JP2018104388A - Lyophilized formulation production method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To achieve a lyophilized formulation production method in which the process window for preliminary freezing is wider than conventional lyophilization techniques and which can carry out successful pre-freezing.SOLUTION: The method comprises a pre-freezing step of freezing a sample containing a pharmaceutical agent, and a dehydration step of dehydrating the frozen sample under reduced pressure. The pre-freezing step comprises a first freezing step of cooling the sample to a target temperature while applying an electric field, and a second cooling step of cooling and freezing the sample after the first cooling step without applying an electric field.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a lyophilized preparation.

  Conventionally, a method of freeze-drying a medicine has been used as a technique for stably holding the medicine. The drug (freeze-dried preparation) obtained by freeze-drying has advantages such as little change in the structure of the substance, good shape retention and good reconstitution. In addition, the lyophilized preparation has an advantage that it can be stored for a long period of time as compared with a liquid preparation. Specifically, lyophilized formulations can remain stable for 2-3 years under proper storage. In contrast, a solution of the same component is only 2-3 days stable. The freeze-dried preparation can be stored at room temperature.

  For example, a method for preparing a freeze-dried antibody preparation by lyophilization from a liquid preparation such as trastuzumab (anti-HER2 antibody) has been disclosed (Patent Document 1 and Patent Document 2).

  Freeze-drying is usually performed by the following procedures: (i) preliminary freezing, (ii) primary drying, and (iii) secondary drying. First, in preliminary freezing, a dissolved drug is filled in a final package such as a vial, a syringe, or a cartridge, and frozen at a low temperature (for example, −60 ° C.). Next, in primary drying, free water is sublimated and removed from the pre-frozen product under reduced pressure. This gives a porous, dry “lyo cake”. In the final secondary drying, the bound water remaining after the primary drying is sublimated and removed from the freeze-dried cake. Depending on the type of drug and the route of the drug delivery system, lyophilization usually takes about 2 days (Non-patent Document 1).

  Among the processes of the freeze-drying method described above, preliminary freezing is an important pretreatment step that determines the success or failure of freeze-drying. If pre-freezing is not performed successfully, moisture will remain in the lyophilizate and the storage stability of the lyophilizate will not be ensured, resulting in poor appearance of the lyophilizate, solubility of the lyophilizate in physiological saline This causes problems such as damage.

  Therefore, in the conventional freeze-drying technique, in order to perform pre-freezing successfully, an accurate temperature gradient called “annealing cycle” is measured for each object to be dried. The process is strictly controlled.

JP 2013-224305 (announced October 31, 2013) Special table 2014-515763 (announced July 3, 2014)

Vetter Pharma homepage [Search December 12, 2016], Internet <https://www.vetter-pharma.com/en/8meu45/u0fvde>

  However, with the conventional freeze-drying technique, the process window for pre-freezing is very narrow, and the profile differs for each freeze-dried sample, so it is not easy to find the optimal pre-freeze conditions for each freeze-dried sample. . Furthermore, since the optimum pre-freezing condition is the pinpoint in the conventional freeze-drying technique, there is a problem that it is not easy to strictly manage the process during the pre-freezing.

  An object of one aspect of the present invention is to realize a method for producing a freeze-dried preparation that has a wider pre-freezing process window than conventional freeze-drying techniques and can be successfully pre-freezed.

  In order to solve the above problems, a method for producing a lyophilized preparation according to one aspect of the present invention is a method for producing a lyophilized preparation of a pharmaceutical product, wherein a pre-freezing step of freezing a sample containing the pharmaceutical product And a drying step of drying the frozen sample under reduced pressure, wherein the preliminary freezing step includes a first cooling step of cooling the sample until the product temperature reaches a target temperature while applying an electric field; And a second cooling step in which the sample after the first cooling step is cooled and frozen without applying an electric field.

