Freeze-drying device, freeze-dried sample, and method for producing same

Abstract

This freeze-drying device (100) heats and dries a freeze-dry sample (S) and comprises: a vacuum container (101) in which the freeze-dry sample (S) is stored; a cavity resonator (102) in which the vacuum container is stored; and a microwave generator (103) that projects microwaves (electromagnetic waves) into the cavity resonator. The cavity resonator forms, from the microwaves, a standing wave that does not resonate with water but can resonate with ice.

Description

Freeze-drying apparatus, freeze-dried sample and its manufacturing method

[0001] This application claims priority to U.S. Patent Application No. 63 / 672,719, filed July 18, 2024, the contents of which are incorporated herein by reference.

[0002] Freeze-drying is known as a technique for preserving substances whose quality must be maintained, such as foods and pharmaceuticals. In freeze-drying, a substance is first frozen, and then the ice contained in the frozen substance is heated under reduced pressure to sublimate. Because drying of frozen substances requires low temperatures, attempting to sublimate the ice by contacting it with a heat source requires a long drying time. In contrast, drying by microwave irradiation can supply the energy required for ice sublimation to the interior of the frozen substance, resulting in more efficient drying than conventional heating (see, e.g., Non-Patent Document 1). However, commonly known multimode microwaves have a high output, which can lead to breakdown when applied to heat-sensitive substances. Furthermore, unlike liquid water, ice is thought to be less likely to resonate with microwaves and therefore more difficult to heat rapidly.

[0003] X. Cao et al., J. Sci. Food Agric., 98(4), 2018, 1599-1605

[0004] The present invention has been made in view of the above circumstances, and aims to provide a freeze-drying apparatus that enables frozen substances, such as liposomes and enzymes, to be dried at high speed without being destroyed, as well as a freeze-dried sample and a method for producing the same.

[0005] In order to solve the above problems, the present invention employs the following means.

[0006] (1) A freeze-drying apparatus according to one aspect of the present invention is a freeze-drying apparatus that heats and dries a sample to be freeze-dried, and includes a vacuum container in which the sample to be freeze-dried is stored, a resonator in which the vacuum container is stored, and an electromagnetic wave generator that irradiates the resonator with electromagnetic waves, and the resonator forms a standing wave from the electromagnetic waves that does not resonate with water but can resonate with ice.

[0007] (2) In the freeze-drying apparatus described in (1) above, the frequency of the standing wave is preferably 20 MHz to 30 GHz.

[0008] (3) In the freeze-drying apparatus described in (2) above, the frequency is preferably 2.45 GHz.

[0009] (4) In the freeze-drying apparatus described in (1) above, the vacuum container preferably has a vacuum insulation structure that suppresses heat conduction to the sample to be freeze-dried.

[0010] (5) In the freeze-drying apparatus described in (1) above, the sample to be freeze-dried preferably contains ice crystals produced by slow freezing.

[0011] (6) A freeze-dried sample according to one aspect of the present invention contains liposomes or an enzyme and a cryoprotectant.

[0012] (7) In the freeze-dried sample described in (6) above, the liposome may contain at least one selected from the group consisting of ionized lipids, phospholipids, polyethylene glycolated phospholipids, and cholesterol.

[0013] (8) In the freeze-dried sample described in (6) above, the glass transition temperature of the cryoprotectant is preferably -50°C to 0°C.

[0014] (9) In the freeze-dried sample described in (6) above, the cryoprotectant is preferably at least one selected from the group consisting of sugars, sugar alcohols, cellulose derivatives, and catechins.

[0015] (10) The freeze-dried sample described in (6) above preferably has voids of 170 μm or more.

[0016] (11) A method for producing a freeze-dried sample according to one aspect of the present invention irradiates a sample to be freeze-dried, which is stored in a vacuum container, with a standing wave formed from an electromagnetic wave having a resonant frequency that does not resonate with water but can resonate with ice.

[0017] (12) In the method for producing a freeze-dried sample described in (11) above, the resonance frequency is preferably 20 MHz to 30 GHz.

[0018] (13) In the method for producing a freeze-dried sample described in (12) above, the resonance frequency is preferably 2.45 GHz.

[0019] (14) In the method for producing a freeze-dried sample described in (11) above, it is preferable that the vacuum container has a vacuum insulation structure that suppresses heat conduction to the sample to be freeze-dried.

[0020] (15) In the method for producing a freeze-dried sample described in (11) above, the freeze-dried sample is preferably a solid obtained by cooling an aqueous solution from room temperature to the freezing temperature at a cooling rate of −1° C. / min or less.

