Spray nozzle, vacuum freeze-drying apparatus, and method for producing frozen fine particles

Abstract

The present invention provides a vacuum freeze-drying apparatus and an injection nozzle used therein that can stably and appropriately form frozen fine particles of the raw material liquid while suppressing blockage of the injection holes due to adhesion and accumulation of the raw material liquid. [Solution] An injection nozzle according to one embodiment of the present invention is an injection nozzle for a vacuum freeze-drying apparatus that generates frozen fine particles by self-freezing of a raw material liquid injected into a vacuum chamber, and comprises a head portion and a cylindrical nozzle portion. The head portion has a first surface having an inlet into which the raw material liquid flows, a second surface having an injection port into which the raw material liquid is injected, and an internal passage connecting the inlet and the injection port. The nozzle portion is provided on the second surface and has an injection hole with a diameter of 15 μm to 80 μm that communicates with the outlet.

Description

Technical Field

[0001] The present invention relates to a vacuum freeze-drying apparatus, an injection nozzle used therein, and a method for producing frozen fine particles.

Background Art

[0002] In recent years, as a vacuum freeze-drying apparatus, a vacuum freeze-drying method and a vacuum freeze-drying apparatus have been proposed in which a liquid is directly injected from an injection nozzle in a vacuum, frozen fine particles are generated by self-freezing due to evaporation of moisture, and then dried to produce a powder (see, for example, Patent Document 1). In this vacuum freeze-drying method, since fine droplets are formed and evaporated in a vacuum with a low water pressure, freezing can be performed at an ultra-high speed of 1 second or less due to the latent heat, and the ice crystals are also miniaturized.

[0003] Such vacuum freeze-drying technology can produce various powders because freeze-dried powders can be obtained directly from liquids. For example, this freeze-drying technology can obtain high-quality dried products without causing deterioration of foods due to moisture or concentration of pharmaceuticals. In addition, since ice is sublimated and dried, the amount of sublimation also increases due to an increase in temperature. Although the freezing methods are different, conventionally, in order to shorten the drying time, the frozen powder is moved by vibration in a vacuum chamber (see Patent Document 2), or a technology of drying by heating while moving in a rotating drum (see Non-Patent Document 1) has been developed. The frozen particles of these prior arts are restricted in the size of the droplets to be sprayed due to heat exchange with a dilute cooling gas, which is not preferable for the generation of frozen fine particles.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0005] [Non-Patent Document 1] "Bulk Dynamic Spray Freeze-Drying Part 2: Model-Based Parametric Study for Spray-Freezing Process Characterization" Journal of Pharmaceutical Science xxx (2019), 1-11 [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] Therefore, in vacuum freeze-drying technology, which involves injecting liquid directly from a nozzle into a vacuum and generating frozen particles through self-freezing by evaporation of water, it is possible to generate fine frozen particles within the limits of nozzle processing. To obtain frozen particles of a raw material liquid using a micro-porous nozzle, it is necessary to set the diameter of the nozzle (the diameter of the injection hole) that injects the raw material liquid into the vacuum chamber to an appropriate size. For example, the larger the diameter of the injection nozzle, the larger the volume of the liquid droplets, which takes more time to self-freeze, and in a vacuum chamber where space is limited, it becomes impossible to stably form frozen particles of the raw material liquid.

[0007] On the other hand, if the nozzle diameter is too small, a large shear force inversely proportional to the nozzle diameter acts on the raw material liquid. If the raw material liquid contains polymer materials, nucleic acids, cells, red blood cells, etc., these substances will be physically damaged and destroyed, making it unsuitable for formulations using fine-diameter nozzles.

[0008] Furthermore, when a nozzle plate with through holes formed in a flat plate is used as an injection nozzle (see, for example, Figure 8 of Patent Document 1), when the raw material liquid is injected, droplets of the raw material liquid adhere to and grow around the through holes, which are the injection holes, causing the injection nozzle to become blocked in a relatively short time.

