Reduced-pressure drying device and reduced-pressure drying method using same

Abstract

According to one embodiment of the present invention, the present invention is characterized in that, in addition to a conventional relief valve (7) into which outside air flows to return the inside of a drying chamber (1) to normal pressure after drying is completed, the present invention is provided with a separate outside air inflow means for introducing the outside air into the drying chamber (1) during reduced-pressure drying. When the internal pressure of the drying chamber (1) reaches around the target pressure, external air flows into the drying chamber (1). Furthermore, the invention is characterized by being used for the drying of pharmaceutical products, in particular for the manufacture of dry cakes of botulinum toxins. According to the present invention, during the reduced pressure drying process, when the internal pressure of the drying chamber reaches a target pressure, the inflow amount of the external gas is finely adjusted and the external gas flows into the drying chamber, such that the pressure inside the drying chamber, especially the pressure around a vial containing a liquid sample, can be prevented from substantially increasing and then decreasing. Therefore, the internal pressure of the drying chamber can be stably maintained as the target pressure.

Description

Technical Field

[0001] The present invention relates to a reduced pressure drying device and a reduced pressure drying method using the same. More specifically, the present invention relates to a reduced pressure drying device and a reduced pressure drying method using the same, wherein when a reduced pressure process is performed and the pressure in a chamber reaches near a target pressure, external gas is introduced into the chamber at a slight flow rate so that the pressure in the chamber can smoothly reach the target pressure without abrupt changes near the target pressure. Background Art

[0002] In many cases, samples containing water need to be dehydrated and dried before shipment. The general drying process uses a high-temperature drying method that heats the sample to evaporate the water.

[0003] However, this high-temperature drying method is not applicable in many cases for samples such as pharmaceuticals whose properties change due to heat.

[0004] Therefore, freeze drying is being applied to dry heat-sensitive samples.

[0005] Freeze drying is a method of repeatedly cooling a liquid sample and then drying it under reduced pressure to remove the water contained in the sample. Figure 1 As shown, if a liquid sample is cooled to form a solid state and then the pressure is reduced, the sample sublimates from a solid state to a gaseous state. Through its sublimation from a solid state to a gaseous state, the solid solvent becomes a gas and is discharged. The method using this principle is the freeze-drying method.

[0006] The freeze-drying method can dry heat-sensitive samples such as drugs without greatly damaging their properties, so it is widely used. However, the drying process requires many steps, such as cooling the liquid sample to make a solid, reducing the pressure of the solid sample to remove the solvent by sublimation, and then secondary drying the residual solvent in the solid sample. Not only is the amount of solvent removed by sublimation small, the drying time is long, and the pressure required for sublimation from solid to gas is very low, which has the disadvantage of requiring a high vacuum device. In addition, for drugs such as botulinum toxin, during the freezing process, which is an essential process of the freeze-drying process, the protein structure is damaged due to the formation of ice nuclei or the imbalance of excipient concentration that occurs partially during freezing, which may also lead to reduced activity.

[0007] Therefore, the reduced pressure drying method is also used as a drying method for drying heat-sensitive samples such as pharmaceuticals.

[0008] from Figure 1It can be seen that the reduced pressure drying method does not freeze the liquid sample into a solid state like the freeze drying method, but directly reduces the pressure in the chamber containing the liquid sample to a pressure range below the vapor pressure curve of the liquid to evaporate the liquid into gas.

[0009] The reduced pressure drying method has the advantage of being able to dry without greatly damaging the properties of heat-sensitive samples such as pharmaceuticals because it does not involve a heating process. The amount of solvent removed by evaporation is much greater than that removed by sublimation, so the time required for the drying process can be reduced compared to the freeze-drying method. The pressure range required for reduced pressure drying is higher than that required for freeze-drying, so it has the advantage of not requiring a high vacuum device like the freeze-drying method.

[0010] The structure of the vacuum drying device suitable for vacuum drying is as follows: Figure 2 shown.

[0011] A shelf 3 on which samples are placed is arranged inside the drying chamber 1 where samples are placed. The shelf 3 can be raised and lowered by a hydraulic cylinder 4 driven by a hydraulic unit 5, so that the height of the shelf can be adjusted. In addition, the shelf is constructed in a hollow form so that a heat medium can pass through the inside. A door 2 is arranged in the drying chamber 1 so that samples can enter and exit. The sample is usually arranged in a liquid state inside a vial. A vacuum sensor 9 for measuring the internal pressure and a temperature sensor 6 for measuring the internal temperature are arranged in the drying chamber 1. In addition, a release valve 7 is arranged to introduce external gas into the interior of the drying chamber 1 so that the internal pressure of the drying chamber 1 can be restored to normal pressure after the reduced pressure drying is completed. A capsule filter 8 for filtering impurities in the external gas can be arranged in front of the release valve.

[0012] The drying chamber 1 is connected to the condensation chamber 18 through the isolation valve 11. A vacuum pump 23 is provided in the condensation chamber 18. When the vacuum pump 23 is driven, the air inside the condensation chamber 18 and the drying chamber 1 is discharged, and the pressure inside the condensation chamber 18 and the drying chamber 1 is reduced. The condensation chamber 18 plays a role as a cold trap. That is, after a large amount of gaseous solvent evaporated from the drying chamber 1 flows into the vacuum pump 23, it can induce the performance of the vacuum pump 23 to decrease, so that the gaseous solvent evaporated from the drying chamber 1 can undergo heat exchange in the condensation chamber 18 and condense and then be discharged through the discharge valve 41, thereby reducing the amount of gaseous solvent flowing into the vacuum pump 23. A condensation coil 15 is provided to allow the gaseous solvent to undergo heat exchange in the condensation chamber 18. The condensing coil 15 is formed of a pipe through which the refrigerant flows. The refrigerant in the condensing coil 15 undergoes a phase change and a temperature drop while passing through the compressor, expansion valves 34, 36, 38, etc. (not shown in the figure), and heat exchange occurs between the refrigerant in the condensing coil 15 and the gas solvent in the condensing chamber 18, so that the gas solvent in the condensing chamber 18 is liquefied. Reference numerals 35, 37, and 39 respectively refer to electromagnetic valves provided in the refrigerant conduit, and reference numeral 40 refers to a VBS valve disposed in front of the vacuum pump 23.

