JP2010124931A - Method for manufacturing package of freeze-dried medicine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for manufacturing the sterile package of a freeze-dried medicine without requiring a large amount of equipment investment to keep sterile property nor having the risk of deformation or deactivation when the medicine is protein, etc., concerning the method for manufacturing the package of the freeze-dried medicine with the sterile property kept therein. <P>SOLUTION: The method includes the following processes (1) to (3), i.e., (1) the process for storing the medicine to be freeze-dried in a container under the sterile property, (2) the process for allowing a sealed sheet with bacteria-blocking property and ventilation to be welded onto the peripheral edge of the container with the medicine stored therein under the sterile property, and (3) the process for freeze-drying the container which is sealed after welding the sealed sheet onto the peripheral edge of the container. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing a lyophilized preparation package that maintains sterility.

  When producing pharmaceuticals in an aseptic manner, the level of cleanliness required for the workplace is high, and a large amount of investment is required for structures and equipment for maintaining and managing the level.

  When manufacturing pharmaceutical products such as lyophilized protein preparations, in general, containers such as vials and trays are filled with the preparation to be lyophilized, and lyophilized in a semi-sealed state. A sealing method is employed.

  However, in such a method, since the hermeticity of the container is not maintained, it is necessary to maintain sterility and dryness over a wide range of manufacturing sites, which increases the equipment cost and running cost for that purpose. Become. For example, expensive capital investment such as an isolator was required.

  In addition, if the sterility of the preparation is not guaranteed after lyophilization, the preparation may be sterilized by electron beam or gamma irradiation, but in the case of protein preparation, denaturation or inactivation is observed depending on the irradiation dose. Therefore, it is necessary to avoid such sterilization by irradiation.

  In addition, in order to solve the problems of using containers such as vials, for example, patent applications as shown in Patent Document 1 below have been made. In the invention described in Patent Document 1, preparations are also made in containers. Since it is freeze-dried before sealing, it has not been able to solve the conventional problems in that it requires an expensive capital investment to maintain sterility. Further, in the invention described in Patent Document 1, ultraviolet sterilization is also performed, and when the preparation is a protein, the possibility of denaturation and inactivation cannot be solved.

Japanese Patent No. 2767616

  The present invention has been made to solve such problems, and does not require expensive capital investment in order to maintain sterility, and when the preparation is a protein or the like, it is denatured or deactivated. It is an object of the present invention to provide a method for producing a package of an aseptic freeze-dried preparation that does not cause the risk of such a problem.

In order to solve the above problems, the present invention
(1) Step of storing a preparation to be lyophilized under aseptic conditions in a container (2) Under aseptic conditions, a sealed sheet having a bacteria-blocking property and air permeability is welded to the peripheral portion of the container in which the preparation is stored. Step (3) A step of freeze-drying the sealed container in which the sealed sheet is welded to the peripheral edge of the container. The method for producing a freeze-dried preparation package comprising the steps (1) to (3) above Is to provide.

  It is desirable that the sealing sheet having the bacteria blocking property and the air permeability is welded to the peripheral portion of the container through a sealing agent. As the sealing agent, for example, a wax-based hot melt adhesive is used. Moreover, as a container which accommodates a formulation, what was comprised, for example with polyethylene, polypropylene, polyethylene terephthalate, or these composite materials is used. Further, as the sealing sheet, for example, a sheet made of a material obtained by bonding heat and pressure to continuous polyethylene fine fibers is used. As the freeze-dried preparation, for example, a protein preparation is used. As the protein preparation, for example, a thrombin-containing preparation or a fibrinogen-containing preparation is used. The protein preparation can be in a form immobilized by, for example, impregnating a protein with a support.

  As described above, the present invention performs aseptic conditions the process of housing an article to be packaged in a container and the process of welding a germ-blocking and air-permeable sealing sheet to the peripheral edge of the container. In order to maintain sterility in the lyophilization process, the hermeticity of the container is maintained by welding the sealing sheet to the peripheral edge of the container before the lyophilization process, that is, before the lyophilization process. There is an effect that a freeze-dried preparation can be obtained aseptically without requiring expensive equipment such as an isolator.

  In addition, when the preparation is a protein or the like, there is an effect that there is no risk of denaturation or inactivation.

Hereinafter, embodiments of the present invention will be described. The method for producing a package of the lyophilized preparation of the present invention, as described above,
(1) Step of storing a preparation to be lyophilized under aseptic conditions in a container (2) Under aseptic conditions, a sealed sheet having a bacteria-blocking property and air permeability is welded to the peripheral portion of the container in which the preparation is stored. Step (3) Step of freeze-drying the sealed container in which the sealed sheet is welded to the peripheral edge of the container. The above steps (1) to (3) are included.