[0009] In view of the above circumstances, the object of the present invention is to provide a vacuum freeze-drying apparatus and an injection nozzle used therein, as well as a method for producing frozen fine particles, that can stably and appropriately form frozen fine particles of the raw material liquid while suppressing blockage of the injection holes due to adhesion and accumulation of the raw material liquid. [Means for solving the problem]

[0010] An injection nozzle according to one embodiment of the present invention is an injection nozzle for a vacuum freeze-drying apparatus that generates frozen fine particles by the self-freezing of a raw material liquid injected into a vacuum chamber, and comprises a head portion and a cylindrical nozzle portion. The head portion has a first surface having an inlet into which the raw material liquid flows, a second surface having a nozzle from which the raw material liquid is sprayed, and an internal passage connecting the inlet and the nozzle. The nozzle portion is provided on the second surface and has an injection hole with a diameter of 15 μm to 80 μm that communicates with the outlet.

[0011] When the diameter of the injection hole is 15 μm, the length of the injection hole may be 0.35 mm or less.

[0012] The diameter of the inlet may be 1.5 mm or more, and the internal passage may have a conical or cylindrical shape with the outlet side as its apex.

[0013] The length of the internal passage along its axial direction may be 2 mm or less.

[0014] The difference between the outer diameter and inner diameter of the nozzle portion may be 0.2 mm or more and 0.3 mm or less.

[0015] A vacuum freeze-drying apparatus according to one embodiment of the present invention comprises a vacuum chamber, an injection nozzle, a cold trap, and a heating device. The vacuum chamber is configured to accommodate a container for containing frozen fine particles produced by self-freezing. The injection nozzle is provided in the vacuum chamber and generates frozen microparticles of the raw material liquid by injecting the raw material liquid supplied from the raw material tank into the vacuum chamber. The cold trap removes moisture in the vacuum chamber. The heating device dries the frozen microparticles contained in the container. The injection nozzle has a head portion and a cylindrical nozzle portion. The head portion has a first surface having an inlet through which the raw material liquid flows in, a second surface having an injection port through which the raw material liquid is injected, and an internal passage communicating between the inlet and the injection port. The nozzle portion is provided on the second surface and has an injection hole with a diameter of 15 μm or more and 80 μm or less that communicates with the outlet. It has.

[0016] The method for producing frozen microparticles according to one embodiment of the present invention is a method for producing frozen microparticles using a vacuum freeze-drying apparatus having the above injection nozzle, The raw material liquid uses an aqueous solution in which a solute is dissolved in a solvent composed of water or a dispersion solution in which a dispersoid is dispersed in a dispersion medium composed of water, The solute or the dispersoid is a material having a cell membrane, The concentration of water used in the solvent or dispersion medium is 80% by weight or more.

Advantages of the Invention

[0017] According to the present invention, when a polymer material, nucleic acid, cell, red blood cell, etc. are contained in the raw material liquid, these substances reduce physical damage, stably and appropriately form frozen microparticles, and suppress clogging of the injection holes due to adhesion and deposition of the raw material liquid.

Brief Description of the Drawings

[0018] [Figure 1] It is a schematic configuration diagram showing the whole of a vacuum freeze-drying apparatus according to an embodiment of the present invention. [Figure 2] It is a schematic side sectional view of an injection nozzle. [Figure 3]This is an enlarged view of section A in Figure 2. [Figure 4] This is a schematic side cross-sectional view of a key part showing a modified configuration of the injection nozzle described above. [Figure 5] This is a schematic side cross-sectional view showing another variation of the above injection nozzle configuration. [Modes for carrying out the invention]

[0019] Embodiments of the present invention will be described below with reference to the drawings.

[0020] Figure 1 is a schematic diagram showing the overall configuration of a vacuum freeze-drying apparatus 1 according to one embodiment of the present invention. First, the overall configuration of the vacuum freeze-drying apparatus 1 will be described.

[0021] [Overall configuration of the device] As shown in Figure 1, the vacuum freeze-drying apparatus 1 of this embodiment includes a vacuum chamber having a freezing chamber 2 and a drying chamber 3 connected to the freezing chamber 2 via a gate valve 4.

[0022] Freezing chamber 2 is connected to an incoming chamber (not shown) and to a vacuum exhaust system 10 via an exhaust volume adjustment device 13. Drying chamber 3 is connected to a vacuum exhaust system 14 via an exhaust volume adjustment device 16, and is also provided with a vent valve (not shown) for repressurization (releasing to the atmosphere). Vacuum gauges 11 and 15 are connected to freezing chamber 2 and drying chamber 3, respectively, to measure the pressure inside them.