  The method for producing a lyophilized product according to one embodiment of the present invention is a method for producing a lyophilized product of one or more substances selected from the group consisting of a high molecular compound, a low molecular compound, and a biological substance. A pre-freezing step of freezing a sample solution containing one or more substances selected from the group consisting of the high molecular compounds, low molecular compounds and biological substances, and the frozen sample solutions The preliminary freezing step includes a first cooling step for cooling the sample solution until the product temperature reaches a target temperature while applying an electric field, and a step after the first cooling step. And a second cooling step in which the sample solution is cooled and frozen without applying an electric field.

  According to the method for producing a lyophilized preparation according to one aspect of the present invention, in the preliminary freezing step, the first cooling step is performed in which the sample is cooled until the product temperature reaches the target temperature while applying an electric field. The sample can be cooled to the target temperature while maintaining the supercooled state. For this reason, it is possible to prevent the formation of ice nuclei in the ice crystal generation temperature range (0 ° C. to −5 ° C.), and it is possible to prevent the formation of giant ice crystals in the sample. As a result, according to the method for producing a lyophilized preparation according to one aspect of the present invention, there is no possibility that giant ice crystals are formed in the sample in the preliminary freezing step. The window can be widened. Therefore, according to the manufacturing method of the freeze-dried preparation which concerns on 1 aspect of this invention, there exists an effect that process management of preliminary freezing becomes easier than the conventional freeze-drying technique.

  Moreover, the same effect as the manufacturing method of the freeze-dried preparation which concerns on 1 aspect of this invention is acquired also about the manufacturing method of the freeze-dried material which concerns on 1 aspect of this invention.

It is a figure which shows the process window of the time in each temperature until the product temperature of a sample reaches 0 degreeC in preliminary freezing, and the process window in the manufacturing method of the lyophilized formulation which concerns on one Embodiment of this invention, and the conventional It is a figure which shows the process window in the freeze-drying method.

  Hereinafter, embodiments of the present invention will be described in detail. Unless otherwise specified in this specification, “A to B” indicating a numerical range means “A or more and B or less”.

[1. (Production method of freeze-dried preparation)
The manufacturing method of the freeze-dried formulation which concerns on 1 aspect of this invention is related with the method of freeze-drying a pharmaceutical and manufacturing a freeze-dried formulation.

  Below, each process of the manufacturing method of the freeze-dried formulation which concerns on 1 aspect of this invention is demonstrated.

(1. Pre-freezing process)
The preliminary freezing step is a step of freezing a sample containing a pharmaceutical product (hereinafter simply referred to as “sample”). In the method for producing a lyophilized preparation according to one aspect of the present invention, the preliminary freezing step includes two sub-steps of a first cooling step and a second cooling step.

  The first cooling step is a step of cooling the sample until the product temperature reaches the target temperature while applying an electric field. The second cooling step is a step of cooling and freezing the sample after the first cooling step without applying an electric field.

  In the method for producing a lyophilized preparation according to one embodiment of the present invention, in the first cooling step, the sample is cooled while an electric field is applied until the product temperature of the sample reaches the target temperature. As a result, the sample can be cooled to the target temperature while maintaining the supercooled state of the sample. Supercooling refers to a state in which the state of a phase change of a substance does not change even at a temperature that should be changed. In the first cooling step, even if water molecules in the sample become below the freezing point temperature (0 ° C.), they remain in a liquid state without being crystallized. For this reason, the sample can be cooled to the target temperature while preventing ice nucleation in the ice crystal generation temperature zone (0 ° C. to −5 ° C.). As a result, the formation of giant ice crystals in the sample can be prevented.

  Here, the “target temperature” is not particularly limited as long as it is lower than −5 ° C., and can be appropriately set according to the purpose. For example, the “target temperature” is usually −80 ° C. to −10 ° C., more preferably −70 ° C. to −20 ° C. If the target temperature is −80 ° C. or higher, damage to various containers can be minimized. Moreover, if the target temperature is −10 ° C. or lower, the risk of melting in the second cooling step can be reduced, and a uniform frozen state can be achieved.