  In the step (1) of storing the preparation to be lyophilized in a container, the support can be filled in advance. As this support, for example, a non-woven fabric is used. By using a support made of such a nonwoven fabric, a preparation such as a chemical solution can be dropped onto the support and the support can be impregnated with the preparation. The form of the support is not questioned, but can be, for example, a sheet form. As the preparation, for example, a protein preparation or the like can be used. As the protein preparation, for example, a thrombin-containing preparation or a fibrinogen-containing preparation can be used, and other protein preparations can be used. In this case, protein preparations such as thrombin-containing preparations and fibrinogen-containing preparations can be in the form of an immobilized sheet preparation that is fixed by impregnating thrombin or fibrinogen into a sheet-like support.

  The material of the container is not particularly limited, but a material that is not easily broken by freeze-drying, for example, polyethylene, polypropylene, polyethylene terephthalate, or a composite material thereof can be used. From the viewpoint of improving the peelability of the sealing sheet described later, it is desirable to use polyethylene or a composite material thereof.

  In the step (2), after the packaged material is accommodated, the bacteria-blocking and air-permeable sealing sheet is welded to the peripheral edge of the container, and the sealing sheet is heated to heat the container with the container installed in the sealing device. It is welded to the peripheral part of. The heating temperature is not particularly limited, but is about 130 to 150 ° C.

  The hermetic sheet is a bacteria-blocking and breathable material. That is, the sealing sheet is formed of a mesh-like material having a large number of fine holes having a diameter (preferably 0.3 μm or less) that allows air to pass but does not allow bacteria or the like to pass. For example, a material made of a material obtained by bonding a continuous ultrafine fiber of polyethylene by applying heat and pressure is used. Specifically, Tyvek (registered trademark) manufactured by DuPont is exemplified.

  Moreover, it is desirable that the sealing sheet be welded to the peripheral edge of the container via a sealing agent. Since the sealant is freeze-dried later, it is desirable to use a material that can withstand the temperature. For example, a wax-based hot-melt adhesive is used. A commercial product (manufactured by Oliver Products, Inc.) obtained by dot-coating such a hot-melt adhesive on the Tyvek (registered trademark) can be used as the sealing sheet.

  As described above, the step (1) of storing the preparation in the container and the step (2) of welding the sealing sheet to the peripheral edge of the container are performed in an aseptic room, but the freeze-drying step (3) Made outside the sterile room. Freeze-drying is performed at a temperature of about −50 ° C. After freeze-drying, the container sealed with a sealing sheet as described above is packaged with an aluminum sheet and provided as a product.

  Hereinafter, the manufacturing method of the lyophilized preparation package according to one embodiment will be described more specifically with reference to the drawings.

  First, a container for storing a freeze-dried preparation is prepared. In this embodiment, as shown in FIGS. 1 and 2, the container 1 has an opening 2 on the upper surface, the side surface 4 is formed to rise obliquely from the bottom surface 3, and the entire surface is substantially rectangular in shape. It is formed in a tray shape. A flange portion 5 protrudes outward from the periphery of the opening 2, and an inclined portion 6 that is inclined obliquely is connected to the flange portion 5 on one end side. As a material of the container 1, a material made of a composite material of polyethylene and polyethylene terephthalate is used.

  Next, as shown in FIG. 3, the support body 7 is accommodated in the container 1, and the support body 7 is placed on the bottom surface 3 of the container 1. This support body 7 is comprised with the nonwoven fabric. Next, as shown in FIG. 4, the liquid preparation 8 is accommodated in the container 1 so as to be dropped onto the support 7. As the preparation 8, a preparation of a protein such as thrombin or fibrinogen is used as described above. By dropping on the support 7, the preparation 8 is impregnated into the support 7.

  Next, as shown in FIGS. 5 and 6, the sealing sheet 9 is welded to the flange portion 5 of the container 1. More specifically, the sealing sheet is applied by applying a sealing agent to the peripheral portion of the sealing sheet 9 facing the flange portion 5, joining the portion where the sealing agent is applied to the flange portion 5 of the container 1, and heating. The peripheral edge portion of 9 is welded to the flange portion 5 of the container 1. As the material of the sealing sheet 9, in this embodiment, a material made of a material obtained by bonding continuous ultrafine fibers of polyethylene by applying heat and pressure, specifically, Tyvek (registered trademark) manufactured by DuPont is used.

  Here, as shown in FIGS. 5 and 6, the one end 9 a side of the sealing sheet 9 is joined to the inclined portion 6 connected to the flange portion 3 on the one end side. No welding is performed at the portion of the one end 9a, and the one end 9a side of the sealing sheet 9 and the inclined portion 6 are separated from each other. This is because when the container is opened, it is easy to lift up the sealing sheet 9 from the flange portion 5 of the container 1 with the one end 9a side of the sealing sheet 9 that is not welded as the opening start point.