[0013] A heat medium conduit is arranged to maintain or cool the shelf temperature within a predetermined range. The heat medium conduit is connected to pass through the inside and outside of the drying chamber 1, and is formed to flow the heat medium inside the shelf 3 inside the drying chamber 1. The heat medium exchanges heat with the refrigerant flowing inside the condensing coil 15 in the heat exchanger 31. The heat medium is supplied to the inside of the conduit through the heat medium supply valve 42, and a heat medium expansion tank 25 is arranged in front of the heat medium supply valve 42. Reference numeral 28 is a check valve 28 for supplying heat medium to the heat medium expansion tank side, reference numeral 27 is a pressure relief valve 27 for relieving the pressure change inside the heat medium expansion tank, and reference numeral 26 is a glass 26 arranged to observe the inside of the heat medium expansion tank 25. The heat medium flowing in the heat medium conduit is discharged to the outside through the heat medium discharge valve 29 as needed. The heat medium circulates inside the conduit through the heat medium pump 30, and the temperature of the heat medium can be adjusted by the heat medium heater 32 before entering the inside of the drying chamber 1.

[0014] After the reduced pressure drying starts, the introduction of external gas into the drying chamber 1 is cut off, and while the vacuum pump 23 is driven, the air inside the drying chamber 1 and the condensation chamber 18 is discharged, and the internal pressure thereof decreases. The heat medium circulates and maintains the shelf temperature within a specified range so that the temperature change inside the drying chamber 1 is not large. If the internal pressure of the drying chamber 1 is lower than the vapor pressure curve of the liquid solvent contained in the sample, the liquid solvent begins to evaporate. If the inside of the drying chamber 1 is maintained at a target pressure having a pressure range lower than the vapor pressure of the liquid solvent, the liquid solvent contained in the sample evaporates and the sample is dried.

[0015] Compared with freeze drying, this reduced pressure drying method can reduce the time required for drying and has the advantage of not requiring the pressure inside the chamber to be maintained at a high vacuum degree as in freeze drying.

[0016] However, the applicant has found that the conventional vacuum drying method has the following major disadvantages.

[0017] In the conventional reduced pressure drying method, in order to restore the inside of the drying chamber 1 to normal pressure after the drying is completed, only a release valve 7 for allowing external gas to flow in is provided as a device for allowing external gas to flow into the drying chamber 1. This release valve 7 is used to play the function of allowing a large amount of external gas to flow into the chamber, and its opening or flow rate cannot be precisely adjusted. That is, the conventional reduced pressure drying method does not have a device that can finely introduce external gas into the vacuum chamber 1 at the time when the vacuum pump 23 is driven and the pressure inside the drying chamber 1 decreases, that is, at the time when the reduced pressure drying starts, and does not recognize the necessity of introducing external gas into the vacuum chamber 1 during the reduced pressure drying.

[0018] However, as a result of research conducted by the present applicant, it was found that as the reduced pressure drying progresses, when the pressure inside the vacuum chamber 1 reaches near the target pressure value, the pressure inside the vacuum chamber 1, especially near the vial containing the sample, changes greatly.

[0019] Figure 4 The figure shows the pressure change inside the drying chamber 1 during the process of performing reduced pressure drying without introducing any external gas or nitrogen into the drying chamber 1. It can be seen that the pressure inside the drying chamber 1 is reduced, and after the internal pressure reaches near the target pressure, a sudden and serious pressure change occurs.

[0020] This is because, at the initial stage of decompression, the pressure inside the drying chamber 1 is still higher than the vapor pressure curve of the liquid solvent, and almost no evaporation of the liquid solvent occurs. Then, from the moment the pressure inside the drying chamber 1 reaches below the vapor pressure curve of the liquid solvent, evaporation occurs rapidly and the gas phase solvent increases sharply. When it reaches near the target pressure below the vapor pressure curve, the amount of evaporated gas phase solvent increases cumulatively. At the same time, due to the pressure of the evaporated gas phase solvent, the pressure inside the drying chamber 1 begins to change sharply.

[0021] It was found that the pressure change was not simply an increase in the pressure inside the drying chamber 1, but a repeated rise and fall, that is, it soared above the target pressure, then fell back below the target pressure, and then soared above the target pressure again.

[0022] It was found that such pressure changes prevented the internal pressure of the drying chamber from being stably maintained at the target pressure, and also had an adverse effect on the drying of the sample. Summary of the invention

[0023] Problems to be solved by the invention

[0024] The problem to be solved by the present invention is to provide a reduced pressure drying device, which improves the problem that the previous reduced pressure drying devices do not have equipment that can finely introduce external gas into the vacuum chamber at the time of starting reduced pressure drying, and can suppress the pressure change inside the drying chamber and stably maintain the target pressure.

[0025] In addition, a reduced-pressure drying method using the reduced-pressure drying device is provided.

[0026] The problems to be solved by the present invention are not limited to the aforementioned technical problems, and those skilled in the art can clearly understand other technical problems not mentioned based on the following description.

[0027] Solutions for solving problems

[0028] A reduced-pressure drying device according to an embodiment of the present invention for solving the above-mentioned problem is characterized in that, in addition to a release valve for allowing external gas to flow in to restore the internal pressure of the drying chamber to normal pressure after the previous drying is completed, a separate external gas inflow device is provided. The above-mentioned separate external gas inflow device allows external gas to flow into the drying chamber when the internal pressure of the drying chamber reaches a target pressure during the reduced-pressure drying process.

[0029] In addition, it is characterized in that the above-mentioned independent external gas inflow device can finely adjust the valve opening to adjust the inflow amount of external gas within a small range.

[0030] In addition, it is characterized in that the above-mentioned independent external gas inflow device includes an automatic vacuum regulating valve which automatically operates according to the pressure change inside the chamber.

[0031] In addition, the separate external air inflow device has a structure in which a manual valve for supplying a predetermined flow rate is arranged in parallel with the automatic vacuum regulating valve.