[0023] Outside the freezing chamber 2, a raw material tank 9 is located to store the raw material liquid at room temperature. Inside the freezing chamber 2, at the top, an injection nozzle 20 connected to the raw material tank 9 is provided. The raw material liquid is supplied to the injection nozzle 20 from the raw material tank 9 via a raw material liquid supply amount adjustment device 12, and the raw material liquid is ejected downward in a column-like manner from the lower end of the injection nozzle 20 into a vacuum atmosphere. Details of the injection nozzle 20 will be described later.

[0024] The raw material liquid supply rate adjustment device 12 typically includes a flow control valve, a liquid delivery pump, etc. The raw material liquid supply rate adjustment device 12 adjusts the injection flow rate of the raw material liquid injected from the injection nozzle 20 into the freezing chamber 2. Alternatively, the raw material tank 9 and the raw material liquid supply rate adjustment device 12 may be integrated into a single unit. A syringe pump is an example of such an integrated unit.

[0025] As shown in Figure 1, a tray 7 for containing the generated frozen fine particles 35 of the raw material liquid is positioned below the injection nozzle 20 inside the freezing chamber 2. In this embodiment, the distance from the injection nozzle 20 to the tray 7 is, for example, within 1.6 m. In other words, the vacuum freeze-drying apparatus 1 is configured to generate frozen fine particles 35 of the raw material liquid at a height of 1.6 m or less from the injection nozzle 20.

[0026] A cold trap 5, connected to a refrigerator (not shown), is provided near the tray 7. As the frozen particles become smaller, the rate at which the frozen particles are collected into the tray decreases due to the flow of water vapor from the cold trap; therefore, it is preferable to install the cold trap 5 near the tray. The tray 7 is configured to be transported from the freezing chamber 2 to the drying chamber 3 using a transport mechanism such as a robot (not shown).

[0027] The drying chamber 3 is equipped with a heating device 8, such as an infrared heater, for drying the frozen particles 35 contained in the tray 7. The drying chamber 3 is also equipped with a cold trap 6 connected to a refrigerator (not shown). The cold trap 6 promotes the drying of the frozen particles in the tray 7 by adsorbing moisture that sublimes from the frozen particles 35 heated in a vacuum by the heating device 8.

[0028] The raw material liquid comprises a solvent or dispersion medium and a solute dissolved in the solvent or a dispersed phase dispersed in the dispersion medium. In this embodiment, the raw material liquid can be, for example, an aqueous solution obtained by dissolving a solute in a solvent consisting of water, or a dispersion solution obtained by dispersing a dispersed phase in a dispersion medium consisting of water. In this case, it is preferable to set the concentration of water used in the solvent and dispersion medium to 80% by weight or more.

[0029] By adjusting the viscosity of the raw material liquid in this way, even when the raw material liquid contains polymer materials or materials having cell membranes such as nucleic acids, cells, or red blood cells, it is possible to prevent physical damage or destruction of these materials when generating frozen microparticles using the spray nozzle 20 described later.

[0030] [Vacuum freeze-drying method] Next, we will explain a method for vacuum freeze-drying a raw material liquid using the vacuum freeze-drying apparatus 1 configured as described above.

[0031] In this embodiment, to produce freeze-dried powder, first, the vacuum evacuation device 10 and cold trap 5 are operated with the gate valve 4 closed to reduce the pressure inside the freezing chamber 2. Then, the cold trap 5 and the injection nozzle 20 are operated to inject the raw material liquid from the injection nozzle 20. The pressure inside the freezing chamber 2 is reduced so that the droplets of the raw material liquid are completely frozen (all droplets are in the solid phase) up to the tray 7 located 1.6 m below the injection nozzle.

[0032] As shown in Figure 1, the raw material liquid injected from the injection nozzle 20 initially forms a columnar liquid column 21. Subsequently, elastic waves on the surface of the liquid column 21 cause a constriction, which overcomes the surface tension of the liquid, and the liquid is sequentially separated from the liquid column 21 to form droplets 30 of the raw material liquid. Since the separation is due to surface tension, the change from columnar to spherical shape occurs as the droplets (31) change to spheres with a diameter larger than the initial cylindrical diameter at injection (which is approximately the same as the diameter of the nozzle opening for the raw material liquid in the injection nozzle 20).

