JPH10305083A - Freeze drying method for medicine solution - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a freeze drying method for medicines which does not require the need for aseptically and dust-freely managing the environment for packing the medicines into a packing container from a container for freeze drying after freeze drying at a high degree with low humidity, is good in the accuracy of the packing quantity of the medicines and allows stable and long- term preservation. SOLUTION: This freeze drying method consists in first aseptically and dust- freely packing a prescribed amt. of the medicine soln. into the flexible container. Next, the container packed with the medicine soln. is placed on a holder having a tapered or recessed slope in such a manner that the aperture of the container is the highest. This holder is carried into a drying cabinet, where the medicine soln. in the container is freeze dried. The holder is ejected out of the inside of this drying cabinet and the mouth part of the container is thermally fused.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for freeze-drying a drug solution. More specifically, the present invention relates to an efficient method for freeze-drying a drug solution, in which a drug container can be filled with an accurate amount of drug without the risk of contamination by foreign substances.

[0002]

2. Description of the Related Art Freeze-drying is a method of drying a drug at a low temperature and under a vacuum, without losing the activity of an unstable drug.
It is known as a method for obtaining a preparation having very good solubility. And as a method for producing a lyophilized preparation,
Conventionally, a drug solution is filled in a container such as a glass vial,
After freeze-drying, a method of introducing a sterile-filtered dry inert gas into a drying chamber in a vacuum state and sealing, and a method of freeze-drying a large number of drugs in a container such as a tray (called tray freeze-drying). ), A method of pulverizing and sizing the dried drug, and filling the drug into a predetermined drug container using a powder filling machine.

[0003] In the above method, the medicine can be filled aseptically, dustlessly and precisely, and since it is dried in a container, there is no risk of contamination by other kinds of medicine. It is widely used as a method for producing freeze-dried preparations. However, glass containers generally used in the above method are more vulnerable to impact and are more likely to be damaged during transportation and use than flexible containers made of plastic or the like. Is necessary, and in recent years, the increase in medical waste has become a problem, and plastic containers that can be incinerated instead of glass, especially oxygen and water vapor Flexible containers made of a laminated film or the like having barrier properties have been proposed as containers for freeze-dried preparations.

[0004] In the above method, it is essential to seal the container in the drying cabinet after the freeze-drying in order to prevent bacteria and foreign substances from being mixed and moisture absorption of the drug. In a vial bottle, a method is generally adopted in which a rubber stopper is half-stopped at the mouth of the bottle, and after the freeze-drying is completed, the drying rack is lowered to completely stopper the rubber stopper. On the other hand, in the case of a flexible container, the mouth of the container cannot be closed with a rubber stopper like a vial bottle. Therefore, the opening of the container is generally sealed by heat welding. However, if there are complicated equipment such as a heat welding machine in the freeze-drying chamber, it becomes extremely difficult to sterilize and maintain the aseptic condition in the chamber. Therefore, it is necessary to heat-weld the opening of the flexible container in the drying chamber. Can not. There is also a method in which the container is carried out without closing the mouth of the container and the opening is heat-sealed outside the container.However, the environment outside the container must be controlled to a high degree of sterility, dust, and low humidity. Also, it is difficult to completely prevent the contamination of chemicals by such management.

[0005] Therefore, in the case of a flexible container, a method is usually employed in which the freeze-dried preparation freeze-dried in a tray is pulverized and sized to fill the powder. There is a risk of contamination due to foreign matter or bacterial contamination,
(B) Since the freeze-dried preparation has a porous structure and easily absorbs moisture from the surrounding environment, it is necessary to maintain a highly sterile, dust-free, and low-humidity production line for powder filling, which increases the production cost. , (C) Because the powder is filled,
Due to variations in the particle size of the powder and other factors, the accuracy of the filling amount of the drug generally becomes worse than the filling of the drug solution,
(D) When different types of preparations are produced in the same production line, there are drawbacks such as the possibility of contamination by other types of drugs, and the flexible container is filled with powder. In this case, the medicine easily adheres to the opening of the container, and if it is welded as it is, the medicine may bite into the welded portion or a sealing failure may occur, which is a problem.