[0032] With respect to the reduced-pressure drying device of the present invention, if the interior of the drying chamber is reduced in pressure to reach a target pressure, the manual valve and the automatic vacuum regulating valve are opened simultaneously, and external gas flows into the interior of the drying chamber. The manual valve allows a prescribed flow rate to flow, and the flow rate flowing through the automatic vacuum regulating valve is finely adjusted, resulting in the amount of external gas flowing into the drying chamber being finely adjusted. Thus, while the amount of external gas flowing into the drying chamber is changed according to the target pressure, the amount of external gas flowing in can be adjusted according to the pressure conditions inside the drying chamber.

[0033] In addition, the reduced-pressure drying device according to an embodiment of the present invention is characterized in that it is used for drying medicines.

[0034] In addition, the reduced pressure drying apparatus according to an embodiment of the present invention is characterized in that it is particularly used for the production of botulinum toxin dry cakes.

[0035] In addition, the reduced pressure drying apparatus according to an embodiment of the present invention is characterized in that it is operated to produce a botulinum toxin dry cake under the pressure conditions of 1500 mTorr to 60000 mTorr and the temperature conditions of 3° C. to 25° C. inside the drying chamber.

[0036] In addition, the reduced pressure drying apparatus according to an embodiment of the present invention is characterized in that the drying is carried out until the moisture content of the botulinum toxin dry cake reaches less than 3%.

[0037] In addition, the reduced pressure drying method according to an embodiment of the present invention is characterized in that during the reduced pressure drying process, when the pressure inside the drying chamber reaches a target pressure, external air is allowed to flow into the drying chamber to suppress pressure changes in the drying chamber near the target pressure.

[0038] In addition, the present invention is characterized in that the separate external gas inflow device used in the above-mentioned reduced-pressure drying method can finely adjust the valve opening to adjust the inflow amount of external gas within a small range.

[0039] In addition, the method is characterized in that the independent external gas inflow device used in the reduced pressure drying method is an automatic regulating valve that automatically operates according to the pressure change inside the chamber.

[0040] In addition, it is characterized in that the above-mentioned independent external gas inflow device includes an automatic vacuum regulating valve which automatically operates according to the pressure change inside the chamber.

[0041] In addition, the separate external air inflow device has a structure in which a manual valve for supplying a predetermined flow rate is arranged in parallel with the automatic vacuum regulating valve.

[0042] In the reduced-pressure drying method of the present invention, if the interior of the drying chamber is reduced in pressure to reach a target pressure, the manual valve and the automatic vacuum regulating valve are opened simultaneously, and external gas flows into the interior of the drying chamber. The manual valve allows a specified flow rate to flow, and the flow rate flowing through the automatic vacuum regulating valve is finely adjusted. As a result, the amount of external gas flowing into the drying chamber can be finely adjusted, so that the amount of external gas flowing into the drying chamber can be changed according to the target pressure while the amount of external gas flowing into the drying chamber can be adjusted according to the pressure conditions inside the drying chamber.

[0043] In addition, the reduced-pressure drying method according to an embodiment of the present invention is characterized in that it is applicable to drying of medicines.

[0044] In addition, the reduced pressure drying method according to an embodiment of the present invention is characterized in that it is particularly used for the production of a botulinum toxin dry cake.

[0045] In addition, the reduced pressure drying method according to an embodiment of the present invention is characterized in that the pressure inside the drying chamber is 1500 to 60000 mTorr and the temperature is 3° C. to 25° C. to produce a botulinum toxin dry cake.

[0046] In addition, the reduced pressure drying method according to an embodiment of the present invention is characterized in that the method is carried out until the moisture content of the botulinum toxin dry cake reaches less than 3%.

[0047] Effects of the Invention

[0048] According to the present invention, during the reduced pressure drying process, when the pressure inside the drying chamber reaches the target pressure, the inflow of external gas is finely adjusted and the external gas is allowed to flow in, thereby preventing the pressure inside the drying chamber, especially around the vial containing the liquid sample, from rising sharply and then falling. Thus, the pressure inside the drying chamber can be stably maintained at the target pressure. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 It is a phase equilibrium diagram showing the state change of water.

[0050] Figure 2 This is a schematic diagram showing a conventional reduced-pressure drying device.

[0051] Figure 3 Schematic diagram of a reduced-pressure drying device according to an embodiment of the present invention.

[0052] Figure 4 1 is a pressure change diagram showing the pressure change inside the drying chamber of a conventional reduced-pressure drying device.

[0053] Figure 5 1 is a pressure change diagram showing a pressure change inside a drying chamber when external gas flows into the drying chamber and the pressure inside the drying chamber is controlled during a reduced pressure drying process according to an embodiment of the present invention. DETAILED DESCRIPTION

[0054] The terms or words used in this specification and claims should not be interpreted as limited to the usual meaning or dictionary meaning. According to the concept of the term or word that the inventor can define to explain the principle of the present invention in the best way, the concept of the corresponding term must be interpreted as the meaning and concept that conforms to the technical idea of ​​the present invention. In addition, the embodiments described in this specification and the structures shown in the drawings are only one embodiment of the present invention, and do not represent all the technical ideas of the present invention. Therefore, it should be understood that the present application may have a variety of equivalents and deformable and applied examples that can replace it.

[0055] The terms first, second, A, B, etc. used in this specification and claims may be used to describe a variety of components, but the above components are not limited to the above terms. The above terms are only used to distinguish one component from another component. For example, without departing from the scope of the claims of the present invention, a first component may be named a second component, and similarly, a second component may be named a first component. The term "and / or" includes a combination of multiple related recorded items or a certain item in multiple related recorded items.

[0056] The terms used in this specification and claims are used only to illustrate specific embodiments and are not intended to limit the present invention. A single expression includes multiple expressions unless the context clearly indicates a different meaning. In this application, the terms "including" or "having" should be understood as not excluding in advance the existence or additional possibility of features, numbers, steps, actions, components, parts, or combinations thereof recorded in the specification.