  FIG. 1 is a diagram showing a process window of time at each temperature until the sample temperature reaches a target temperature from 0 ° C. in preliminary freezing, in the method for producing a lyophilized preparation according to one embodiment of the present invention. It is a figure which shows the process window in a process window and the conventional freeze-drying method. As shown in FIG. 1, in the preliminary freezing in the conventional freeze-drying method, it is necessary to rapidly cool the sample to a target temperature in order to prevent the formation of giant ice crystals. For example, in the conventional freeze-drying technique, the sample is cooled to the target temperature at a plate cooling rate of 1 ° C./min. For this reason, the process window of the time at each temperature until the sample temperature reaches the target temperature from 0 ° C. is narrow, and the same depending on the volume of the solution to be lyophilized and the design of the shelf in the lyophilizer. There is a risk of uneven temperature even between lots. In contrast, in the method for producing a lyophilized preparation according to one aspect of the present invention, in the first cooling step, the sample is cooled while applying an electric field until the sample temperature reaches the target temperature. As described above, the sample can be cooled to the target temperature in the liquid state without being crystallized. As a result, as shown in FIG. 1, in the method for producing a lyophilized preparation according to one embodiment of the present invention, it is possible to widen the process window for preliminary freezing as compared with the conventional lyophilization method.

  Next, after the sample temperature reaches the target temperature in the first cooling step, the application of the electric field to the sample is stopped, and the process proceeds to the second cooling step. In the second cooling step, when the application of the electric field is stopped, the sample is rapidly frozen. The ice crystals formed at this time have a small particle size.

  Thus, in the method for producing a lyophilized preparation according to one aspect of the present invention, since the preliminary freezing step includes the first cooling step and the second cooling step, fine ice crystals can be formed. . As a result, it is possible to prevent the pharmaceutical ingredient from being damaged by the formation of giant ice crystals in the preliminary freezing step.

  In the preliminary freezing step, the first cooling step and the second cooling step may be repeated. For example, the sample temperature may rise to −5 ° C. or higher during the second cooling step. This is because the temperature of unfreezing water in the sample rises to the freezing point temperature (0 ° C.) by stopping the application of the electric field. In such a case, it is preferable to cool the sample until the product temperature of the sample reaches the target temperature while reapplying the electric field to the sample. As a result, the unfrozen water becomes supercooled again and is cooled to the target temperature, thereby preventing the ice crystals formed during the second cooling step from becoming coarse. After the sample temperature reaches the target temperature again, the application of the electric field to the sample may be stopped and the process may proceed to the second cooling step again. Thus, in the preliminary freezing step, by repeating the first cooling step and the second cooling step until the sample is completely frozen, it is possible to prevent the ice crystals from becoming coarse, and fine ice crystals. Can be formed.

  Hereinafter, the cooling conditions in the first cooling step and the second cooling step will be specifically described.

(A) First Cooling Step The electric field applied to the sample in the first cooling step may be an electrostatic field, an alternating electric field, or a combination thereof.

  When the electric field is an electrostatic field, the strength of the electric field is preferably 0.02 kV / m to 100 kV / m, more preferably 1 kV / m to 50 kV / m, and 2 kV / m to 30 kV / m. More preferably. If the strength of the electric field applied to the sample is 0.02 kV / m or more, the sample can be cooled without starting freezing. Moreover, if the strength of the electric field applied to the sample is 100 kV / m or less, the electric field can be applied without impairing the components contained in the sample.

  When the electric field is an alternating electric field, the strength of the electric field is preferably 0.02 kV / m to 100 kV / m, more preferably 1 kV / m to 50 kV / m, and 2 kV / m to 30 kV. More preferably, it is / m. If the strength of the electric field applied to the sample is 0.02 kV / m or more, the sample can be cooled without starting freezing. Moreover, if the strength of the electric field applied to the sample is 100 kV / m or less, the electric field can be applied without impairing the components contained in the sample.