Therefore, a method of freeze-drying a drug using a dedicated freeze-drying container whose inner surface is easily peeled off, and filling the freeze-dried preparation in the freeze-drying container into a filling container (Japanese Patent Application Laid-Open No. JP-A-5-3904, JP-A-6-3097
No. 4) has been proposed. All of these have the advantage that the pulverizing and sizing step after the freeze-drying treatment is omitted, but similarly to the above-mentioned method, the filling environment of the drug is controlled to be highly aseptic, dust-free, and low in humidity. Need
In addition, there is a possibility that a small amount of the drug may remain in the container, so that the accuracy of filling the drug is deteriorated.

[0007]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above circumstances, and is capable of providing a preparation with high accuracy of drug loading, stable and long-term storage. An object of the present invention is to provide a method for freeze-drying a drug solution.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, adopted a flexible container as a freeze-drying container, and used this flexible container as it is as a filling container. As a result, the present invention has been reached.
That is, according to the present invention, 1) a predetermined amount of a drug solution is aseptically and dustlessly filled in a flexible container. 2) The container filled with the drug solution is placed on a holder having a tapered inclined surface such that the opening of the container is the highest.
3) The holder is carried into the drying cabinet, and the drug solution in the container is freeze-dried. 4) The holder is carried out of the drying cabinet, and the mouth of the container is thermally welded. A freeze-drying method comprising the steps of: Here, in the present freeze-drying method, after freeze-drying the drug solution and before heat-welding the mouth of the container, a clean inert gas is introduced into the drying chamber to fill the inside of the container with the inert gas. Preferably, the method includes a step of sealing the opening of the container with a sealing means in a state of being filled with the inert gas. Further, the holder is preferably provided with a sealing means so that the opening of the flexible container can be sealed in the drying cabinet after the freeze-drying, and the flexible container has a gas barrier property and water vapor. A film made of a synthetic resin film having barrier properties is preferred. Incidentally, antibiotics and physiologically active substances are preferably employed as the lyophilized drug.

[0009]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Next, an embodiment of the present invention will be described with reference to FIG. First, a drug (raw material) is prepared (S1), which is dissolved and prepared with a dissolving solution (S2), and a predetermined amount of the drug solution is aseptically and dustlessly filled in a flexible container (S1). S3). For example, the drug solution aseptically filtered may be accurately weighed so that the drug after drying becomes a predetermined amount and filled in a flexible container. here,
The flexible container is formed from a laminate film having a barrier layer for oxygen, water, and light in an outer layer or an intermediate layer in order to enable stable storage of the medicine inside, and the inner layer of the laminate film is made of polyethylene or polypropylene. And the like. As the barrier layer,
Examples of the oxygen and moisture barrier layer include aluminum foil, silica-deposited polyester, ethylene vinyl alcohol copolymer resin (EVOH), and Saran. Examples of the light (ultraviolet) barrier layer include an ultraviolet / visible light shielding film and an aluminum foil. . In addition, instead of using a laminate film having a barrier layer in the outer layer or the intermediate layer, a barrier film may be used as a secondary packaging material, and a deoxidizer or a desiccant is enclosed in the barrier packaging material. May be.