[0021] (16) In the method for producing a freeze-dried sample described in (15) above, the freezing temperature is preferably −196° C. or higher and 0° C. or lower.

[0022] (17) In the method for producing a freeze-dried sample described in (15) above, the room temperature is preferably 10°C or higher and 30°C or lower.

[0023] (18) In the method for producing a freeze-dried sample described in (15) above, the aqueous solution may contain liposomes or an enzyme and a cryoprotectant.

[0024] (19) In the method for producing a freeze-dried sample described in (18) above, the liposome may contain at least one selected from the group consisting of ionized lipids, phospholipids, polyethylene glycolated phospholipids, and cholesterol.

[0025] (20) In the method for producing a freeze-dried sample described in (18) above, the glass transition temperature of the cryoprotectant is preferably −50° C. to 0° C.

[0026] (21) In the method for producing a freeze-dried sample described in (18) above, the cryoprotectant is preferably at least one selected from the group consisting of sugars, sugar alcohols, cellulose derivatives, and catechins.

[0027] According to the present invention, it is possible to provide a freeze-drying apparatus that can dry frozen substances at high speed without causing them to collapse, as well as a freeze-dried sample and a method for producing the same.

[0028] 1 is a diagram illustrating the configuration of a freeze-drying apparatus according to one embodiment of the present invention; FIG. 2 is a diagram illustrating the configuration of a freeze-drying apparatus according to a modified example of the same embodiment; FIG. 3 is a diagram illustrating the evaporation of water vapor by drying after normal freezing; FIG. 4 is a diagram illustrating the evaporation of water vapor by drying after slow freezing; FIG. 5 is a graph showing the change in resonance state with changes in the state of water at 2.45 GHz; FIG. 6 is a part of a graph showing the resonance state in each state of water at 20-40 MHz; FIG. 7 is a graph showing a cooling curve; FIG. 8 is a cross-sectional image of a dried product obtained by slow freezing a sample to be freeze-dried and then drying it; FIG. 9 is a cross-sectional image of a dried product obtained by normal freezing a sample to be freeze-dried and then drying it; FIG. 10 is a graph comparing the diameter of voids when slow freezing is performed and when normal freezing is performed; and FIG. 11 is a graph comparing the drying speed when microwave freeze-drying and normal freeze-drying are performed on a sample to be freeze-dried, which is an aqueous solution containing dextran and liposomes.

[0023] Figure 1 is a graph comparing the particle size distribution of the dried product obtained when a sample to be freeze-dried is an aqueous solution containing dextran and liposomes, and when it is subjected to microwave freeze-drying and conventional freeze-drying.

[0024] Figure 2 is a graph comparing the drying rate when a sample to be freeze-dried is an aqueous solution containing trehalose and liposomes, and when it is subjected to microwave freeze-drying and conventional freeze-drying.

[0025] Figure 3 is a graph comparing the particle size distribution of the dried product obtained when a sample to be freeze-dried is an aqueous solution containing trehalose and liposomes, and when it is subjected to microwave freeze-drying and conventional freeze-drying.

[0026] Figure 4 is a graph comparing the fructose yield when an enzymatic reaction to recover fructose is performed on a glucose isomerase aqueous solution, prepared by microwave freeze-drying and redissolving the sample, conventional freeze-drying and redissolving the sample, and non-freeze-dried.

[0029] A freeze-drying apparatus according to an embodiment of the present invention, a freeze-dried sample, and a method for producing the same will be described in detail below with reference to the drawings. Note that the drawings used in the following description may show characteristic portions enlarged for ease of understanding, and the dimensional proportions of the components may not be the same as those in reality. Furthermore, the materials, dimensions, etc. exemplified in the following description are merely examples, and the present invention is not limited thereto. Appropriate modifications may be made within the scope of the present invention.

[0030] In this specification, "water" means water (molecules) in a liquid state, and "ice" means water (molecules) in a solid state. In this specification, microwaves (300 MHz or higher) and high frequencies (less than 300 MHz) are collectively referred to as "electromagnetic waves."

[0031] (Freeze-drying apparatus) Fig. 1 is a diagram illustrating the configuration of a freeze-drying apparatus 100 according to a first embodiment of the present invention. The freeze-drying apparatus 100 is a freeze-drying apparatus that heats and dries a sample S to be freeze-dried, and mainly includes a vacuum container 101, a cavity resonator 102, and a microwave generator 103. In this embodiment, a sample obtained by freezing a predetermined sample during the freeze-drying process is referred to as a sample to be freeze-dried, and a sample obtained by drying the sample to be freeze-dried is referred to as a freeze-dried sample.

