Method for manufacturing freeze-dried body and manufacturing device for same

Abstract

The present invention aims to provide a method and an apparatus for producing a lyophilized body, each of which can achieve energy saving, low cost, and a reduction in processing time and can provide a lyophilized body less damaged by a freezing process and a drying process. The present invention relates to a method for lyophilizing a substance using an electromagnetic wave, and the lyophilization method includes freezing the substance under irradiation of at least an electromagnetic wave and reduced-pressure drying the frozen substance under irradiation of at least an electromagnetic wave.

Claims

1. A method for producing a lyophilized body, comprising: freezing a substance to produce a frozen substance, which is a raw material of the lyophilized body, under irradiation of a first electromagnetic wave during a freezing stage; and reduced-pressure drying the frozen substance under irradiation of a second electromagnetic wave during a sublimation stage.

2. The method for producing a lyophilized body according to claim 1, further comprising: the freezing being performed under irradiation of the first electromagnetic wave and a first magnetic field, and the reduced-pressure drying being performed under irradiation of the second electromagnetic wave and a second magnetic field.

3. The method for producing a lyophilized body according to claim 1, wherein the reduced-pressure drying includes primary reduced-pressure drying and secondary reduced-pressure drying.

4. The method for producing a lyophilized body according to claim 2, wherein the first and second magnetic fields are static magnetic fields.

5. The method for producing a lyophilized body according to claim 1, wherein the substance is a drug-containing material containing water and at least one drug.

6. The method for producing a lyophilized body according to claim 5, wherein the at least one drug includes a protein.

7. The method for producing a lyophilized body according to claim 6, wherein the protein is a physiologically active protein.

8. The method for producing a lyophilized body according to claim 7, wherein the physiologically active protein is at least one selected from the group consisting of an antibody protein, an antigen protein, and an allergenic protein.

9. A lyophilizer for producing a lyophilized body, the lyophilizer comprising: a freezer configured to freeze a substance to produce a frozen substance, which is a raw material of the lyophilized body, during a freezing stage; a chamber configured to reduce an ambient pressure around the frozen substance during a sublimation stage; and an electromagnetic wave generator configured to generate an electromagnetic wave to be applied to the substance during both the freezing stage and the sublimation stage.

10. The lyophilizer according to claim 9, further comprising: a magnetic field generator configured to generate a magnetic field to be applied to the sub stance.

11. The lyophilizer according to claim 10, wherein the magnetic field generator is a static magnetic field generator configured to generate a static magnetic field.

12. The lyophilizer according to claim 9, wherein the electromagnetic wave generator comprises an electromagnetic wave oscillator, an amplifier, and an electromagnetic wave emitting antenna.

13. The method for producing a lyophilized body according to claim 1, wherein, during the freezing stage, the substance is irradiated under the irradiation of the first electromagnetic wave while lowering a temperature of the substance from room temperature to a freezing temperature.

14. The method for producing a lyophilized body according to claim 13, wherein the freezing temperature is from −40° Celsius to −70° Celsius.

15. The lyophilizer according to claim 9, wherein the chamber is a vacuum chamber.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 is a graph visually showing a water content in Examples 1 to 5 and Comparative Examples 1 to 15.

(2) FIG. 2 is a graph visually showing a water content in Examples 6 to 9 and Comparative Examples 16 to 27.

DESCRIPTION OF EMBODIMENTS

(3) The following describes examples of the present invention. The present invention is specifically described with reference to these examples, but is not limited thereto.

Example 1

(4) (Lyophilized Preparation Obtained by Lyophilization Under Irradiation of Electromagnetic Wave)

(5) To purified water (989.9 parts by weight) was dissolved HPC-SSL (an excipient) (Nippon Soda Co., Ltd.) to prepare a 5% HPC-SSL solution. The solution was dispensed in 0.5-mL portions into plastic blister cases (Cryomold (0.5 mL, square), Sakura Finetek). The blister cases were arranged on a shelf plate in a lyophilization chamber. The solutions in each blister case were frozen at −60° C. under irradiation of an electromagnetic wave, dried at −10° C. and 1.5 Pa for 12 hours under irradiation of an electromagnetic wave (primary reduced-pressure drying), and then dried at 30° C. and 1.5 Pa for 4.5 hours under irradiation of an electromagnetic wave (secondary reduced-pressure drying). Thus, a lyophilized preparation was obtained. Each obtained lyophilized preparation portion was quickly put in a dry aluminum pouch and sealed with a heat sealer.