Next, a flexible container B filled with a drug solution
Is placed on a holder H having a tapered or concave inclined surface such that the opening of the container is highest (S).
4, see FIG. 5). As shown in FIGS. 2 to 4, the holder H has an inclined surface in which the pedestal 1 is tapered from the front end to the rear end direction at an inclination angle α. The angle between the line connecting the rear end and the bottom surface is defined as an inclination angle), and the highest portion of the rear end of the pedestal 1 is provided with a ventilation means (claw 2) for securing a ventilation hole in the opening of the flexible container. Is provided. After the freeze-drying is completed, a sealing means 3 is preferably provided at an appropriate position in the middle portion to protect the dried drug from bacteria and air from entering. The sealing means 3 seals a portion close to a portion where the dry medicine is stored (hereinafter, an opening side portion including the close portion is referred to as an opening), and includes a pressing member 31 and a lever 32.
The pressing member 31 is urged toward the bottom surface of the pedestal 1 by a spring (not shown). When the lever 32 is tilted toward the distal end of the pedestal 1 (FIG. 6)
Reference) The pressing member 31 is disengaged from the support portion 33, and the opening of the flexible container B is pressed and sealed by the pressing member 31 urged by the spring. A cover 4 for holding the flexible container B may be provided on the tip side of the pedestal 1.

When the holder H has no inclined surface,
In order to prevent the drug solution from spilling, a method of placing the opening on a pillow is also conceivable, but in this method, the flexible container B is bent, and the solution rises due to the decrease in the capillary and rises to the portion to be sealed, There are inconveniences such as poor discharge of water vapor. Therefore, the pedestal 1 of the holder H is inclined. The inclination angle α is determined so that the drug solution does not reach the opening when the flexible container B is placed on the holder H. It is regulated by the size of the flexible container B and the amount of the drug solution to be freeze-dried.
10 to 10 degrees, preferably 5 to 10 degrees. 5-1
At an inclination angle of 0 degrees, the thickness of the solution is small, and the upper end of the solution is sufficiently separated from the opening end, so that the freeze-drying time is short, and the opening is easily sealed and heat-sealed.

Next, the holder H on which the flexible container B is placed is carried into the drying cabinet, and the drug solution in the container is freeze-dried (S5). During the freeze-drying process, since the evacuation of water vapor is indispensable, it is necessary to insert the claw 2 into the opening of the container and secure a sufficient vent. The operation conditions for freeze-drying are the same as those for the freeze-drying of the target drug in a glass vial, and thus description thereof will be omitted. However, in the method of the present invention, since the drug solution is contained in the flexible container B, Since the contact area with the pedestal 1 is large, the heat conduction area to the drug solution is large, and the thickness of the solution layer is small.
Thermal efficiency is better than with glass vials. Therefore, when a flexible container is used, a space is required in the drying cabinet, but the time required for freeze-drying can be greatly reduced, so that freeze-drying can be performed efficiently.

After the freeze-drying is completed, preferably, a clean inert gas is introduced into the drying chamber to fill the inside of the container with the inert gas, and the opening of the container is filled with the inert gas. Is sealed using the sealing means 3 (S6). As the unfinished gas, dry nitrogen gas that has been sterilized and filtered is used. The sealing of the flexible container B by the sealing means 3 can be performed by lowering the shelf on which the holder H is placed and pushing the lever 32 downward so that the lever 32 falls down toward the tip of the pedestal 1. The lever 32 may be pushed in the direction of the tip of the pedestal 1 and fall down by a bar (not shown) arranged in the refrigerator. When the lever 32 falls down toward the distal end of the pedestal 1, the pressing member 31 comes off the supporting portion 33 and presses the opening of the flexible container B by the biasing force of the spring, thereby sealing the opening. Next, the holder H is taken out of the drying cabinet,
The mouth of the flexible container B is thermally welded (S7). At this time, the claw 2 having the vent hole secured is removed from the opening while the sealed state of the flexible container B is maintained, and the holder is loaded together with the holder into the heat welding machine HS to perform the heat welding (see FIG. 7). Finally, the flexible container B is removed from the holder H (S8).