[0032] The sample S to be freeze-dried is placed in a vial (container) inside the vacuum vessel 101. Examples of the sample S to be freeze-dried include, but are not limited to, substances whose quality must be maintained, such as foods and pharmaceuticals, and biomaterials such as liposomes and enzymes such as glucose isomerase. The liposome is at least one selected from the group consisting of ionized lipids, such as cationic lipids like DOTMA, phospholipids like DPhPC, polyethylene glycolated phospholipids, and cholesterol. The liposome may also contain a useful substance (such as an mRNA drug or a functional component) inside.

[0033] The sample S to be freeze-dried may contain a cryoprotectant as a cryoprotectant to prevent freezing damage and the like. The cryoprotectant has functions such as controlling osmotic pressure, maintaining the shape of the sample by vitrification, and preventing particle aggregation. The cryoprotectant is at least one selected from the group consisting of sugars such as dextran 40, sugar alcohols such as trehalose, cellulose derivatives, and catechins. The glass transition temperature of the cryoprotectant is preferably −50°C to 0°C.

[0034] A freeze-dryer 104 and a vacuum pump 105 are connected to the vacuum vessel 101, and the interior of the vacuum vessel 101 can be depressurized. The vacuum vessel 101 preferably has a vacuum insulation structure that suppresses heat conduction to the freeze-dried sample S contained therein. The vacuum insulation structure can be achieved, for example, by arranging the freeze-dried sample S, which is contained in a vial and frozen, in the vacuum vessel 101 so that the vial does not come into contact with the inner wall of the cylindrical vacuum vessel 101. The vacuum vessel 101 can be, for example, a quartz tube.

[0035] The vacuum vessel 101 is inserted into a cavity resonator (microwave cavity) 102. Microwaves generated by a microwave generator 103 are irradiated onto the cavity resonator 102 via a tuner (matching device) 106. The cavity resonator 102 is configured to generate a standing wave from the microwaves that does not resonate with water but can resonate with ice. From the viewpoint of strengthening the resonance with ice, the frequency of the standing wave is preferably 300 MHz to 30 GHz, more preferably 915 MHz or 2.45 GHz, and even more preferably 2.45 GHz.

[0036] Although the first embodiment described above uses a cavity resonator 102 as the resonator, a parallel-plate resonator 202 may be used instead. FIG. 2 is a diagram illustrating the configuration of a freeze-drying apparatus 200 according to a modified example of the first embodiment of the present invention. The freeze-drying apparatus 200 heats and dries a sample S to be freeze-dried, and mainly includes a vacuum vessel 101, a parallel-plate resonator 202, and a high-frequency generator 203. The vacuum vessel 101 is inserted into the parallel-plate resonator 202 so as to be sandwiched between a pair of flat plates 202a. The parallel-plate resonator 202 is configured to generate a standing wave from the high-frequency wave generated by the high-frequency generator 203. The parallel-plate resonator 202 is configured to generate a standing wave from the high-frequency wave that does not resonate with water but can resonate with ice. From the viewpoint of strengthening the resonance with ice, the frequency of the standing wave is preferably 20 MHz to 300 MHz, and more preferably 27 MHz.

[0037] (Sample to be freeze-dried and its manufacturing method) FIG. 3A shows a sample S １ In freeze-drying, drying starts from the surface, and the dried layer V １ Through the frozen layer C １ If the sublimation speed is too fast, the water vapor will accumulate in a localized area, causing an increase in pressure and resulting in the melting and collapse of the sample.

[0038] To avoid this problem, the freeze-dried sample S of this embodiment is a sample that has been slowly frozen. ２ In the drying process, ice crystals C ２ and gap V ２ The formed ice crystal C ２ and gap V ２can be observed using X-ray CT or the like, and their shape, size, etc. can be confirmed. Slow freezing is freezing performed from room temperature to the freezing temperature at a slower freezing rate (cooling rate) than normal freezing. Note that normal freezing is freezing performed at a freezing rate higher than -5°C / min in the temperature range in which ice crystal growth occurs, and slow freezing can also be freezing performed at a low freezing rate of -5°C / min or less in the temperature range in which ice crystal growth occurs. The room temperature is, for example, 10°C or higher and 30°C or lower. The freezing temperature is, for example, -196°C or higher and 0°C or lower. The slow freezing rate is preferably as low as possible, for example, -1°C / min or lower.