(6) The lyophilization conditions are shown in Table 1 (lyophilization conditions A).

(7) TABLE-US-00001 TABLE 1 Process Temperature (° C.) Time (hr) Freezing 25 0.5   25 to −60 3 −60 0.5 Primary reduced- −60 to −10 2.5 pressure drying −10 12 Secondary reduced- −10 to 30   1 pressure drying 30 4.5

Examples 2 to 5

(8) Lyophilized preparations were each obtained by the same procedure as in Example 1, except that the concentration and type of the excipient were changed according to the following Table 2. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

(9) Dextran 70 (Meito Sangyo Co., Ltd.)

(10) Gelatin (Nippi. Inc., product name: Nippi Gelatin SCF)

(11) Pectin (Sansho Co., Ltd., distributed by: P Kelco Japan, product name: GENU pectin type LM-102AS-J)

Comparative Example 1

(12) (Lyophilized Preparation Obtained by Lyophilization Under No Irradiation of Electromagnetic Wave)

(13) A lyophilized preparation was produced under the same conditions as in Example 1, except that the freezing and the reduced-pressure drying were performed under no irradiation of an electromagnetic wave. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

Comparative Examples 2 to 5

(14) Lyophilized preparations were each obtained by the same procedure as in Comparative Example 1, except that the concentration and type of the excipient were changed according to the following Table 2. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

Comparative Example 6

(15) (Lyophilized Preparation Obtained Through Freezing Under Irradiation of Electromagnetic Wave)

(16) A lyophilized preparation was obtained as in Example 1, except that the reduced-pressure drying was performed under no irradiation of an electromagnetic wave. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

Comparative Examples 7 to 10

(17) Lyophilized preparations were each obtained by the same procedure as in Comparative Example 6, except that the concentration and type of the excipient were changed according to the following Table 2. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

Comparative Example 11

(18) (Lyophilized Preparation Obtained Through Reduced-Pressure Drying Under Irradiation of Electromagnetic Wave)

(19) A lyophilized preparation was prepared as in Example 1, except that the freezing was performed under no irradiation of an electromagnetic wave. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

Comparative Examples 12 to 15

(20) Lyophilized preparations were each obtained by the same procedure as in Comparative Example 11, except that the concentration and type of the excipient were changed according to the following Table 2. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

(21) (Method for Evaluating Water Content of Lyophilized Preparation)

(22) The lyophilized preparation was taken out from the aluminum pouch. The water content of the preparation was quickly determined using a Karl Fischer moisture meter. The weight percentage of the water relative to the weight of the preparation was determined as the water content (%) of the lyophilized preparation. The results are shown in Table 2 and the graph in FIG. 1.

(23) TABLE-US-00002 TABLE 2 Static magnetic field OFF OFF OFF OFF Electromagnetic wave ON/ON OFF/OFF ON/OFF OFF/ON Rh % 44 40 45 43 Composition Water content (%) Water content (%) Water content (%) Water content (%) 5% HPC-SSL Example 1 1.0 Comparative 1.3 Comparative 1.0 Comparative 1.1 Example 1 Example 6 Example 11 5% Dextran Example 2 3.2 Comparative 3.6 Comparative 3.7 Comparative 3.2 Example 2 Example 7 Example 12 10% Gelatin Example 3 1.7 Comparative 2.3 Comparative 2.8 Comparative 2.3 Example 3 Example 8 Example 13 3% Pectin Example 4 3.9 Comparative 4.8 Comparative 4.2 Comparative 4.4 Example 4 Example 9 Example 14 10% Dextran Example 5 2.0 Comparative 2.2 Comparative 2.4 Comparative 2.4 Example 5 Example 10 Example 15

(24) The results shown in Table 2 and the graph in FIG. 1 demonstrate that among the lyophilized preparations produced with the same length of lyophilization time, the lyophilized preparations produced through the freezing and the reduced-pressure drying which were both performed under irradiation of an electromagnetic wave tend to have the lowest water content. This shows that the lyophilization can be efficiently performed through the freezing and the reduced-pressure drying which are both performed under irradiation of an electromagnetic wave and can achieve energy saving, low cost, and a reduction in processing time. Also, the quality of the preparations is effectively maintained.