  In this way, by containing the support 7 impregnated with the preparation 8 in the container 1 and sealing the container 1 with the sealing sheet 9, the package 10 as shown in FIGS. 5 and 6 is obtained. Become. After such a package 10 is freeze-dried, the package 10 after freeze-drying is packaged with a packaging material 11 made of an aluminum sheet, as shown in FIG. In this case, although not shown, the desiccant can be enclosed in the packaging material 11 together with the package 10.

  Next, although the manufacturing method of the package of the freeze-dried preparation of this invention is demonstrated in detail according to an Example, this invention is not limited only to this Example.

Example 1
First, a container as shown in FIGS. 1 and 2 is molded from a resin made of a composite material of polyethylene and polyethylene terephthalate by vacuum or pressure molding.

  Next, the support is accommodated in the container obtained by the molding method as described above and placed on the bottom surface of the container. As the support, a polyglycolic acid sheet (PGA sheet: manufactured by Gunze) was used. 50 μL of 1850 U / mL thrombin solution (180 mM histidine, 3% by weight trehalose, 1% by weight glycerin, 20 mM calcium chloride, 0.1% by weight Tween 80), which is a protein preparation, was filled in this PGA sheet.

  Next, the sealing sheet is layered on the peripheral part (flange part) of the container filled with the support and the protein preparation as described above, and the layered part is heat-treated at 130 to 160 ° C. for 0.5 to 10 seconds to perform pressure bonding. went. As a sealing sheet, it is a mesh-like material with many fine pores, and it is bonded to Tyvek (manufactured by DuPont), which is a material bonded to continuous polyethylene ultrafine fibers by applying heat and pressure, and wax-based hot-melt bonding. An agent coated with dots (manufactured by Oliver Products, USA) was used. Such dot coating of hot melt adhesive is applied to the peripheral portion of the sealing sheet material made of Tyvek facing the peripheral portion of the container.

  The container thus sealed with a sealing sheet was frozen at −50 ° C. for 2 hours and then vacuum-dried to prepare a thrombin-immobilized sheet preparation. The thrombin-immobilized sheet preparation after freeze-drying was sealed and stored using an aluminum sheet with the desiccant enclosed in the container.

(Comparative Example 1)
The same operation as in Example 1 was performed using a petri dish made of polystyrene instead of packaging with the container and the sealing sheet of Example 1 above. That is, a PGA sheet was accommodated in a petri dish made of polystyrene, and the same thrombin solution as in Example 1 was dropped and impregnated into the PGA sheet.

  The polystyrene petri dish containing the PGA sheet and the thrombin solution was fitted in a semi-sealed state with the polystyrene petri dish as a lid, frozen at −50 ° C. for 2 hours, and then vacuum dried to obtain a thrombin-immobilized sheet. A formulation was prepared. Further, such a thrombin-immobilized sheet preparation was stored in a sealed manner using an aluminum sheet with a desiccant enclosed in the container as in Example 1.

(Test Example 1)
For the thrombin-immobilized sheet preparations of Example 1 and Comparative Example 1, the water content immediately after lyophilization and after one month of storage at 37 ° C. was measured using a Karl Fischer moisture meter (manufactured by Kyoto Electronics Co., Ltd.). did. The test results are shown in Table 1.

  As is apparent from Table 1, there is no difference in moisture content immediately after freeze-drying and after storage for 1 month in Example 1 and Comparative Example 1, and the packaging in the form of a container and a sealing sheet as in Example 1 It was shown that the body can be freeze-dried as in the case of the semi-sealed packaging with the petri dish made of polystyrene as in Comparative Example 1.

(Test Example 2)
For the thrombin-immobilized sheet preparations of Example 1 and Comparative Example 1, the thrombin activity was measured for each water content immediately after lyophilization and one month after storage at 37 ° C. The temperature condition of 37 ° C. is a severe temperature condition for storing thrombin, but in order to measure the residual activity in a short period of time, the temperature condition of 37 ° C. was intentionally tested.

  The activity of thrombin was measured by the following method. That is, 60 μl of a buffer composed of 50 mM Tris-HCl (pH 8.5) and 50 mM NaCl was added to 20 μl of the sample of Example 1 and Comparative Example 1 in a Falcon 2008 tube, and further 0.1 wt% PULURONIC F. 20 μl of -68 was added and incubated at 37 ° C. for 3 minutes.

  Human plasma-derived purified α-thrombin (manufactured by Hematologic Technology: KCT-0020) diluted to 5, 2.5, 1.25, 0.625, 0.3125 μg / ml with the above buffer as a standard product Using.