[0039] FIG. 3B shows the freeze-dried sample S after slow freezing and drying. ２ 1 is a diagram showing the evaporation of water vapor from the ice crystals C by slow freezing compared to normal freezing. ２ As a result, the void V ２ This increases the size of the hole, allowing the water vapor to escape, preventing the water vapor from accumulating and preventing the sample from melting or collapsing.

[0040] The size of the ice crystals (the size (diameter) of the voids in the freeze-dried sample) is preferably 150 μm or more, more preferably 170 μm or more, and even more preferably 180 μm or more. The size of the ice crystals is preferably 10 mm or less, more preferably 3 mm or less, and even more preferably 500 μm or less.

[0041] (Freeze-dried sample and its manufacturing method) In this embodiment, the freeze-dried sample S is dried by irradiating microwaves onto the freeze-dried sample S placed in the cavity resonator 102. Unlike a typical microwave oven, which heats random positions inside the cavity resonator 102, the cavity resonator 102 forms an electric field concentrated at a predetermined position (for example, the center), enabling heating.

[0042] By adjusting the frequency of the irradiated microwaves, a standing wave that resonates only with solid ice and does not resonate easily with liquid water can be formed in the center of the cavity resonator 102 where the sample S to be freeze-dried is placed. The frequency of such a standing wave is preferably 20 MHz to 30 GHz, and more preferably 27 MHz, 915 MHz, or 2.45 GHz. By generating such a standing wave, energy can be efficiently supplied to the solid ice, allowing concentrated heating of the ice and achieving faster sublimation.

[0043] As described above, in the freeze-drying method of this embodiment, microwaves at a frequency that resonates only with ice are irradiated onto the freeze-dried sample obtained by slow freezing. By resonating only with the ice, the ice can be heated intensively and rapidly sublimated, thereby speeding up the drying process. Furthermore, the freeze-dried sample obtained by slow freezing has large voids, from which the water vapor heated during the drying process can be efficiently released. Therefore, even if the ice is rapidly sublimated, water vapor does not remain within the freeze-dried sample, preventing collapse due to an increase in water vapor pressure.

[0044] The effects of the present invention will be more clearly understood from the following examples. Note that the present invention is not limited to the following examples and can be practiced with appropriate modifications within the scope of the present invention.

[0045] (Example 1) Three samples, 1 to 3, containing different states of water, were prepared as samples to be freeze-dried. Sample 1 contained only solid ice. Sample 2 contained ice and liquid water after melting the ice. Sample 3 contained only water after further melting the ice. Samples 1 to 3 were placed in the cavity resonator of the above embodiment, and TM ０１０ The cavity was irradiated with microwaves in mode 2.45 GHz to cause resonance, and the resonance frequency was measured. The height of the cavity was set to 5 cm.

[0046] Figure 4 is a graph showing the resonance state in each state of water obtained by this measurement. A resonance peak is seen in sample 1, but not in samples 2 and 3. From this result, it can be seen that when there is only ice, there is resonance with the microwave. In contrast, as the ice melts and changes to ice and water, the resonance peak disappears and it is clear that there is no resonance. This is because the dielectric loss of water is too high and TM ０１０ This is thought to be because resonance does not occur in the TM mode. ０１０ It can be seen that microwaves in mode 2.45 GHz resonate with solid ice and can efficiently transfer energy to ice, but do not resonate with liquid water and do not easily transfer energy to water.

[0047] Furthermore, Samples 1 and 3, sealed in glass vials, were placed in a parallel-plate resonator according to a modification of the first embodiment, and 20-40 MHz high-frequency waves were applied to cause resonance, and the resonance frequency was measured. The height of the parallel-plate resonator was set to 5 cm. Figure 5 is a graph showing the resonance state of water in each state obtained by this measurement. Resonance peaks were observed in all cases, but shifts in the resonance peaks were confirmed. From the above results, it can be seen that by adjusting the resonance frequency, resonance can be induced with solid ice, allowing energy to be efficiently transferred to ice, but resonance cannot be induced with liquid water, making it difficult to transfer energy to water.

[0048] (Example 2) A sample of an aqueous sugar solution of dextran 40 was subjected to slow freezing at -1°C / min to obtain freeze-dried sample 1, and a sample to be freeze-dried was obtained by normal freezing. These samples were then dried to obtain freeze-dried samples (dried products) 1 and 2. Note that normal freezing refers to freezing along the cooling curve shown in Figure 6. The cross sections of freeze-dried samples 1 and 2 were observed using X-ray CT. Figures 7 and 8 are images of the cross sections (1 mm x 1 mm) of freeze-dried samples 1 and 2, respectively.

