， 属于安全范围内； 冻干吋间较常规冷冻干燥吋间缩短 20h， 较新型的微 波冻干吋间缩短 10h。
[0050] 实施例 3
[0051] 称取一定量的多西他赛， 大豆磷脂、 胆固醇、 表面活性剂、 甘露醇各适量， 加 入少量乙醇超声至溶解， 减压旋转蒸发至乙醇挥干， 用含甘露醇和抗氧剂的水 合介质水合， 即得到多西他赛脂质体混悬液 （含水量为 40%) ， 总体积为 4L。 置 于脱水器的样品槽内， 给予 5kV， 500Hz的高压交流电处理 lOmin (此吋交流脉冲 空占 50%) ， 破乳脱水至含水量 18%; 在制备多西他赛素脂质体悬混液的同吋， 打半导体电源控制箱， 正接制冷控制系统， 设定温度为 -30。C; 脱水后的样品经 管道输送泵流入高 /低温处理室的样品槽内 （此吋样品高度约为 5cm) ， 关闭管 道幵关， 打幵真空泵， 并给予 10kHz， 0.5kV， 至冷冻完成， 即样品核心温度为- 20。C; 打幵半导体电源控制箱， 反接加热控制系统， 设置温度为 30。C， 当样品 核心温度为 20。C吋， 表示干燥阶段完成； 关闭设备， 取出多西他赛脂质体冻干 粉， 装于无菌瓶中。 所得的多西他赛脂质体冻干粉含水量仅为 0.2%， 颗粒直径 均匀， 色呈乳白色； 包封率为 85%， 水化再分散容易； 水化再分散容易； 在模拟 的生物膜表面药量大于普通输液； 在模拟的小鼠损伤上治疗效果明显优于多西 他赛原药； 微生物杀灭方面， 较常规冻干降低了 2.5个数量级， 较新型的微波冻 干降低了 1.5个数量级， 属于安全范围内； 冻干吋间较常规冷冻干燥吋间缩短 30h ， 较新型的微波冻干吋间缩短 15h。
上述实施例为本发明较佳的实施方式， 但本发明的实施方式并不受所述实施例 的限制， 其他的任何未背离本发明的精神实质与原理下所作的改变、 修饰、 替 代、 组合、 简化， 均应为等效的置换方式， 都包含在本发明的保护范围之内。

Claims

权利要求书
[权利要求 1] 变频交流电场辅助冻干药物脂质体粉的方法， 其特征在于， 包括以下 步骤：
(1) 制备药物-脂质体混悬液样品；
(2) 在给予 l~10kHz、 3~10kV的高压交流电处理的条件下， 对样品 进行脱水；
(3) 在 -20〜- 40。C、 给予 10~25kHz， 0.2~lkV高压交流电处理， 对经 步骤 （2) 处理后的样品进行冷冻干燥， 直至冷冻完成；
(4) 在真空条件下对样品进行加热干燥， 直至升华及解析完成， 获 得药物脂质体冻干粉。
[权利要求 2] 根据权利要求 1所述的变频交流电场辅助冻干药物脂质体粉的方法， 其特征在于， 步骤 （1) 所述药物 -脂质体混悬液的含水率为 40~80%
[权利要求 3] 根据权利要求 1所述的变频交流电场辅助冻干药物脂质体粉的方法， 其特征在于， 步骤 （2) 所述脱水， 具体为： 脱水至样品含水率为 18~ 35<¾。
[权利要求 4] 根据权利要求 1所述的变频交流电场辅助冻干药物脂质体粉的方法， 其特征在于， 步骤 （3) 所述直至冷冻完成， 具体为： 样品核心温度 达到 -20。C。
[权利要求 5] 根据权利要求 1所述的变频交流电场辅助冻干药物脂质体粉的方法， 其特征在于， 步骤 （4) 所述直至升华及解析完成， 具体为： 样品核 心温度达到 20。C。
[权利要求 6] 实现权利要求 1所述的变频交流电场辅助冻干药物脂质体粉方法的变 频交流电场辅助冻干药物脂质体粉的设备， 其特征在于， 包括依次连 接的调配罐、 计量泵、 脱水器、 高 /低温处理室； 所述脱水器中的样品槽的上、 下方设有各设一个电极板； 所述高 /低 温处理室中的样品槽的上、 下方设有各设一个电极板； 所述电极板与 高压变频交流电源控制箱连接； 所述高 /低温处理室还与真空泵连接；
所述高 /低温处理室用于对样品进行冷冻干燥和加热干燥。
[权利要求 7] 根据权利要求 6所述的变频交流电场辅助冻干药物脂质体粉的设备， 其特征在于， 所述高 /低温处理室的样品槽下设有半导体制冷 /加热片 ， 半导体制冷 /加热片下设有风机； 所述高 /低温处理室的样品槽上设 有无线热电偶探头。
[权利要求 8] 根据权利要求 6所述的变频交流电场辅助冻干药物脂质体粉的设备， 其特征在于， 所述脱水器通过螺旋泵与高 /低温处理室连接。
[权利要求 9] 根据权利要求 6所述的变频交流电场辅助冻干药物脂质体粉的设备， 其特征在于， 所述脱水器还与废液罐连接。
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