[0033] Furthermore, a portion of this raw material liquid turns into a gas and is mainly exhausted by the cold trap 5 during flight after being injected into the freezing chamber 2, but the exhaust rate is affected by the partial pressure of water vapor in the freezing chamber 2. The raw material liquid remains in the liquid phase throughout until it changes from a columnar to a spherical shape (the range of droplet 30), but due to the synergistic effect of the increase in specific surface area, water vaporizes from the surface of droplet 30, causing the droplet 30 to lose heat (due to heat transfer accompanying the phase change). This is the main reason why the surface layer of droplet 30 undergoes supercooling and reaches the spontaneous freezing temperature at which self-freezing begins, and thereafter self-freezing rapidly progresses from the surface towards the center. This portion is referred to as droplet 31. Droplet 31 represents the state after supercooling has broken, and since ice crystal growth has begun in droplet 31, it is assumed that the surface temperature of droplet 31 is at least near the triple point of water, and thereafter it moves towards the temperature based on the partial pressure of water vapor in the freezing chamber 2.

[0034] It should be noted that the spontaneous freezing temperature of pure water is said to be -40°C, and since the raw material liquid is not pure water, it does not need to be cooled below this temperature. In other words, since the raw material liquid typically has a spontaneous freezing temperature higher than -40°C, it is sufficient to maintain the freezing chamber 2 below the water vapor partial pressure corresponding to that temperature. For example, by keeping the water vapor partial pressure in the freezing chamber 2 below 50 Pa, it is possible to sufficiently guide the liquid droplets 30 to the spontaneous freezing temperature, but this is not limited to this, and depending on the type of raw material liquid, a water vapor partial pressure higher than 50 Pa may be acceptable.

[0035] Furthermore, the crystal nucleation temperature (for spontaneous freezing) for each raw material liquid may be experimentally determined, and the saturated vapor pressure value corresponding to that nucleation temperature, i.e., the water vapor partial pressure in the freezing chamber 2, may be determined. However, since this is a method of cooling droplets 30 using heat removal based on the phase change of water, it is desirable to keep the water vapor partial pressure below 50 Pa in order to achieve the desired cooling rate. This allows the solute or dispersed phase of the raw material liquid to be frozen at a rate that does not destroy cells or denature proteins during vacuum freeze-drying. In this case, the lower limit of the water vapor partial pressure should be set so that it does not exceed 50 Pa due to the pressure increase (water vapor partial pressure) during injection, that is, a value that depends on the exhaust capacity of the device should be calculated or experimentally determined.

[0036] The self-freezing of droplet 31 progresses during flight, and at least the entire surface of droplet 31 changes into a solid phase. This forms frozen fine particles 32. After changing into these frozen fine particles 32, they land in tray 7 and accumulate as frozen fine particles 35. If the entire surface of droplet 30 has not changed into a solid phase, the rebound upon impact will be different (if the liquid phase is dominant, the coefficient of restitution is much smaller than if the solid phase is dominant, making it easy to distinguish). For example, image analysis using a camera can be used to distinguish between an unfrozen state and a state of frozen fine particles 32 (if it is confirmed that it rebounds to a certain height or higher, it can be determined to be in a frozen state). Also, if a liquid phase is present on the surface, the frozen fine particles 32 will stick together, so it is possible to distinguish by checking this.

[0037] Furthermore, due to surface tension and other factors, the raw material liquid injected from the injection nozzle 20 may not always have the same injection direction (directivity). In this case, by making the injection direction of the raw material liquid the same as the direction of gravitational acceleration and by creating a gas flow of water vapor adsorbed to the cold trap 5, the directivity of the frozen fine particles 32 can be increased, thereby confining the spread of the frozen fine particles 32 within the range of the tray 7, causing the frozen fine particles 32 to fall and be collected in the tray 7.