[0057] In this specification and claims, when it is recorded that one component is "connected" to another component, it should be understood that it includes not only the case of direct connection, but also the case of connection through other components in the middle. Only when it is recorded as "directly connected" or "directly connected", it should be understood that one component is connected to another component without other components in the middle. Similarly, other expressions describing the relationship between components should also be understood to have the same purpose.

[0058] Without other definition, all terms used herein including technical terms or scientific terms have the same meanings as commonly understood by those skilled in the art.

[0059] Commonly used terms such as pre-defined terms should be understood as having the same meaning based on the context of the relevant technology, and will not be understood as idealized or overly formalized meanings without clear definitions in this application.

[0060] In addition, the various structures, processes, techniques or methods included in the various embodiments of the present invention can be shared within the scope of not being technically contradictory.

[0061] Hereinafter, embodiments of the present invention will be described in more detail with reference to the accompanying drawings.

[0062] The structure of the reduced pressure drying device suitable for the drying method of the present invention is as follows: Figure 3 shown.

[0063] A shelf 103 on which the sample is placed is arranged inside the drying chamber 101 where the sample is placed. The shelf 103 is operated to be raised and lowered by a hydraulic cylinder 104 driven by a hydraulic unit 105, so that the height of the shelf can be adjusted. In addition, the shelf is constructed in a hollow form so that a heat medium can pass through the inside thereof. A door 102 is arranged in the drying chamber 101 so that the sample can enter and exit. The sample is usually arranged in a liquid state inside a vial. A vacuum sensor 109 for measuring the internal pressure and a temperature sensor 106 for measuring the internal temperature are arranged in the drying chamber 101. In addition, a release valve 107 for introducing external gas into the interior of the drying chamber 101 is arranged so that the internal pressure of the drying chamber 101 can be restored to normal pressure after the reduced pressure drying is completed. A capsule filter 108 for filtering impurities in the external gas can be arranged in front of the release valve 107. A vacuum gauge 118 capable of measuring the internal pressure of the external gas introduction pipeline can be arranged behind the release valve 107.

[0064] The drying chamber 101 is connected to the condensation chamber through the isolation valve 111. A vacuum pump 123 is provided in the condensation chamber. If the vacuum pump 123 is driven, the air inside the condensation chamber and the drying chamber 101 is discharged, and the pressure inside the condensation chamber and the drying chamber 101 decreases. The condensation chamber plays a role of a cold trap. That is, after a large amount of gaseous solvent evaporated from the drying chamber 101 flows into the vacuum pump 123, it can induce the performance of the vacuum pump 123 to decrease, so that the gaseous solvent evaporated from the drying chamber 101 can be discharged through the exhaust valve 121 after heat exchange and condensation in the condensation chamber, thereby reducing the amount of gaseous solvent flowing into the vacuum pump 123. A condensation coil 116 is configured to allow the gaseous solvent to undergo heat exchange in the condensation chamber. The condensing coil 116 is formed of a pipe for the refrigerant to flow. When passing through the compressor, expansion valves 134, 136, etc., which are not shown in the figure, the refrigerant in the condensing coil 116 undergoes a phase change and a temperature drop, and heat exchange occurs between the refrigerant in the condensing coil 116 and the gas solvent in the condensing chamber, and the gas solvent in the condensing chamber is liquefied. Reference numeral 137 refers to a solenoid valve provided in the refrigerant conduit, reference numeral 122 refers to a VBS valve arranged in front of the vacuum pump 23, and reference numeral 124 is an oil mist filter for filtering oil contained in the gas exhausted from the vacuum pump 123.

[0065] A heat medium conduit is configured to maintain or cool the temperature of the shelf 103 within a specified range. The heat medium conduit is connected to pass through the inside and outside of the drying chamber 101, and is formed to allow the heat medium to flow inside the shelf 103 inside the drying chamber 101. The heat medium exchanges heat with the refrigerant flowing inside the condensing coil 116 in the heat exchanger 133. The heat medium is supplied to the inside of the conduit through the heat medium supply valve 125, and a heat medium expansion tank 126 is configured in front of the heat medium supply valve 125. Reference numeral 129 is a check valve for supplying heat medium to the heat medium expansion tank side, reference numeral 128 is a pressure relief valve for relieving pressure changes inside the heat medium expansion tank, and reference numeral 127 is a glass configured to observe the inside of the heat medium expansion tank 126. The heat medium flowing in the heat medium conduit is discharged to the outside through the heat medium discharge valve 130 as needed. The heat medium circulates inside the conduit through the heat medium pump 131 , and the temperature of the heat medium may be adjusted by the heat medium heater 132 before entering the drying chamber 101 .

[0066] After the reduced pressure drying starts, the introduction of external gas into the drying chamber 101 is cut off, and while the vacuum pump 123 is driven, the air inside the drying chamber 101 and the condensation chamber is discharged, and the internal pressure thereof decreases. The heat medium circulates and maintains the shelf temperature within a specified range so that the temperature inside the drying chamber 101 does not change much. If the internal pressure of the drying chamber 101 is lower than the vapor pressure curve of the liquid solvent contained in the sample, the liquid solvent begins to evaporate. If the inside of the drying chamber 101 is maintained at a target pressure having a pressure range lower than the vapor pressure of the liquid solvent, the sample is dried while the liquid solvent contained in the sample evaporates.

[0067] As the drying chamber 101 approaches the target pressure, the amount of evaporated liquid solvent increases. Therefore, pressure caused by the evaporated liquid solvent occurs in the drying chamber 101. The greater the amount of liquid solvent, the greater the pressure change in the drying chamber 101 caused by the evaporated liquid solvent. At the moment when the target pressure is reached and the amount of evaporated liquid solvent is maximized, there is a hidden danger that the pressure inside the drying chamber 101, especially near the vial containing the sample placed on the shelf 103, will rise sharply and then drop.

[0068] In the reduced pressure drying apparatus according to an embodiment of the present invention, when the internal pressure of the drying chamber 101 reaches near the target pressure, the separate external air inflow device for flowing external air into the drying chamber 101 is opened in conjunction with the internal pressure of the drying chamber 101 .