[0049] The diameters of the voids formed in freeze-dried samples 1 and 2 are approximately 180 μm and approximately 130 μm, respectively. Also, 90 voids were obtained from the cross sections of freeze-dried samples 1 and 2, and the average void diameters are shown in Figure 9. Freeze-dried sample 1, which was subjected to slow freezing, had larger voids than freeze-dried sample 2, which was subjected to normal freezing. This is because ice crystals grow larger during slow freezing than during normal freezing, and the grown ice crystals evaporate during drying, forming larger voids. The larger voids during drying provide larger escape routes for water vapor, suppressing collapse due to increased pressure caused by trapped water vapor.

[0050] Example 3 Two samples obtained by mixing an aqueous solution of dextran 40 and an aqueous solution of liposomes were slowly frozen at -1°C / min to obtain two freeze-dried samples. One of the two freeze-dried samples was dried by microwave irradiation as in the above embodiment to obtain freeze-dried sample 3 (MWFD). The other of the two freeze-dried samples was freeze-dried in the same manner as in the conventional method without high-frequency heating to obtain freeze-dried sample 4 (CFD).

[0051] Figure 10 is a graph showing the relationship between the drying time of a freeze-dried sample and the resonant frequency. The horizontal axis of the graph represents the drying time (minutes), and the vertical axis of the graph represents the change in resonant frequency. The resonant frequency increases as the freeze-dried sample dries. By measuring this resonant frequency, the degree of dryness of the resulting freeze-dried sample (dried product) can be evaluated in real time without contact.

[0052] 10, the drying time for freeze-dried sample 3 is approximately 70% shorter than that for freeze-dried sample 4. This is thought to be because the energy required for sublimation of water vapor during freeze-drying is supplied by irradiating the sample to be freeze-dried with microwaves, thereby shortening the drying time compared to normal freeze-drying, which does not involve heating.

[0053] The particle size distribution was measured for freeze-dried samples 3 and 4. Figure 11 is a graph showing the measurement results. The horizontal axis of the graph represents particle size (nm), and the vertical axis of the graph represents particle size ratio (% / nm).

[0054] There was no significant difference in the particle size distribution between freeze-dried samples 3 and 4. There was also no significant difference in the appearance of freeze-dried samples 3 and 4. These results show that even when the energy required for sublimation is supplied by microwaves, the freeze-dried sample can be dried at high speed without aggregation and while maintaining the drying quality, just as when heating is not performed.

[0055] Example 4 Two samples obtained by mixing an aqueous trehalose solution and an aqueous liposome solution were slowly frozen at -1°C / min to obtain two freeze-dried samples. One of the two freeze-dried samples was dried using microwave irradiation as described in the above embodiment to obtain freeze-dried sample 5 (MWFD). The other of the two freeze-dried samples was dried without heating to obtain freeze-dried sample 6 (CFD).

[0056] Figure 12 is a graph showing the relationship between the drying time and the resonant frequency of the freeze-dried sample. The horizontal and vertical axes of the graph are the same as those in Figure 10. In Figure 12, the drying time of freeze-dried sample 5 is reduced by approximately 70% compared to the drying time of freeze-dried sample 6. This is thought to be because the microwave irradiation of the freeze-dried sample supplies the energy necessary for the sublimation of water vapor during freeze-drying, thereby reducing the drying time compared to normal freeze-drying, which does not involve heating.

[0057] The particle size distribution of freeze-dried samples 5 and 6 was measured. Figure 13 is a graph showing the measurement results. The horizontal and vertical axes of the graph are the same as those in Figure 11. No significant difference was observed in the particle size distribution of freeze-dried samples 5 and 6. Furthermore, no significant difference was observed in the appearance of freeze-dried samples 5 and 6. These results show that even when the energy required for sublimation is supplied by microwaves, the freeze-dried sample can be dried quickly without aggregation and while maintaining drying quality, just as when heating is not performed.

[0058] A glucose isomerase aqueous solution was used as a sample and slowly frozen at -1°C / min to obtain two freeze-dried samples. One of the two freeze-dried samples was dried using microwave irradiation as described above to obtain freeze-dried sample 7 (MWFD). The other of the two freeze-dried samples was dried without heating to obtain freeze-dried sample 8 (CFD). A comparison sample 9 (without FD) was also prepared, which was not freeze-dried.