[0038] Furthermore, while the shape of the frozen particles 35 is typically spherical, other shapes such as elliptical or spindle-shaped particles may also be included. The shape of the frozen particles 35 is determined, for example, by the diameter of the injection hole of the injection nozzle 20, the injection flow rate (or injection pressure), the initial injection velocity, the flight time (fall time), and the viscosity of the raw material liquid. Therefore, by adjusting these conditions, it is possible to produce frozen particles 35 of a desired shape.

[0039] Subsequently, using a transport mechanism such as a robot (not shown), the tray 7 is moved into the drying chamber 3, which has been pre-pressurized by a vacuum exhaust device 14. The heating device 8 heats the frozen particles 35 in the tray 7 in a vacuum, drying the frozen particles 35 by sublimating any ice remaining on them. The cold trap 6 adsorbs the moisture sublimated from the frozen particles 35.

[0040] Furthermore, the drying process of the frozen fine particles 35 in the drying chamber 3 is carried out with the gate valve 4 closed. As a result, the freezing chamber 2 is atmospherically separated from the drying chamber 3, allowing the subsequent injection of the raw material liquid, as well as the freezing and drying processes, to be carried out continuously in the freezing chamber 2.

[0041] [Details of the spray nozzle] Next, the details of the injection nozzle 20 of this embodiment will be described. Figure 2 is a schematic side cross-sectional view of the injection nozzle 20, and Figure 3 is an enlarged view of part A in Figure 2.

[0042] The injection nozzle 20 is used to generate frozen fine particles by the self-freezing of the raw material liquid injected into the vacuum chamber (freezing chamber 2). The injection nozzle 20 comprises a head portion 40 and a nozzle portion 50.

[0043] The head portion 40 forms the main body of the injection nozzle 20 and is typically made of a metal material such as stainless steel (e.g., SUS316L). The head portion 40 has a first surface 41 having an inlet E1 through which the raw material liquid flows in, a second surface 42 having an outlet E2 through which the raw material liquid flows out, and an internal passage 43 connecting the inlet E1 and the outlet E2.

[0044] The inlet E1 and outlet E2 are concentric circular openings, with the diameter of the inlet E1 being larger than the diameter of the outlet E2. The internal passage 43 is a flow path that guides the raw material liquid supplied to the inlet E1 to the outlet E2, and in this embodiment, it has a conical shape (an inverted cone shape in Figure 2) with the outlet E2 side as its apex. However, it is not limited to this, and the internal passage 43 may be a cylindrical shape with a diameter larger than the diameter D of the injection hole 51a, or it may include a cylindrical passage section 43h (see Figure 4).

[0045] The nozzle portion 50 is provided on the second surface 42 of the head portion 40. The nozzle portion 50 has a cylindrical portion 51 that forms an injection hole 51a communicating with the outlet E2. The injection hole 51a is formed as a cylindrical round hole concentric with the outlet E2. The diameter (hole diameter) D of the injection hole 51a is 15 μm or more and 80 μm or less.

[0046] If the diameter D of the injection hole 51a exceeds 80 μm, it becomes difficult to properly generate frozen fine particles 35 of the raw material liquid at a height of 1.6 m or less from the injection nozzle 20. In other words, the larger the diameter D of the injection hole 51a, the larger the volume of the droplets of the raw material liquid injected from the injection hole 51a, which means that it takes longer for the raw material liquid to self-freeze, and it becomes impossible to stably form frozen fine particles of the raw material liquid. As a result, the raw material liquid that falls onto the tray 7 may not freeze and become slushy, or the particle size may increase, making it impossible to stably obtain the desired frozen fine particles 35. For this reason, in this embodiment, the diameter D of the injection hole 51a is set to 80 μm or less.

[0047] On the other hand, if the diameter D of the injection hole 51a is too small, a large shear force inversely proportional to the diameter of the injection hole 51a acts on the raw material liquid. If the raw material liquid contains polymer materials or materials with cell membranes such as nucleic acids, cells, or red blood cells, these materials may be physically damaged or destroyed. For this reason, in this embodiment, the diameter D of the injection hole 51a is set to 15 μm or more. This makes it possible to stably form dry powder with a diameter of several tens of micrometers without causing physical damage.