  It is preferable that the electric field is an alternating electric field because damage to the pharmaceutical ingredient contained in the sample is small. The alternating electric field can usually have a power frequency of 61 Hz to 3 MHz, but the power frequency is preferably 0.1 kHz to 5 kHz, more preferably 0.5 kHz to 4 kHz, and 1 kHz to 3 kHz. More preferably it is. If the power frequency of the alternating electric field applied to the sample is 61 Hz or higher, the sample can be cooled without starting freezing. Moreover, if the power supply frequency of the alternating electric field applied to the sample is 0.1 kHz or more, the supercooled state can be maintained more efficiently. Moreover, if the power supply frequency of the alternating electric field applied to a sample is 3 MHz or less, it can cool, suppressing the damage to the component by local heating. Moreover, if the power frequency of the alternating electric field applied to the sample is 5 kHz or less, it is possible to prevent denaturation of proteins and the like that easily cause structural changes. Here, “power supply frequency” refers to the set frequency of the power supply.

  In the first cooling step, a method for applying an electric field to the sample is not particularly limited. For example, when an alternating electric field is applied as an electric field, a pair of electrodes connected to an AC power source are arranged so as to sandwich the sample from both sides, and a predetermined alternating current is applied to the electrodes to apply the electric field to the sample. can do. The material, shape, and thickness of the container are not particularly limited as long as a predetermined electric field that achieves the present invention is applied to the sample. For this purpose, it is necessary to select an appropriate container. Specifically, from the viewpoints of strength and fastness, glass, metal, plastics and the like are preferably used. Whether a predetermined electric field that achieves the present invention is applied to the sample is determined by measuring the electric field strength in the vicinity of the container using a commercially available device, or if this is difficult, an applied voltage is generated with the target container. It can be confirmed by simulation from the distance to the source.

  The cooling rate in the first cooling step is preferably 0.005 ° C./min to 20 ° C./min, and more preferably 0.01 ° C./min to 10 ° C./min. If the cooling rate is 0.005 ° C./min or more, cooling can be performed without generating ice crystals. Moreover, if a cooling rate is 20 degrees C / min or less, the temperature nonuniformity in a store | warehouse | chamber can be suppressed and it can cool uniformly. The temperature shown in the “cooling rate” is the shelf temperature in the cooling device that performs the preliminary cooling step.

  The processing time of the first cooling step is not particularly limited, and the first cooling step may be performed until the product temperature of the sample reaches the target temperature.

(B) Second cooling step In the second cooling step, the cooling temperature is preferably -80 ° C to -10 ° C. Here, the cooling temperature is the shelf temperature in the cooling device that performs the preliminary cooling step. If the cooling temperature is −80 ° C. or higher, breakage of the container due to low temperature embrittlement can be suppressed. Moreover, if the cooling temperature is −10 ° C. or lower, the sample can be sufficiently frozen.

  The processing time of the second cooling step is not particularly limited, and the second cooling step may be performed until the sample is completely frozen. However, as described above, the sample temperature may rise to −5 ° C. or higher during the second cooling step. In such a case, it is preferable to end the second cooling step and perform the first cooling step again even before the sample is completely frozen.

(2. Drying process)
A drying process is a process of drying freezing under reduced pressure. The treatment conditions in the drying step are not particularly limited, and the treatment conditions performed in the drying step in a conventionally known freeze-drying method can be applied. For example, primary drying is performed at −25 ° C. (shelf temperature) under reduced pressure (8 Pa), and then from −25 ° C. (shelf temperature) to 25 ° C. (shelf temperature) at 0.2 ° C./shelf temperature under reduced pressure (8 Pa). The sample can be sufficiently dried by performing secondary drying at a temperature rising rate of minutes.