[0059] Freeze-dried Samples 7 and 8 were redissolved in an aqueous magnesium sulfate solution and ultrapure water, respectively, to obtain Samples 7' and 8'. Samples 7', 8', and Comparative Sample 9 were mixed with an aqueous D-glucose (D-Glc) solution to initiate the enzymatic reaction for recovering fructose. Figure 14 is a graph comparing the fructose yields (%) of Samples 7', 8', and Comparative Sample 9 15 minutes after the start of the enzymatic reaction.

[0060] The fructose yield 15 minutes after the start of the enzyme reaction was not significantly different between the non-lyophilized comparative sample 9 and the freeze-dried samples 7' and 8'. These results demonstrate that freeze-drying does not reduce the activity of glucose isomerase. Furthermore, drying by microwave irradiation can shorten the drying time while maintaining the enzyme activity of glucose isomerase.

[0061] 100, 200... Freeze-drying apparatus 101... Vacuum vessel 102... Cavity resonator (resonator) 103... Microwave generator (electromagnetic wave generator) 104... Freeze-dryer 105... Vacuum pump 106... Tuner 202... Parallel plate resonator 203... High frequency generator (electromagnetic wave generator) S... Sample to be freeze-dried

Claims

1. A freeze-drying apparatus that heats and dries a sample to be freeze-dried, comprising: a vacuum container in which the sample to be freeze-dried is stored; a resonator in which the vacuum container is stored; and an electromagnetic wave generator that irradiates the resonator with electromagnetic waves, wherein the resonator forms a standing wave from the electromagnetic waves that does not resonate with water but can resonate with ice.

2. The freeze-drying apparatus according to claim 1, wherein the frequency of the standing wave is 20 MHz to 30 GHz.

3. The freeze-drying apparatus of claim 2, wherein the frequency is 2.45 GHz.

4. The freeze-drying apparatus according to claim 1, wherein the vacuum container has a vacuum insulation structure that suppresses heat conduction to the sample to be freeze-dried.

5. The freeze-drying apparatus according to claim 1, wherein the sample to be freeze-dried contains ice crystals produced by slow freezing.

6. A freeze-dried sample containing liposomes or an enzyme and a cryoprotectant.

7. The freeze-dried sample according to claim 6, wherein the liposome contains at least one selected from the group consisting of ionized lipids, phospholipids, polyethylene glycolated phospholipids, and cholesterol.

8. The freeze-dried sample according to claim 6, wherein the glass transition temperature of the cryoprotectant is between -50°C and 0°C.

9. The freeze-dried sample according to claim 6, wherein the cryoprotectant is at least one selected from the group consisting of sugars, sugar alcohols, cellulose derivatives, and catechins.

10. The freeze-dried sample of claim 6, having voids of 170 μm or more.

11. A method for producing freeze-dried samples, in which a sample to be freeze-dried stored in a vacuum container is irradiated with a standing wave formed from electromagnetic waves having a resonant frequency that does not resonate with water but can resonate with ice.

12. The method for producing a freeze-dried sample according to claim 11, wherein the resonant frequency is between 20 MHz and 30 GHz.

13. The method for producing a freeze-dried sample according to claim 12, wherein the resonant frequency is 2.45 GHz.

14. The method for producing a freeze-dried sample according to claim 11, wherein the vacuum container has a vacuum insulation structure that suppresses heat conduction to the sample to be freeze-dried.

15. The method for producing a freeze-dried sample according to claim 11, wherein the freeze-dried sample is a solid obtained by cooling an aqueous solution from room temperature to the freezing temperature at a cooling rate of -1°C / min or less.

16. The method for producing a freeze-dried sample according to claim 15, wherein the freezing temperature is -196°C or higher and 0°C or lower.

17. The method for producing a freeze-dried sample according to claim 15, wherein the room temperature is 10°C or higher and 30°C or lower.

18. The method for producing a freeze-dried sample according to claim 15, wherein the aqueous solution contains liposomes or an enzyme and a cryoprotectant.

19. The method for producing a freeze-dried sample according to claim 18, wherein the liposome contains at least one selected from the group consisting of ionized lipids, phospholipids, polyethylene glycolated phospholipids, and cholesterol.

20. The method for producing a freeze-dried sample according to claim 18, wherein the glass transition temperature of the cryoprotectant is between -50°C and 0°C.

21. The method for producing a freeze-dried sample according to claim 18, wherein the cryoprotectant is at least one selected from the group consisting of sugars, sugar alcohols, cellulose derivatives, and catechins.

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