[0069] The above-mentioned separate external gas inflow device is composed of a manual valve 114 and an automatic vacuum regulating valve 113 configured in parallel, wherein the above-mentioned manual valve 114 is configured to allow a specified flow rate to flow in, and the above-mentioned automatic vacuum regulating valve 113 is configured to finely adjust the inflow flow rate according to the internal pressure conditions of the chamber.

[0070] The separate external gas inflow device can be arranged in a bypass form at the release valve 107, which is conventionally arranged to restore the internal pressure of the drying chamber 101 to normal pressure after the reduced pressure drying is completed. In this way, in addition to the bypassed portion of the pipeline for introducing external gas, the pipeline of the conventional release pipeline can be used, which has an advantage in space utilization. Of course, the separate external gas inflow device can be optionally arranged separately at a position separated from the release valve 107.

[0071] The conventional release valve 107 is used not for finely adjusting the internal pressure of the drying chamber 1, but for restoring the internal pressure of the drying chamber 1 maintained at a low pressure to normal pressure during the reduced pressure drying process. Therefore, it only allows a large amount of external gas to be temporarily introduced, and there is no need to finely adjust the inflow rate of the introduced external gas.

[0072] In comparison, the above-mentioned separate external gas inflow device of the present invention is not used to restore the internal pressure of the drying chamber 101 to normal pressure, but is used to allow external gas to flow in finely during the process of reduced pressure drying to finely control the pressure inside the drying chamber. Therefore, the inflow amount of external gas is smaller than that of the release valve 107, and the inflow amount of external gas can be adjusted within a small range.

[0073] Preferably, the separate external air inflow device of the present invention is implemented to automatically operate in conjunction with the internal pressure of the drying chamber 101 .

[0074] According to a preferred embodiment, if the interior of the drying chamber 101 is depressurized to reach the target pressure, the automatic vacuum regulating valve 113 is opened, and while external air flows in, the on-off switch 115 is switched on, and external air also flows into the manual valve 114 side.

[0075] The manual valve 114 can be set to allow a predetermined flow rate to flow through the inside thereof, and to allow the amount of external gas flowing in to be greater than that of the automatic vacuum regulating valve 113. When the amount of external gas that needs to flow into the drying chamber 101 is large, it is often difficult to ensure the amount of external gas flowing in only through the automatic vacuum regulating valve 113, and thus a considerable amount of the external gas that needs to flow into the drying chamber 101 can be ensured through the manual valve 114.

[0076] The automatic vacuum regulating valve 113 can finely adjust the amount of external gas flowing in according to the pressure condition inside the drying chamber 101. Therefore, by adjusting the opening of the automatic vacuum regulating valve 113, the pressure condition inside the drying chamber 101 can be maintained at an optimal condition.

[0077] Therefore, in a preferred embodiment of the present invention, if the interior of the drying chamber 101 is depressurized to reach a target pressure, the automatic vacuum regulating valve 113 is opened, and while external gas flows in, the on-off switch 115 is switched to on, and at the same time, external gas also flows into the manual valve 114 side. Then, the opening of the automatic vacuum regulating valve 113 can be adjusted to adjust the amount of external gas flowing into the drying chamber 101 as a whole.

[0078] Figure 4 is a pressure change diagram showing the pressure change inside the drying chamber of a conventional reduced pressure drying device. Figure 5 1 is a pressure change diagram showing a pressure change inside a drying chamber when external gas flows into the drying chamber and the pressure inside the drying chamber is controlled during a reduced pressure drying process according to an embodiment of the present invention.

[0079] from Figure 4 It can be seen that if the internal pressure of the drying chamber 101 reaches near the target pressure, the pressure rises and falls rapidly within the predetermined period of time. It can also be seen that the pressure drop reaches a range below the target pressure. In reduced pressure drying, the evaporation amount depends on the pressure conditions. If the internal pressure of the drying chamber rises or falls sharply, it will also have a great impact on the evaporation of the liquid solvent.

[0080] pass Figure 5 It can be confirmed that, in comparison, when the pressure inside the drying chamber reaches near the target pressure using the reduced-pressure drying device of the present invention, when the automatic vacuum regulating valve 113 is operated to allow a small amount of external gas to flow in, even when the pressure inside the drying chamber reaches near the target pressure, there is no sharp rise or fall in pressure, but the target pressure is stably maintained. Figure 5 The portion indicated by the wavy lines in FIG. 1 represents the maximum pressure increase value and pressure drop value occurring near the target pressure when the external gas inflow device alone is not operated.

[0081] Therefore, it can be confirmed from the experiment that according to the present invention, during the reduced pressure drying process, when the internal pressure of the drying chamber reaches near the target pressure, by finely adjusting the inflow of external gas and allowing the external gas to flow in, the phenomenon of the pressure inside the drying chamber, especially around the vial containing the liquid sample, rising sharply and then falling can be prevented, and the pressure inside the drying chamber can be stably maintained at the target pressure.

[0082] The present invention is particularly effective in the drying process of medicines whose properties are easily changed by heat.

[0083] The present invention is particularly effective in the drying process of botulinum toxin, which may be damaged due to local formation of ice nuclei or uneven excipient concentration during the freeze-drying process, resulting in reduced activity, and which may be damaged due to boiling of liquid solvents during the reduced pressure drying process.

[0084] Next, the vacuum drying process applicable to the drying process of botulinum toxin is described. This has been described in detail in the 2021 patent application No. 155208 filed and authorized by the applicant of the present application on November 11, 2011, and the PCT application filed by the applicant as a priority. It is summarized as follows.

[0085] In the past, botulinum toxin was generally dried by freeze-drying process. However, as described above, the freeze-drying process must be accompanied by a freezing process and the water is removed by a gasification process, which takes a long time (about 18 to 48 hours) and may cause problems such as ice nucleation or uneven excipient concentration.

[0086] Therefore, the applicant has made great efforts to develop an optimized method for reducing pressure and drying botulinum toxin that maintains effectiveness and stability. As a result, it has been found that by effectively adjusting parameters related to the drying process, such as pressure and temperature, botulinum toxin, which is a protein, can be protected from external stimuli occurring during the process, thereby greatly shortening the drying time.