  Particularly in primary drying, a good quality lyophilized product can be obtained by controlling the drying temperature (shelf temperature) to a temperature slightly lower than the collapse temperature (Tc) of the sample. Here, the “collapse temperature” is a temperature at which structural collapse (collapse phenomenon) starts from the drying interface of the concentrated phase of the sample. The “concentrated phase” refers to a phase formed in a frozen product of an aqueous solution as a sample, in which most of the solute contained in the aqueous solution is highly concentrated between ice crystals by freezing. In the frozen product of the aqueous solution after the preliminary freezing step, the concentrated phase is considered to exist as an amorphous solid in a glassy state having extremely high viscosity and low molecular mobility. The “collapse temperature” can be directly measured using, for example, a device (a freeze-drying microscope: FDM) that observes the drying interface of the frozen solution under reduced pressure with a microscope. The above-mentioned “collapse temperature” is often observed at the same temperature as the maximum concentrated phase glass transition (Tg ′) or on the high temperature side of about several degrees C (reference: Netsu Sokutei 36 (2) 112-120). Therefore, in the primary drying, the drying temperature (shelf temperature) may be controlled to a temperature slightly lower than the maximum concentrated phase glass transition (Tg ′) of the sample. The “slightly low temperature” is preferably a temperature lower by 0.5 ° C. to 30 ° C., more preferably a temperature lower by 1 ° C. to 20 ° C.

  In the method for producing a lyophilized preparation according to one embodiment of the present invention, the kind of the pharmaceutical contained in the sample is not particularly limited. Examples of pharmaceuticals include biopharmaceuticals, chemically synthesized low molecular weight pharmaceuticals, and the like.

  The “biopharmaceutical” refers to a pharmaceutical whose active ingredient is a biological substance or protein. Examples of biopharmaceuticals include monoclonal antibodies, hormones, hematopoietic factors, blood coagulation factors, cytokines, interferons, enzymes and other proteins; cells, transplantation materials used for somatic cell therapy such as cell sheets for transplantation, etc. be able to.

  When the sample containing a pharmaceutical product is a solution containing a pharmaceutical product, the sample further contains at least one substance selected from the group consisting of sugars, amino acids, and surfactants as an additive. May be.

As the saccharide, a monosaccharide and a derivative thereof represented by the general formula (CH ₂ O) _n (n is an integer of 3 or more) are intended. Examples of the saccharide include monosaccharide, disaccharide, trisaccharide, polysaccharide, sugar alcohol, reducing sugar, and non-reducing sugar. More specifically, glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, dextran, erythritol, glycerol, arabitol, sitolitol, sorbitol, mannitol, melibiose, meletitol, raffinose, mannotriose, stachyose, maltose, Examples include lactulose, maltulose, glucitol, maltitol, lactitol, and iso-maltulose.

  Examples of the amino acid include alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, threonine and the like.

  The surfactant is intended to be a pharmaceutically acceptable surfactant, such as a pharmaceutically acceptable nonionic surfactant. For example, polysorbates (eg, polysorbate 20, polysorbate 80, etc.); poloxamers (eg, poloxamer 188, etc.); Triton; sodium dodecyl sulfate (SDS); sodium lauryl sulfate; sodium octyl glucoside; sulfobetaine (eg, lauryl- Sarcosine (eg, lauryl-sarcosine, myristyl-sarcosine, etc.); betaine (eg, linoleyl-betaine, myristyl-betaine, etc.); dimethylamine (eg, myristamidopropyl-dimethylamine, Palmidopropyl-dimethylamine, etc.); Taurates (eg, sodium methyl cocoyl-taurate, etc.); polyethyl glycol, polypropyl glycol, ethylene It can be exemplified propylene glycol copolymer.

  The said additive may be used individually by 1 type, and may use 2 or more types together. The content of the additive is preferably 0.1 to 300 parts by weight, more preferably 0.5 to 200 parts by weight as a total amount with respect to 100 parts by weight of the pharmaceutical product.

  When the sample contains saccharides or amino acids, it is possible to control the size of ice crystals formed in the preliminary freezing step.

  Further, since the sample contains a surfactant, it becomes possible to improve the dispersibility of the pharmaceutical ingredient during use (when the lyophilized preparation is dissolved in physiological saline).

  If the sample containing the drug is a solution containing the drug, the solution is dissolved or dispersed in an aqueous solvent such as water or physiological saline, or an organic solvent such as ethanol or t-butyl alcohol. Says what you are doing.