As the material for forming the holder H used in the freeze-drying method of the present invention, the pedestal 1 is preferably a metal having good thermal conductivity such as brass or copper, and is not limited. A metal such as brass or brass, or a synthetic resin such as polyethylene or polypropylene is employed.
The sealing means 3 is made of metal such as stainless steel or brass, but the pressing portion of the pressing member 31 preferably has a structure in which a metal rod is covered with a rubber tube. The cover 4 is generally formed of a metal such as stainless steel, aluminum, or brass, but is not particularly limited.

Example 1 A commercially available solution prepared by dissolving 1 g of commercially available cefazolin sodium in 4.4 ml of water and adding 0.23 g of isopropyl alcohol, and a flexible container having an inner size of 80 × 115 were prepared according to the present invention. Frozen at -40 ° C,
Dry at 0.1 mbar, 30 ° C. Table 1 shows the results. In the flexible container, the rear sheet is made of a laminated film comprising an outer layer made of polyester, an inner layer containing no added low-density polyethylene, and an intermediate layer made of aluminum foil. The intermediate layer is made of a laminated film made of silica-deposited PET, the cover sheet is made of a polyester film for the outer layer, a low-density polyethylene-polypropylene blend for the inner layer, and a laminated film made of an aluminum foil for the intermediate layer.

Comparative Example The same solution as in Example 1 was prepared, filled in a vial (diameter: 23 mm), and freeze-dried in the same drying chamber atmosphere as in Example 1. Table 1 shows the results. From Table 1, it can be seen that both the freezing time and the drying time are significantly reduced in this example as compared with the case where the vial is filled and freeze-dried.

[0017]

[Table 1]

[0018]

As is apparent from the above description, since the method for freeze-drying a drug solution of the present invention employs a flexible container as a filling container,
It is superior in disposability and impact resistance compared to glass containers, and can supply lyophilized preparations that are stable and can be stored for a long period of time. Advantages such as the ability to determine the filling amount can be obtained.

[Brief description of the drawings]

FIG. 1 is an explanatory diagram showing a freeze-drying step.

FIG. 2 is a side view of a holder used in the present invention.

FIG. 3 is a plan view of the holder shown in FIG. 2;

FIG. 4 is a side view of another embodiment of the holder used in the present invention.

FIG. 5 is a view for explaining an operation of sealing an opening of a flexible container with a holder, showing a state where a flexible container filled with a drug solution is placed on the holder and claws are inserted into the opening. .

FIG. 6 is a diagram illustrating an operation of sealing an opening of a flexible container with a holder, and is a diagram illustrating an operation of tilting a lever.

FIG. 7 is a diagram illustrating an operation of sealing an opening of a flexible container with a holder, and shows a state in which the opening of the flexible container is sealed with a pressing member.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Pedestal 2 Claw (venting means) 3 Sealing means 31 Pressing member 32 Lever 33 Supporting part 4 Cover B Flexible container H holder HS heat welding machine

Claims (6)

[Claims] 1. A method for freeze-drying a drug solution comprising the following steps: 1) A predetermined amount of a drug solution is aseptically and dustlessly filled in a flexible container. 2) The container filled with the drug solution is placed on a holder having a tapered or concave inclined surface such that the opening of the container is the highest. 3) The holder is carried into the drying cabinet, and the drug solution in the container is freeze-dried. 4) The holder is carried out of the drying cabinet, and the mouth of the container is thermally welded. 2. After freeze-drying the drug solution and before heat-sealing the mouth of the container, an inert gas is introduced into the drying chamber to fill the inside of the container with a clean inert gas. The freeze-drying method according to claim 1, further comprising a step of sealing the opening of the container with a sealing means in a state of being filled with the gas. 3. The freeze-drying method according to claim 2, wherein the holder comprises a sealing means. 4. The freeze-drying method according to claim 1, wherein the flexible container is made of a synthetic resin film having gas barrier properties and water vapor barrier properties. 5. The freeze-drying method according to claim 1, wherein the drug is an antibiotic. 6. The drug according to claim 1, wherein the drug is a physiologically active substance.
The freeze-drying method according to any one of the above.