[0087] Specifically, it was found that it is preferable to perform reduced pressure drying under pressure conditions of 1500 mTorr to 60000 mTorr and temperature conditions of 3°C to 25°C.

[0088] More specifically, the reduced pressure drying may be performed at 1500 to 60000 mTorr, 1500 to 55000 mTorr, 1500 to 50000 mTorr, 1500 to 45000 mTorr, 1500 to 40000 mTorr, 1500 to 35000 mTorr, 1500 to 30000 mTorr, 1500 to 25000 mTorr, 1500 to 20000 mTorr, 1500 to 15000 mTorr, 1500 to 14000 mTorr, 1500 to 16000 mTorr, 1600 to 18000 mTorr, 1600 to 19000 mTorr, 1600 to 20 ... to 13000 mTorr, 1500 to 12000 mTorr, 1500 to 11000 mTorr, 1500 to 10000 mTorr, 1500 to 9000 mTorr, 1500 to 8000 mTorr, 1500 to 7000 mTorr, 1500 to 6000 mTorr, 1500 to 5000 mTorr, 1500 to 4000 mTorr, 1500 to 3500 mTorr, 1500 to 3000 mTorr, 1500 to 2500 mTorr, 1500 0 to 2000 mTorr, 2500 to 3000 mTorr, 2500 to 3500 mTorr, 2500 to 4000 mTorr, 2500 to 4500 mTorr, 2500 to 5000 mTorr, 2500 to 6000 mTorr, 2500 to 7000 mTorr, 2500 to 8000 mTorr, 2500 to 9000 mTorr, 2500 to 10000 mTorr, 2500 to 11000 mTorr, 2500 to 12000 mTorr, 250 The method is carried out at a pressure of 0 to 13000 mTorr, 2500 to 14000 mTorr, 2500 to 15000 mTorr, 2500 to 20000 mTorr, 2500 to 25000 mTorr, 2500 to 30000 mTorr, 2500 to 35000 mTorr, 2500 to 40000 mTorr, 2500 to 45000 mTorr, 2500 to 50000 mTorr, 2500 to 55000 mTorr or 2500 to 60000 mTorr.

[0089] More specifically, the reduced pressure drying may be performed at 3000 to 3500 mTorr, 3000 to 4000 mTorr, 3000 to 4500 mTorr, 3000 to 5000 mTorr, 3000 to 6000 mTorr, 3000 to 7000 mTorr, 3000 to 8000 mTorr, 3000 to 9000 mTorr, 3000 to 10000 mTorr, 3000 to 11000 mTorr, 3000 to 12000 mTorr, 3000 to 13000 mTorr, 3000 to 14000 mTorr, 3000 to 15000 mTorr, 3000 to 16000 mTorr, 3000 to 17000 mTorr, 3000 to 18000 mTorr, 3000 to 19000 mTorr, 3000 to 20000 mTorr, 3000 to 21000 mTorr, 3000 to 22000 mTorr, 3000 to 23000 mTorr, 3000 to 24000 mTorr, 3000 to 25000 mTorr, 3000 to 3000 The present invention is carried out at a pressure of 3,000 mTorr, 3,000 to 14,000 mTorr, 3,000 to 15,000 mTorr, 3,000 to 20,000 mTorr, 3,000 to 25,000 mTorr, 3,000 to 30,000 mTorr, 3,000 to 35,000 mTorr, 3,000 to 40,000 mTorr, 3,000 to 45,000 mTorr, 3,000 to 50,000 mTorr, 3,000 to 55,000 mTorr or 3,000 to 60,000 mTorr.

[0090] When the above range is exceeded, there is a problem that protein damage may occur due to phenomena such as boiling over, and a perfect dried product cannot be obtained due to insufficient drying.

[0091] More specifically, drying under reduced pressure can be carried out at a temperature of 3°C to 25°C, 5°C to 25°C, 7°C to 25°C, 9°C to 25°C, 11°C to 25°C, 12°C to 25°C, 3°C to 20°C, 5°C to 20°C, 7°C to 20°C, 9°C to 20°C, 11°C to 20°C, 12°C to 20°C, 3°C to 18°C, 3°C to 16°C, 3°C to 14°C or 3°C to 12°C.

[0092] When the temperature exceeds the above range, the structural instability of the botulinum toxin may increase or physical damage and deformation may occur due to high or low temperature, which may lead to a decrease in efficacy.

[0093] Furthermore, the reduced pressure drying may be performed until the moisture content of the botulinum toxin dry cake reaches 3% or less.

[0094] Alternatively, the botulinum toxin may be produced by drying under reduced pressure for 0.5 hours or longer, or for 0.5 hours to 4 hours.

[0095] Specifically, it can be performed in the range of 0.5 hour to 4 hours, 0.5 hour to 3 hours, 0.5 hour to 2 hours, 0.5 hour to 1 hour, 1 hour to 4 hours, 2 hours to 4 hours, or 3 hours to 4 hours.

[0096] On the other hand, in such reduced-pressure drying process, it is necessary to reach the target pressure in a stable and controlled state under normal pressure as a normal atmospheric condition.

[0097] The present application is proposed to solve the need to control the pressure to be maintained near the target pressure without sudden changes when the reduced pressure drying starts and the internal pressure of the drying chamber is reduced from normal pressure to the target pressure.

[0098] According to the present invention, during the reduced pressure drying process, when the pressure inside the drying chamber reaches near the target pressure, by finely adjusting the inflow of external gas and allowing the external gas to flow in, the phenomenon of the pressure inside the drying chamber, especially around the vial containing the liquid sample, rising sharply and then falling can be prevented. Thus, the pressure inside the drying chamber can be stably maintained at the target pressure. This can prevent the local generation of ice nuclei in the sample or the boiling of the liquid solvent, which may cause damage to the sample.