Embodiment 1
A solution sample in which trastuzumab is dissolved in pH 6.0 histidine buffer to a concentration of 200 mg / mL is sterile filtered through a 0.22 μm filter. Aseptically fill the sterilized solution sample into an equal volume in a sterile 20 mL glass vial. After the filled vial is partially closed with an ETFE (ethylene tetrafluoroethylene copolymer) coated rubber stopper suitable for use in the lyophilization process, the solution sample is brought from room temperature (23 ° C.) to approximately 5 ° C. Cool in advance. Then, it cools until the product temperature of a solution sample becomes target temperature (-45 degreeC), applying an electric field on the following conditions (1st cooling process).

Electric field: Alternating electric field Power frequency: 2 kHz
Electric field strength: 7500V / m
Cooling rate (shelf temperature): 0.1 ° C./min When the product temperature of the solution sample reaches the target temperature (−40 ° C.), the application of the electric field is stopped and the solution sample is frozen under the following conditions ( Second cooling step).

Cooling temperature (shelf temperature): -60 ° C
After the solution sample is completely frozen and pre-freezing is complete, the vial is subjected to primary drying under reduced pressure (8 Pa) at −25 ° C. (shelf temperature) for approximately 76 hours. Thereafter, secondary drying is performed under reduced pressure (8 Pa) from −25 ° C. (shelf temperature) to 25 ° C. (shelf temperature) at a temperature rising rate of 0.2 ° C./min, and freezing according to Embodiment 1 of the present invention. A dry product is produced.

[2. Evaluation method〕
The quality of the lyophilized product obtained by the method for producing a lyophilized preparation according to one embodiment of the present invention can be evaluated by the following method.

(1. Evaluation by observation of appearance)
By visually observing the appearance of the freeze-dried product, the quality of the freeze-dried product can be evaluated. For example, if the shape of the freeze-dried product is a cake that has been uniformly made porous by shrinkage in accordance with the container shape, the shape of the freeze-dried product is compared to this, and deformation such as depressions or local In particular, if the liquid component remains, it is determined that freeze-drying has not been performed successfully.

(2. Evaluation of solubility or dispersibility in purified water)
When the pharmaceutical is a water-soluble substance or a fat-soluble substance, the solubility or dispersibility in purified water is further evaluated. Purified water is added so that the pharmaceutical concentration is 20 mg / mL, and mixed by inverting at 10 ° C. for 10 minutes to dissolve the lyophilized product. By visually inspecting the obtained solution, the solubility or dispersibility of the lyophilized product in purified water can be evaluated. For example, when no insoluble foreign matter or turbidity derived from aggregates is visually observed, it is determined that the solubility or dispersibility is good. On the other hand, when insoluble foreign matter or turbidity is visually observed, it is determined that the solubility or dispersibility is poor.

  The method for producing a lyophilized preparation according to one embodiment of the present invention can be used not only as a method for producing a lyophilized preparation of a pharmaceutical product but also as a method for producing a lyophilized product of a substance other than a pharmaceutical product. Examples of substances other than pharmaceuticals include one or more substances selected from the group consisting of high molecular compounds, low molecular compounds, and biological substances that are not pharmaceuticals.

  There are no particular limitations on the types of high molecular compounds, low molecular compounds and biological substances that are not pharmaceuticals. Examples of the “polymer compound” include peptides (oligopeptides, polypeptides), proteins, nucleic acids (deoxyribonucleic acid, ribonucleic acid) and the like. These polymer compounds may be artificially synthesized or may be obtained by gene recombination techniques. In addition, the “biological substance” is intended to include biological proteins such as antibodies, hormones, hematopoietic factors, blood coagulation factors, cytokines, interferons, and enzymes; cells and the like. Biologically derived substances that are not pharmaceuticals include not only cells but also cell extracts and the like. The origin of the “biological substance” is not particularly limited, and may be derived from mammals including humans or may be derived from microorganisms.

  The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope shown in the claims, and embodiments obtained by appropriately combining technical means disclosed in different embodiments. Is also included in the technical scope of the present invention.

