JPH08164186A - Method for sterilizing liquid agent made into single agent containing reducing sugar and bicarbonate - Google Patents

Abstract

PURPOSE: To make it possible to suppress the decomposition of a reducing sugar and to suppress the fluctuation in pH by housing the liquid agent into a soft plastic bag, thereafter, packaging the bag with a packaging material having a high gas barrier property then, thermally sterilizing the bag in a method for sterilizing the liquid agent made into the single agent contg. the reducing sugar and bicarbonate. CONSTITUTION: The liquid agent made into the single agent contg. a reducing sugar and a bicarbonate is housed into the soft plastic bag, is then vacuum packaged with the packaging material having the high gas barrier property and is so treated as to be thermally sterilized at the time of sterilizing the pharmaceutical prepn. which is a liquid agent for medical treatment, such as perfusate, for artificial kidneys, contg. the reducing agent and bicarbonate ions, and made into the single agent. The materials of the soft plastic bag include, for example, a polyethylene, polypropylene, polyvinyl chloride, etc., and the materials which withstand the thermal sterilization are more preferable. Materials which withstand the thermal sterilization and gas carbon dioxide permeability of <=50ml/m<2> .24hr.atm (25 deg.C-70%RH) are more preferable as the packaging material and include, for example, a polyethylene terephthalate, etc.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for stably sterilizing a solution containing a reducing sugar and bicarbonate and having a weakly acidic to neutral pH, while suppressing decomposition of the reducing sugar.

[0002]

2. Description of the Related Art Conventionally, when bicarbonate is added to an infusion solution, an artificial kidney perfusion solution, a filtration type artificial kidney replenishment solution, a peritoneal dialysis solution, etc., the reduction caused by the increase in pH is caused. Coloring due to sugar decomposition is a problem. Therefore, medical fluids containing reducing sugars and bicarbonate ions, such as infusions, artificial kidney perfusates, filtration artificial kidney replenishers, and peritoneal dialysis fluids, are divided into two parts and stored separately in two containers. Sometimes mixed. Although such a preparation requires a complicated aseptic mixing operation at the time of use, it is difficult to avoid the risk of bacterial contamination during the mixing.

In order to solve such a point, a method of providing a single container with separate chambers has been studied (for example, JP-A-61-355, JP-B-63-19149, and JP-A-5-195149). 31153, JP-A-5-5138), the mixing operation at the time of use is still complicated, and fine particles are generated by the mixing operation that consists of peeling or destruction of partition walls and chips dividing the two chambers, and the number of parts of the container There is a problem in quality such as increase in number and complexity of structure, and decrease in reliability.

From these things, it is strongly desired to develop a preparation in which reducing sugar and bicarbonate are combined into one agent. However, by adding bicarbonate, the reducing sugar is mixed with a liquid agent whose liquidity changes from weakly acidic to neutral. Since the carbon dioxide gas is generated and volatilized over time, the pH of the above product increases during the manufacturing process and long-term storage of the product, which causes a problem in quality control. Furthermore, in such a liquid agent, reducing sugar is decomposed by heat applied by high-pressure steam sterilization or hot water sterilization due to an increase in pH, and coloring of the liquid agent occurs. To avoid this, under a carbon dioxide gas atmosphere. Manufacturing difficulties such as sterilization at room temperature occur.
Due to such difficulties, such liquid preparations have not yet been marketed.

[0005]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a stable sterilization method for a liquid preparation in which reducing sugar and bicarbonate are combined.

[0006]

Means for Solving the Problems As a result of intensive studies conducted by the inventor of the present invention, the present inventors have found that after packaging a liquid formulation containing reducing sugar and bicarbonate into a soft plastic bag, the liquid package has a high gas barrier property. It was found that not only the decomposition of reducing sugars can be suppressed but also the fluctuation of pH can be suppressed by vacuum packaging with a material and performing heat sterilization such as high-pressure steam sterilization or hot water sterilization, thus completing the present invention. It was

That is, according to the present invention, in a method for sterilizing a one-component liquid agent containing reducing sugar and bicarbonate, the liquid agent is contained in a soft plastic bag, and then the soft plastic bag containing the liquid agent is gasified. This is a liquid agent sterilization method characterized in that it is vacuum-packed in a packaging material having a high barrier property and heat-sterilized.