[0099] Description of Reference Numerals

[0100] 101: Drying chamber

[0101] 102: Door

[0102] 103: Shelf

[0103] 104: Hydraulic cylinder

[0104] 105: Hydraulic unit

[0105] 106: Temperature sensor

[0106] 107: Release valve

[0107] 108: Capsule filter

[0108] 109: Vacuum sensor

[0109] 111: Isolation valve

[0110] 112: Bellows

[0111] 113: Automatic vacuum regulating valve

[0112] 114: Manual valve

[0113] 115: On / off switch

[0114] 116: Condensing coil

[0115] 117: Temperature sensor

[0116] 120: Door

[0117] 121: Discharge valve

[0118] 122: VBS valve

[0119] 123: Vacuum pump

[0120] 124: Oil mist filter

[0121] 125: Heat medium supply valve

[0122] 126: Heat medium expansion tank

[0123] 127: Glass

[0124] 128: Pressure relief valve

[0125] 129: Check valve

[0126] 130: Thermal medium discharge valve

[0127] 131: Thermal medium pump

[0128] 132: Thermal medium heater

[0129] 133: Heat exchanger

[0130] 134: Expansion valve

[0131] 136: Expansion valve

[0132] 137: Solenoid valve.

Claims

1. A vacuum drying device, characterized in that: A separate external gas inflow device is provided for causing external gas to flow into the drying chamber when the pressure inside the drying chamber reaches near a target pressure during the reduced-pressure drying process.

2. The reduced pressure drying device according to claim 1, characterized in that: The separate external gas inflow device automatically operates when the pressure inside the drying chamber reaches a target pressure.

3. The reduced pressure drying device according to claim 1 or 2, characterized in that: The separate external gas inflow device includes an automatic vacuum regulating valve capable of finely adjusting the valve opening to adjust the inflow amount of external gas within a micro range.

4. The vacuum drying device according to any one of claims 1 to 3, characterized in that: In the separate external gas inflow device, a manual valve set to flow a specified flow rate is arranged in parallel with the automatic vacuum regulating valve. If the pressure inside the drying chamber reaches the target pressure, the manual valve and the automatic vacuum regulating valve are opened at the same time, and the external gas flows into the drying chamber. Thereafter, the flow rate of the inflowing external gas is regulated by the automatic vacuum regulating valve, thereby being able to regulate the entire flow rate of the external gas flowing into the drying chamber.

5. The vacuum drying device according to any one of claims 1 to 4, characterized in that: The flow rate of the manual valve is greater than the flow rate of the automatic vacuum regulating valve.

6. The vacuum drying device according to any one of claims 1 to 5, characterized in that: The reduced pressure drying device is used for manufacturing medicines.

7. The reduced pressure drying device according to any one of claims 1 to 6, characterized in that: The reduced pressure drying device is used for producing a botulinum toxin dry cake.

8. The vacuum drying device according to any one of claims 1 to 7, characterized in that: The reduced pressure drying device is 1500 to 60000 mTorr, 1500 to 55000 mTorr, 1500 to 50000 mTorr, 1500 to 45000 mTorr, 1500 to 40000 mTorr, 1500 to 35000 mTorr, 1500 to 30000 mTorr, 1500 to 25000 mTorr, 1500 to 20000 mTorr, 1500 to 15000 mTorr, 1500 to 14000 mTorr, 1500 to 1 3000 mTorr, 1500 to 12000 mTorr, 1500 to 11000 mTorr, 1500 to 10000 mTorr, 1500 to 9000 mTorr, 1500 to 8000 mTorr, 1500 to 7000 mTorr, 1500 to 6000 mTorr, 1500 to 5000 mTorr, 1500 to 4000 mTorr, 1500 to 3500 mTorr, 1500 to 3000 mTorr, 1500 to 2500 mTorr, 1500 to 2 000 mTorr, 2500 to 3000 mTorr, 2500 to 3500 mTorr, 2500 to 4000 mTorr, 2500 to 4500 mTorr, 2500 to 5000 mTorr, 2500 to 6000 mTorr, 2500 to 7000 mTorr, 2500 to 8000 mTorr, 2500 to 9000 mTorr, 2500 to 10000 mTorr, 2500 to 11000 mTorr, 2500 to 12000 mTorr, 2500 to 13 The reduced pressure drying is carried out under a pressure condition of 2,000 to 14,000 mTorr, 2,500 to 15,000 mTorr, 2,500 to 20,000 mTorr, 2,500 to 25,000 mTorr, 2,500 to 30,000 mTorr, 2,500 to 35,000 mTorr, 2,500 to 40,000 mTorr, 2,500 to 45,000 mTorr, 2,500 to 50,000 mTorr, 2,500 to 55,000 mTorr or 2,500 to 60,000 mTorr.

9. The reduced pressure drying device according to any one of claims 1 to 8, characterized in that: The reduced pressure drying device is 3000 to 3500 mTorr, 3000 to 4000 mTorr, 3000 to 4500 mTorr, 3000 to 5000 mTorr, 3000 to 6000 mTorr, 3000 to 7000 mTorr, 3000 to 8000 mTorr, 3000 to 9000 mTorr, 3000 to 10000 mTorr, 3000 to 11000 mTorr, 3000 to 12000 mTorr, 3000 to 13000 mTorr. , 3000 to 14000 mTorr, 3000 to 15000 mTorr, 3000 to 20000 mTorr, 3000 to 25000 mTorr, 3000 to 30000 mTorr, 3000 to 35000 mTorr, 3000 to 40000 mTorr, 3000 to 45000 mTorr, 3000 to 50000 mTorr, 3000 to 55000 mTorr or 3000 to 60000 mTorr.

10. The vacuum drying device according to any one of claims 1 to 9, characterized in that: The reduced pressure drying device performs reduced pressure drying under a temperature condition of 3°C to 25°C, 5°C to 25°C, 7°C to 25°C, 9°C to 25°C, 11°C to 25°C, 12°C to 25°C, 3°C to 20°C, 5°C to 20°C, 7°C to 20°C, 9°C to 20°C, 11°C to 20°C, 12°C to 20°C, 3°C to 18°C, 3°C to 16°C, 3°C to 14°C or 3°C to 12°C.

11. The vacuum drying device according to any one of claims 1 to 10, characterized in that: The reduced pressure drying device performs reduced pressure drying in the range of more than 0.5 hours, 0.5 hours to 4 hours, 0.5 hours to 3 hours, 0.5 hours to 2 hours, 0.5 hours to 1 hour, 1 hour to 4 hours, 2 hours to 4 hours or 3 hours to 4 hours.