Example 6

(25) (Lyophilized Preparation Obtained by Lyophilization Under Irradiation of Electromagnetic Wave and Static Magnetic Field)

(26) To purified water (989.9 parts by weight) was dissolved HPC-SSL (an excipient) (Nippon Soda Co., Ltd.) to prepare a 5% HPC-SSL solution. The solution was dispensed in 0.5-mL portions into plastic blister cases (Cryomold (0.5 mL, square), Sakura Finetek). The blister cases were arranged on a shelf plate in a lyophilization chamber. The solutions in each blister case were frozen at −60° C. under irradiation of an electromagnetic wave and a static magnetic field, dried at −10° C. and 1.5 Pa for 12 hours under irradiation of an electromagnetic wave and a static magnetic field (primary reduced-pressure drying), and then dried at 30° C. and 1.5 Pa for 4.5 hours under irradiation of an electromagnetic wave and a static magnetic field (secondary reduced-pressure drying). Thus, a lyophilized preparation was obtained. Each obtained lyophilized preparation portion was quickly put in a dry aluminum pouch and sealed with a heat sealer.

(27) The lyophilization conditions in Example 6 are the same as the lyophilization conditions A in Example 1.

Examples 7 to 9

(28) Lyophilized preparations were each obtained by the same procedure as in Example 6, except that the concentration and type of the excipient were changed according to the following Table 3. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

(29) Dextran 70 (Meito Sangyo Co., Ltd.)

(30) Gelatin (Nippi. Inc., product name: Nippi Gelatin SCF)

(31) Pectin (Sansho Co., Ltd., distributed by: P Kelco Japan, product name: GENU pectin type LM-102AS-J)

Comparative Example 16

(32) (Lyophilized Preparation Obtained by Lyophilization Under No Irradiation of Electromagnetic Wave or Static Magnetic Field)

(33) A lyophilized preparation was obtained as in Example 6, except that the lyophilization was performed under no irradiation of an electromagnetic wave or a static magnetic field. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

Comparative Examples 17 to 19

(34) Lyophilized preparations were each obtained by the same procedure as in Comparative Example 16, except that the concentration and type of the excipient were changed according to the following Table 3. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

Comparative Example 20

(35) (Lyophilized Preparation Obtained Through Freezing Under Irradiation of Electromagnetic Wave and Static Magnetic Field)

(36) A lyophilized preparation was obtained as in Example 6, except that the reduced-pressure drying was performed under no irradiation of an electromagnetic wave or a static magnetic field. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

Comparative Examples 21 to 23

(37) Lyophilized preparations were each obtained by the same procedure as in Comparative Example 20, except that the concentration and type of the excipient were changed according to the following Table 3. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

Comparative Example 24

(38) (Lyophilized Preparation Obtained Through Reduced-Pressure Drying Under Irradiation of Electromagnetic Wave and Static Magnetic Field)

(39) A lyophilized preparation was obtained as in Example 6, except that the freezing was performed under no irradiation of an electromagnetic wave or a static magnetic field. The obtained lyophilized preparation was quickly put in a dry aluminum pouch and sealed with a heat sealer.

Comparative Examples 25 to 27

(40) Lyophilized preparations were each obtained by the same procedure as in Comparative Example 24, except that the concentration and type of the excipient were changed according to the following Table 3. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

(41) The lyophilized preparation was taken out from the aluminum pouch. The water content of the preparation was quickly determined using a Karl Fischer moisture meter. The weight percentage of the water relative to the weight of the preparation was determined as the water content (%) of the lyophilized preparation. The results are shown in Table 3 and the graph in FIG. 2.