  Add 100 μl of test team chromogenic substrate S-2238 (1 mM: manufactured by Daiichi Chemicals Industries) to the above reaction mixture and mix by stirring. After reaction at 37 ° C. for 5 minutes, add 800 μl of 0.1 M citric acid solution. The reaction was stopped. 200 μl of the reaction solution was transferred to a 96-well plate, and OD405 / 650 was measured. In both Example 1 and Comparative Example 1, the measurement value immediately after lyophilization was taken as 100%, and the measurement value after one month of storage was shown as a percentage. The test results are shown in Table 2.

  As is clear from Table 2, there is no difference in thrombin activity between Example 1 and Comparative Example 1 immediately after lyophilization and after storage for 1 month. It was shown that the package could be freeze-dried as in Comparative Example 1 as in the case of a semi-sealed package with a petri dish made of polystyrene.

(Test Example 3)
There are various methods for sterilizing pharmaceuticals, which can be selected depending on the dosage form. For example, the solution is sterilized by filtration, and the medical material is ethylene oxide gas sterilized. However, when the preparation is a protein such as thrombin, it is expected that denaturation occurs and inactivation when ethylene oxide gas, electron beam, γ-ray sterilization, or the like is used.

  Therefore, in this test example, the thrombin-immobilized sheet prepared as in Comparative Example 1 was tested for thrombin activity after irradiation with γ rays having various irradiation energies (kGy: kilogray). γ-ray irradiation was performed at Nippon Irradiation Service Co., Ltd. The measured thrombin activity without γ-ray irradiation was taken as 100%, while the measured thrombin activity with each dose of γ-ray irradiation was shown as a percentage. The test results are shown in Table 3.

  As is apparent from Table 3, the residual activity of thrombin decreased according to the irradiation dose of γ rays. This indicates that it is difficult to sterilize the thrombin-immobilized sheet after production, and it was found that the environment and operation during production must be kept sterile in order to produce a sterile formulation. .

(Test Example 4)
The sterility test was performed on the thrombin-immobilized sheet preparation of Example 1 above. In the sterility test, thrombin was extracted from the thrombin-immobilized sheet using physiological saline, and the extract was subjected to the method described in the Japanese Pharmacopoeia. As a result of the test, no growth of bacteria and fungi was observed in the extract from the thrombin-immobilized sheet preparation of Example 1.

  Therefore, it was found that the sterility can be maintained by using the package of the container and the sealing sheet as in Example 1 and filling the PGA sheet and the protein component.

(Other examples)
The thrombin used in the above examples is a proteolytic enzyme involved in the blood coagulation reaction and is used as a hemostatic agent. The present invention is applied to protein preparations other than thrombin, for example, protein preparations such as fibrinogen. Of course it is possible. The present invention can also be applied to formulations other than protein formulations.

The top view of the process of preparing a container. AA sectional view taken on the line AA of FIG. Sectional drawing of the process of accommodating a support body in a container. Sectional drawing of the process of accommodating a formulation in a container. The top view of the process of sealing a container with a sealing sheet. BB sectional drawing of FIG. Sectional drawing of the process packaged with an aluminum sheet.

Explanation of symbols

1 Container 8 Formulation 9 Sealed Sheet 10 Package

Claims (8)

A method for producing a freeze-dried preparation package comprising the following steps (1) to (3):
(1) Step of storing a preparation to be lyophilized under aseptic conditions in a container (2) Under aseptic conditions, a sealed sheet having a bacteria-blocking property and air permeability is welded to the peripheral portion of the container in which the preparation is stored. Step (3) Step of freeze-drying the sealed container with the sealed sheet welded to the peripheral edge of the container   The method for producing a freeze-dried preparation package according to claim 1, wherein the container for storing the preparation is composed of polyethylene, polypropylene, polyethylene terephthalate, or a composite material thereof. The method for producing a lyophilized preparation package according to claim 1 or 2, wherein the hermetic sealing and breathable sealing sheet is made of a material bonded to polyethylene continuous ultrafine fibers by applying heat and pressure. The method for producing a freeze-dried preparation package according to any one of claims 1 to 3, wherein the sealing sheet having bacteria-blocking properties and air permeability is welded to the peripheral portion of the container through a sealing agent.   The method for producing a freeze-dried preparation package according to claim 4, wherein the sealant is a wax-based hot melt adhesive. The method for producing a freeze-dried preparation package according to any one of claims 1 to 5, wherein the freeze-dried preparation is a protein preparation. The method for producing a freeze-dried preparation package according to claim 6, wherein the protein preparation is a thrombin-containing preparation or a fibrinogen-containing preparation. The method for producing a freeze-dried preparation package according to claim 6, wherein the protein preparation is a preparation in which a protein is immobilized on a support.

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