[Summary]
The method for producing a lyophilized preparation according to aspect 1 of the present invention is a method for producing a lyophilized preparation of a pharmaceutical product, comprising a preliminary freezing step of freezing the sample containing the pharmaceutical product, and decompressing the frozen sample. The preliminary freezing step includes a first cooling step for cooling the sample until the product temperature reaches a target temperature while applying an electric field, and the step after the first cooling step. And a second cooling step in which the sample is cooled and frozen without applying an electric field.

  The method for producing a lyophilized preparation according to aspect 2 of the present invention may be a method in which the electric field is an alternating electric field in aspect 1 described above.

  In the method for producing a lyophilized preparation according to aspect 3 of the present invention, in the above aspect 2, the alternating electric field has a frequency of 61 Hz to 3 MHz and an electric field strength of 0.02 kV / m to 100 kV / m. A certain method may be used.

  In the method for producing a lyophilized preparation according to Aspect 4 of the present invention, in any one of Aspects 1 to 3, the preliminary freezing step repeats the first cooling step and the second cooling step. It is good also as a method to perform.

  The method for producing a lyophilized preparation according to Aspect 5 of the present invention is the method according to any one of Aspects 1 to 4, wherein the sample is a solution containing a pharmaceutical, and the sample is a saccharide, an amino acid, and a surfactant. The method may further include one or more substances selected from the group consisting of:

  The method for producing a lyophilized preparation according to Aspect 6 of the present invention may be the method according to any one of Aspects 1 to 5, wherein the pharmaceutical is a biopharmaceutical.

  The method for producing a lyophilized product according to aspect 7 of the present invention is a method for producing a lyophilized product of one or more substances selected from the group consisting of a high molecular compound, a low molecular compound, and a biological substance. A pre-freezing step of freezing a sample solution containing one or more substances selected from the group consisting of the high molecular compounds, low molecular compounds and biological substances, and the frozen sample solutions are subjected to reduced pressure. The pre-freezing step includes a first cooling step for cooling the sample solution until the product temperature reaches a target temperature while applying an electric field, and the first cooling step after the first cooling step. And a second cooling step in which the sample solution is cooled and frozen without applying an electric field.

  The present invention can be used in the pharmaceutical industry and the like.

Claims (7)

A method for producing a lyophilized pharmaceutical product comprising:
A pre-freezing step of freezing a sample containing a pharmaceutical product, and a drying step of drying the frozen sample under reduced pressure,
The preliminary freezing step is
A first cooling step of cooling the sample until the product temperature reaches a target temperature while applying an electric field;
A method for producing a freeze-dried preparation, comprising a second cooling step in which the sample after the first cooling step is cooled and frozen without applying an electric field.   The method for producing a lyophilized preparation according to claim 1, wherein the electric field is an alternating electric field.   The method for producing a freeze-dried preparation according to claim 2, wherein the alternating electric field has a frequency of 61 Hz to 3 MHz and an electric field strength of 0.02 kV / m to 100 kV / m.   The method for producing a freeze-dried preparation according to any one of claims 1 to 3, wherein the preliminary freezing step is performed by repeatedly performing the first cooling step and the second cooling step. The sample is a solution containing a pharmaceutical product,
The frozen sample according to any one of claims 1 to 4, wherein the sample further contains one or more substances selected from the group consisting of sugars, amino acids, and surfactants. A method for producing a dry preparation.   The method for producing a freeze-dried preparation according to any one of claims 1 to 5, wherein the pharmaceutical is a biopharmaceutical. A method for producing a lyophilizate of one or more substances selected from the group consisting of high molecular compounds, low molecular compounds and biological substances,
A pre-freezing step of freezing the sample solution containing one or more substances selected from the group consisting of the high molecular compounds, low molecular compounds and biological substances, and the frozen sample solution under reduced pressure A drying step of drying,
The preliminary freezing step is
A first cooling step of cooling the sample solution until the product temperature reaches a target temperature while applying an electric field;
A method for producing a freeze-dried product, comprising: a second cooling step in which the sample solution after the first cooling step is cooled and frozen without applying an electric field.

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