(42) TABLE-US-00003 TABLE 3 Application of electromagnetic wave and static magnetic field in freezing/ Application of electromagnetic wave and static magnetic field in reduced-pressure drying ON/ON OFF/OFF ON/OFF OFF/ON Composition Water content (%) Water content (%) Water content (%) Water content (%) 5% HPC-SSL Example 6 0.86 Comparative 2.88 Comparative 3.70 Comparative 3.32 Example 16 Example 20 Example 24 5% Dextran70 Example 7 7.90 Comparative 8.17 Comparative 8.74 Comparative 8.17 Example 17 Example 21 Example 25 10% Gelatin Example 8 2.95 Comparative 3.56 Comparative 6.81 Comparative 6.40 Example 18 Example 22 Example 26 3% Pectin Example 9 5.16 Comparative 7.74 Comparative 8.82 Comparative 8.12 Example 19 Example 23 Example 27

(43) The results shown in Table 3 and the graph of FIG. 2 demonstrate that the lyophilized preparations produced through the freezing and the reduced-pressure drying which were both performed under irradiation of a static magnetic field and an electromagnetic wave obviously have a lower water content than the lyophilized preparations (Comparative Examples 16 to 27) produced through the freezing and the reduced-pressure drying one or both of which were performed without irradiation of a static magnetic field and an electromagnetic wave. This shows that the lyophilization process under irradiation of an electromagnetic wave and a static magnetic field can achieve energy saving, low cost, and a reduction in processing time and can provide a preparation having advantages in stability and maintaining the quality.

Examples 10, 11, and 12

(44) (Lyophilized Preparation Obtained by Lyophilization Under Irradiation of Electromagnetic Wave and Static Magnetic Field)

(45) Lyophilized preparations (Examples 10 to 12) were obtained by the same procedure as in Example 6, except that the lyophilization conditions in Examples 10, 11, and 12 were respectively changed according to Table 1 (lyophilization conditions A), Table 4 (lyophilization conditions B), and Table 5 (lyophilization conditions C), Dextran 70 (Meito Sangyo Co., Ltd.) was used as an excipient, and a 10% Dextran 70 solution was used. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

Comparative Examples 28, 29, and 30

(46) (Lyophilized Preparation Obtained by Lyophilization Under No Irradiation of Electromagnetic Wave or Static Magnetic Field)

(47) Lyophilized preparations (Comparative Examples 28 to 30) were obtained by the same procedure as in Comparative Example 16, except that the lyophilization conditions in Comparative Examples 28, 29, and 30 were respectively changed according to Table 1 (lyophilization conditions A), Table 4 (lyophilization conditions B), and Table 5 (lyophilization conditions C), Dextran 70 (Meito Sangyo Co., Ltd.) was used as an excipient, and a 10% Dextran 70 solution was used. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

(48) The lyophilized preparation was taken out from the aluminum pouch. The water content of the preparation was quickly determined using a Karl Fischer moisture meter. The weight percentage of the water relative to the weight of the preparation was determined as the water content (%) of the lyophilized preparation.

(49) The results are shown in Table 6.

(50) TABLE-US-00004 TABLE 4 Process Temperature (° C.) Time (hr) Freezing 25 0.5   25 to −60 3 −60 0.5 Primary reduced- −60 to −10 2.5 pressure drying −10 6 Secondary reduced- −10 to 30   1 pressure drying 30 4.5

(51) TABLE-US-00005 TABLE 5 Process Temperature (° C.) Time (hr) Freezing 25 0.5   25 to −60 3 −60 0.5 Primary reduced- −60 to −10 2.5 pressure drying −10 4 Secondary reduced- −10 to 30   1 pressure drying 30 4.5

(52) TABLE-US-00006 TABLE 6 Example Comparative Example Application of static Water Application of static Lyophilization magnetic field and content magnetic field and Water Composition conditions electromagnetic wave (%) electromagnetic wave content (%) 10% Dextran70 A Example 10 Applied 1.8 Comparative Not applied 2.58 Example 28 10% Dextran70 B Example 11 Applied 1.71 Comparative Not applied 4.65 Example 29 10% Dextran70 C Example 12 Applied 1.44 Comparative Not applied Unmeasurable Example 30

(53) The results in Table 6 demonstrate that comparing Examples 10 and 11 shows that despite the length of time of the primary reduced-pressure drying in Example 11 is half of that in Example 10, the water contents of the preparations in Examples 10 and 11 are nearly equal to each other. Despite the length of the time of the primary reduced-pressure drying in Example 12 is one third of that in Example 10, the water contents of the preparations in Examples 10 and 12 are nearly equal to each other. Comparing Comparative Examples 28 (lyophilization conditions A) and 29 (lyophilization conditions B) shows that when the length of time of the primary reduced-pressure drying is short, the water content is high.