[0048] The shear force acting on the raw material liquid passing through the injection hole 51a varies not only with the diameter of the injection hole 51a but also with the length of the injection hole 51a. That is, even with the same hole diameter, the longer the injection hole 51a is, the slower the flow velocity of the raw material liquid in the injection hole becomes. Therefore, to obtain the same amount of injection volume, a further increase in flow velocity is necessary, and as a result, a large shear force acts on the raw material liquid passing through the injection hole 51a. If the raw material liquid contains polymer materials or materials with cell membranes such as nucleic acids, cells, red blood cells, etc., these substances may be physically damaged or destroyed. Therefore, when using this type of raw material liquid, it is necessary to consider not only the diameter of the injection hole 51a but also the length of the injection hole 51a and the injection volume simultaneously.

[0049] For example, the guidelines for the use of blood products for transfusion state that "red blood cells are easily destroyed when injected at a rate exceeding approximately 0.3 mL / second through a 24-gauge needle, and there is almost no hemolysis until the rate exceeds 1.5 mL / second when using a 22-gauge needle" (Japanese Red Cross Society, Handling Manual for Blood Products for Transfusion, December 2018 revised edition, page 9). Therefore, if the same relationship between shear stress (radial gradient of flow velocity) as the flow conditions in which hemolysis of red blood cells does not occur is satisfied, it can be said that the nozzle conditions in the injection nozzle 20 result in less cell damage in the raw material solution.

[0050] The radial gradient of the flow velocity (du / dr) can be expressed as follows, where ΔP is the pressure, r is the hole diameter, and L is the hole length. (du / dr)∝ΔP·r / L In the example of the 22-gauge injection needle described above, if we let the pressure be ΔP1, the hole diameter be r1, and the hole length be L1, the nozzle conditions that do not cause hemolysis are ΔP1 = 0.484 (MPa), r1 (radius) = 210 μm, and L1 = 32 mm. Therefore, if we set the pressure of the injection nozzle 20 to 0.15 (MPa) and the hole diameter (radius) of the injection hole 51 to 7.5 μm, the length of the injection hole 51a must be 0.35 mm or less to achieve conditions equivalent to the shear stress that does not cause hemolysis of red blood cells.

[0051] As described above, when the diameter D of the injection hole 51a of the nozzle section 50 is 15 μm, physical damage to cells in the raw material liquid can be suppressed by making the length L of the injection hole 51a 0.35 mm or less. The lower limit of the length L of the injection hole 51a is not particularly limited, and for example, it can be set to a length of 20% (0.2 L) or more of the length L of the injection hole 51a.

[0052] Furthermore, in this embodiment, the internal passage 43 in the head portion 50 of the injection nozzle 20 is formed in a conical shape with the outlet E2 side as its apex, thereby reducing the pressure loss of the raw material liquid introduced from the raw material tank 9 to the injection nozzle 20. More specifically, in this embodiment, the axial length S of the internal passage 43 is 2 mm or less, and the diameter P of the inlet E1 is 1.5 mm or more.

[0053] Furthermore, in this embodiment, the cylindrical portion 51 that forms the injection hole 51a is formed in a cylindrical shape with a difference Δd between its outer diameter and inner diameter of 0.15 mm or more and 0.3 mm or less. By reducing the thickness dimension of the cylindrical portion 51 along the radial direction in this way, the area of ​​the tip of the nozzle portion 50 that forms the area around the exit of the injection hole 51a can be minimized. This suppresses the adhesion and growth of droplets of the raw material liquid around the injection hole 51a, and prevents the injection hole 51a from being blocked by such deposits.

[0054] Furthermore, as shown in Figure 3, the nozzle portion 50 of this embodiment further has a base portion 52 provided between the second surface 42 of the head portion 40 and the cylindrical portion 51. The base portion 52 is an inverted truncated cone-shaped projection that connects the head portion 40 and the cylindrical portion 51, and is provided with a part of an internal passage 43 in its center, which includes an outlet E2 that communicates with the injection hole 51a.

[0055] By providing a base portion 52 between the head portion 40 and the cylindrical portion 51, the cylindrical portion 51 and the injection hole 51a can be manufactured with high precision and stability, and the tip of the injection hole 51a can be moved away from the second surface 42 of the head portion 40, making it even less likely for splashes of the raw material liquid ejected from the injection hole 51a to adhere to the area around the nozzle portion 51.