12. The vacuum drying device according to any one of claims 1 to 11, characterized in that: The reduced pressure drying in the reduced pressure drying device is performed until the moisture content of the botulinum toxin dry cake reaches less than 3%.

13. A reduced pressure drying method, characterized in that: A separate external gas inflow device is provided, which allows external gas to flow into the drying chamber when the pressure inside the drying chamber reaches near the target pressure during the reduced pressure drying process. Thus, during the reduced pressure drying process, when the pressure inside the drying chamber reaches near the target pressure, external gas is flowed into the drying chamber to adjust the pressure inside the drying chamber.

14. The reduced pressure drying method according to claim 13, characterized in that: The separate external gas inflow device automatically operates when the pressure inside the drying chamber reaches a target pressure.

15. The reduced pressure drying method according to claim 13 or 14, characterized in that: The separate external gas inflow device includes an automatic vacuum regulating valve capable of finely adjusting a valve opening to adjust an inflow amount of external gas within a micro range.

16. The reduced pressure drying method according to any one of claims 13 to 15, characterized in that: In the separate external gas inflow device, a manual valve set to flow a specified flow rate is arranged in parallel with the automatic vacuum regulating valve. If the pressure inside the drying chamber reaches the target pressure, the manual valve and the automatic vacuum regulating valve are opened at the same time, and the external gas flows into the drying chamber. Thereafter, the flow rate of the inflowing external gas is regulated by the automatic vacuum regulating valve, thereby being able to regulate the entire flow rate of the external gas flowing into the drying chamber.

17. The reduced pressure drying method according to any one of claims 13 to 16, characterized in that: The flow rate of the manual valve is greater than the flow rate of the automatic vacuum regulating valve.

18. The reduced pressure drying method according to any one of claims 13 to 17, characterized in that: The reduced-pressure drying method is used for the manufacture of medicines.

19. The reduced pressure drying method according to any one of claims 13 to 18, characterized in that: The reduced pressure drying method is used for the preparation of botulinum toxin dry cake.

20. The reduced pressure drying method according to any one of claims 13 to 19, characterized in that: The reduced pressure drying method is carried out at a pressure of 1500 to 60000 mTorr, 1500 to 55000 mTorr, 1500 to 50000 mTorr, 1500 to 45000 mTorr, 1500 to 40000 mTorr, 1500 to 35000 mTorr, 1500 to 30000 mTorr, 1500 to 25000 mTorr, 1500 to 20000 mTorr, 1500 to 15000 mTorr, 1500 to 14000 mTorr, 1500 to 1 3000 mTorr, 1500 to 12000 mTorr, 1500 to 11000 mTorr, 1500 to 10000 mTorr, 1500 to 9000 mTorr, 1500 to 8000 mTorr, 1500 to 7000 mTorr, 1500 to 6000 mTorr, 1500 to 5000 mTorr, 1500 to 4000 mTorr, 1500 to 3500 mTorr, 1500 to 3000 mTorr, 1500 to 2500 mTorr, 1500 to 2 000 mTorr, 2500 to 3000 mTorr, 2500 to 3500 mTorr, 2500 to 4000 mTorr, 2500 to 4500 mTorr, 2500 to 5000 mTorr, 2500 to 6000 mTorr, 2500 to 7000 mTorr, 2500 to 8000 mTorr, 2500 to 9000 mTorr, 2500 to 10000 mTorr, 2500 to 11000 mTorr, 2500 to 12000 mTorr, 2500 to 13 The reduced pressure drying is carried out under a pressure condition of 2,000 to 14,000 mTorr, 2,500 to 15,000 mTorr, 2,500 to 20,000 mTorr, 2,500 to 25,000 mTorr, 2,500 to 30,000 mTorr, 2,500 to 35,000 mTorr, 2,500 to 40,000 mTorr, 2,500 to 45,000 mTorr, 2,500 to 50,000 mTorr, 2,500 to 55,000 mTorr or 2,500 to 60,000 mTorr.

21. The reduced pressure drying method according to any one of claims 13 to 20, characterized in that: The reduced pressure drying method is carried out at 3000 to 3500 mTorr, 3000 to 4000 mTorr, 3000 to 4500 mTorr, 3000 to 5000 mTorr, 3000 to 6000 mTorr, 3000 to 7000 mTorr, 3000 to 8000 mTorr, 3000 to 9000 mTorr, 3000 to 10000 mTorr, 3000 to 11000 mTorr, 3000 to 12000 mTorr, 3000 to 13000 mTorr. , 3000 to 14000 mTorr, 3000 to 15000 mTorr, 3000 to 20000 mTorr, 3000 to 25000 mTorr, 3000 to 30000 mTorr, 3000 to 35000 mTorr, 3000 to 40000 mTorr, 3000 to 45000 mTorr, 3000 to 50000 mTorr, 3000 to 55000 mTorr or 3000 to 60000 mTorr.

22. The reduced pressure drying method according to any one of claims 13 to 21, characterized in that: The reduced pressure drying method is carried out under reduced pressure drying at a temperature of 3°C to 25°C, 5°C to 25°C, 7°C to 25°C, 9°C to 25°C, 11°C to 25°C, 12°C to 25°C, 3°C to 20°C, 5°C to 20°C, 7°C to 20°C, 9°C to 20°C, 11°C to 20°C, 12°C to 20°C, 3°C to 18°C, 3°C to 16°C, 3°C to 14°C or 3°C to 12°C.

23. The reduced pressure drying method according to any one of claims 13 to 22, characterized in that: The reduced pressure drying method performs reduced pressure drying in the range of more than 0.5 hours, 0.5 hours to 4 hours, 0.5 hours to 3 hours, 0.5 hours to 2 hours, 0.5 hours to 1 hour, 1 hour to 4 hours, 2 hours to 4 hours or 3 hours to 4 hours.

24. The reduced pressure drying method according to any one of claims 13 to 23, characterized in that: The reduced pressure drying in the reduced pressure drying method is carried out until the moisture content of the botulinum toxin dry cake reaches less than 3%.

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