(54) This shows that the lyophilization process under irradiation of an electromagnetic wave and a static magnetic field can achieve energy saving, low cost, and a reduction in processing time and provide a preparation having advantages in stability and maintaining the quality.

Examples 13 to 17

(55) (Lyophilized Preparation Obtained Through Very Short Time of Primary Reduced-Pressure Drying)

(56) A 10% Dextran 70 solution was dispensed in 2.0-mL portions into plastic blister cases (Cryomold (2.0 mL, round), Sakura Finetek). The blister cases were arranged on a shelf plate in a lyophilization chamber. The solutions in each blister case were frozen at −60° C. under irradiation of an electromagnetic wave and a static magnetic field, dried at −10° C. and 1.5 Pa for four hours under irradiation of an electromagnetic wave and a static magnetic field (primary reduced-pressure drying), and then dried at 30° C. and 1.5 Pa for 4.5 hours under irradiation of an electromagnetic wave and a static magnetic field (secondary reduced-pressure drying). Thus, lyophilized preparations (Examples 13 to 17) were obtained. Each lyophilized preparation portion was quickly put in a dry aluminum pouch and sealed with a heat sealer.

(57) The lyophilization conditions in Examples 13 to 17 are the same as the lyophilization conditions C in Example 12.

Test Examples 1 to 5

(58) Lyophilized preparations (Test Examples 1 to 5) were obtained by the same procedure as in Examples 13 to 17, respectively, except that the freezing and the reduced-pressure drying were performed under no irradiation of a static magnetic field. Each lyophilized preparation portion was put in a dry aluminum pouch and sealed with a heat sealer.

(59) The lyophilized preparation was taken out from the aluminum pouch. The water content of the preparation was quickly determined using a Karl Fischer moisture meter. The weight percentage of the water relative to the weight of the preparation was determined as the water content of the lyophilized preparation. The appearance of the lyophilized preparation taken out was observed from the upper surface and the lower surface.

(60) The results are shown in Table 7.

(61) TABLE-US-00007 TABLE 7 Static magnetic field ON/ON OFF/OFF Electromagnetic wave ON/ON ON/ON Water Water Composition content (%) Appearance content (%) Appearance 10% Dextran70 Example 13 1.4 n = 3 Test 1.3 n = 5 slight depression is Example 1 depression is Example 14 1.2 observed Test 1.4 observed in all test Example 2 examples Example 15 1.7 Test 1.4 Example 3 Example 16 1.6 Test 1.5 Example 4 Example 17 1.5 Test 1.6 Example 5 Average 1.46 Average 1.44 water water content content

(62) The results in Table 7 demonstrate that even when the primary reduced-pressure drying time is shorter (the drying conditions in Examples 13 to 17 and Test Examples 1 to 5 are the same as those in Example 12, but the size of each of the preparations in Examples 13 to 17 and Test Examples 1 to 5 is four times the size of the preparation in Example 12), no significant change in water content was found when the freezing and the reduced-pressure drying were performed under irradiation of an electromagnetic wave. With regard to the appearance, in Examples 13 to 17 in which a static magnetic field was further applied in the freezing and the reduced-pressure drying, some of the preparations have a slight depression on their upper surface or lower surface, but are acceptable for appearance. On the other hand, in Test Examples 1 to 5, all the preparations have a depression on their upper surface or lower surface. These demonstrate that a very short time of the primary reduced-pressure drying is preferably performed under irradiation of an electromagnetic wave and a static magnetic field.

(63) The ambient environmental humidity (Rh %) has a considerable influence on the results of water contents in the examples, comparative examples, and test examples. The effects and technical significance of the present invention can be fully understood by the difference between the presence and absence of an electromagnetic wave and/or a static magnetic field under the same conditions.

INDUSTRIAL APPLICABILITY

(64) The present invention aims to provide a method and an apparatus for producing a lyophilized body, each of which can achieve energy saving, low cost, and a reduction in processing time and can provide a lyophilized body less damaged by a freezing process and a drying process.