[0056] The length L1 of the cylindrical portion 51 is not particularly limited as long as it is long enough to form the injection hole 51a. The length L1 of the cylindrical portion 51 may be smaller than the length L of the injection hole 51a, as shown in Figure 3, or it may be larger than the length L of the injection hole 51a, as shown in Figure 4. Figure 4 shows an example in which the outlet E2 of the internal passage 43 is formed at the bottom of a cylindrical passage portion 43h having an inner diameter larger than the diameter D of the injection hole 51a.

[0057] The length L2 of the base portion 52 is not particularly limited and may be, for example, twice or more the length L1 of the cylindrical portion 51. The base portion 52 may be omitted, in which case the length L1 of the cylindrical portion 51 should be such that the tip of the injection hole 51a is kept away from the second surface 42 of the head portion 40 to the extent that splashes of the raw material liquid injected from the injection hole 51a are prevented from adhering to the area around the nozzle portion 51.

[0058] As described above, the spray nozzle 20 of this embodiment can stably and appropriately form frozen fine particles of the raw material liquid without causing physical damage to the cells contained in the raw material liquid, and can also suppress blockage of the spray hole due to adhesion and accumulation of the raw material liquid.

[0059] Although embodiments of the present invention have been described above, it goes without saying that the present invention is not limited to the embodiments described above and can be modified in various ways.

[0060] For example, in the embodiments described above, a spray nozzle 20 in which a single nozzle portion 50 is provided on the head portion 40 was used as an example, but of course, it is not limited to this, and as shown in Figure 5, a plurality of nozzle portions 50 may be provided on the head portion 40. In this case, the same raw material liquid is injected into the freezing chamber 2 simultaneously from multiple nozzles 50. This increases the amount of frozen fine particles 45 formed per unit time, thereby improving productivity.

[0061] In the injection nozzle 20 shown in Figure 5, it is preferable that each nozzle section 50 is arranged at equal intervals and that the axial directions of each nozzle section 50 are parallel so that the raw material liquid injected from each injection hole 51a is directed in the same direction. This increases the rigidity of each nozzle section 50 against spray pressure and allows for the stable generation of frozen fine particles 45 without the raw material liquid injected from each nozzle section 50 interfering with each other. Furthermore, from the viewpoint of increasing rigidity against spray pressure, it is preferable that the thickness of the head section 40 be, for example, 4 to 10 times or more the length (L1 + L2) of each nozzle section 50.

[0062] Furthermore, in the above embodiments, the freezing chamber 2 and the drying chamber 3 are connected via a gate valve 4, but the present invention is not limited thereto, and a heating device for drying frozen fine particles can also be provided in a single vacuum chamber. In this case, in order to keep the partial pressure of water vapor below 50 Pa while the liquid is being injected, it is advisable to maintain the temperature of the tray containing the frozen particles at a low temperature during injection, thereby reducing the amount of sublimation gas generated from the frozen particles.

[0063] Furthermore, in the above embodiment, the cold traps 5 and 6 are provided in the freezing chamber 2 and the drying chamber 3, respectively. However, the present invention is not limited to this, and the cold traps can also be placed in a room separate from the freezing chamber and the drying chamber, and this room can be connected to the freezing chamber. In this case, by connecting multiple cold traps to both the freezing chamber and the drying chamber, and switching to another cold trap when the maximum amount of moisture that one cold trap can adsorb is reached, and simultaneously removing the moisture adsorbed by the cold trap that was previously in use, the processing capacity that can be continuously operated can be further increased. [Explanation of Symbols]

[0064] 1...Vacuum freeze drying equipment 2…Freezing room 3…Drying room 4…Gate valve 5, 6… Cold trap 7...Tray 8...Heating device 9… Raw material tank 10,14… Vacuum exhaust system 11,15...Vacuum gauge 13, 16… Displacement adjustment device 20... Spray nozzle 35...Frozen particles 40... Head part 41...First surface 42...Second surface 43...Internal passage 50... Nozzle part 51...Cylindrical part 51a...Injection hole E1...Inlet E2…outlet

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