Although the reducing sugar and the monocarbonate-containing liquid preparation containing bicarbonate to be sterilized according to the present invention are not particularly limited,
Examples of medical fluids include infusion solutions, perfusion solutions for artificial kidneys, replenishers for filtration type artificial kidneys, and peritoneal dialysis solutions.

The composition of the reducing sugar is not particularly limited, but the reducing sugar content is 10 W / V% or less, preferably 5%.
W / V% or less, and the amount of bicarbonate ion is 1 to 40
Those contained in the range of mEq / l are preferable. Other ingredients are not particularly limited, sodium, potassium, calcium, magnesium, chlor,
Examples thereof include phosphoric acid, organic acids, trace elements and the like.

When calcium and magnesium are mixed, there is a problem that carbonate precipitation occurs, but in the amounts usually used for infusion, perfusion solution for artificial kidney, replenishing solution for filtration type artificial kidney, peritoneal dialysis solution, etc. , 40 if maintained at an appropriate pH
There is no problem at a bicarbonate ion concentration of mEq / l or less, and it can be avoided by adding a chelating agent that suppresses precipitation (for example, citric acid, chondroitin sulfate, glycylglycine, etc.). The suitable pH is in the range of weak acidity to neutrality, specifically pH 5-8.
Range.

The reducing sugar to be added to the liquid preparation to be sterilized according to the present invention may be an ordinary reducing sugar such as glucose and maltose.

The material of the soft plastic bag used in the present invention may be any ordinary one as long as it is compatible with the infusion plastic container test, such as polyethylene,
Examples thereof include polypropylene, polyvinyl chloride, ethylene-vinyl acetate copolymer and the like, and those which can withstand heat sterilization are particularly desirable. Specific examples include Terpack, blood bag, Medifial I-300 (manufactured by Terumo) and the like.

The packaging material having a high gas barrier property used in the present invention is one that can withstand heat sterilization and has a carbon dioxide gas permeability of 50 ml / m ² · 24 hr · atm (25 ° C-70% RH) or less. Desirably, for example, polyethylene terephthalate (PET), ethylene vinyl alcohol copolymer (EV
OH), polyvinylidene chloride (PVDC), polyamide (PA), aluminum laminate, etc., or a multilayer film made of a combination of these materials,
Alternatively, those obtained by depositing metal oxide or ceramic on these multilayer films by vapor deposition may be used. Specifically, P
ET / EVOH / NY (nylon) / CPP (polypropylene) (manufactured by Fuji Sangyo Co., Ltd.), PET / alumina deposited PE
T / CPP (Fuji Sangyo Co., Ltd.), metal oxide vapor deposition PET / P
VDC-MA (methyl acrylate) / PA / CPP
(Manufactured by Hosokawa Yoko), PET / SiO _X vapor deposition PET / CP
P (manufactured by Toppan Printing Co., Ltd.) and the like.

As for the form of packaging the container with the gas barrier packaging material, vacuum packaging which is carried out by an ordinary process may be used.

Examples of the heat sterilization in the present invention include high-pressure steam sterilization and hot water sterilization. When high-pressure steam sterilization is performed, it is preferable that the temperature is 100 to 133 ° C., more preferably 100 to 126 ° C., and the time is 1 to 120 minutes, more preferably 5 to 60 minutes. When hot water sterilization is performed, it is preferable that the temperature is 60 to 100 ° C., more preferably 80 to 100 ° C., and the time is 30 to 60 minutes, more preferably 30 to 40 minutes.

[0016]

The present invention will be described below in more detail with reference to Examples and Comparative Examples. (Examples 1 to 8) Glucose, maltose, sodium chloride, potassium chloride, calcium chloride (dihydrate), magnesium chloride (hexahydrate), sodium lactate, and sodium hydrogencarbonate were each adjusted to have the concentrations shown in Table 12. Dissolved in water for injection.

The pH of the drug solution was adjusted to the value shown in the table by passing carbon dioxide gas or a nitrogen-carbonate mixed gas through this, and the solution was filtered through a 0.45 μm membrane filter to obtain 200 ml each in a soft plastic container (Medical I-300, Terumo). Manufactured). This is a packaging material with high gas barrier properties (EVOH [PET / EVOH / NY / CPP] (manufactured by Fuji Sangyo Co., Ltd.), PET-Al [PET / alumina vapor deposition PE]
T / CPP] (manufactured by Fuji Sangyo Co., Ltd.), PVDC [metal oxide deposition PET / PVDC-MA / PA / CPP] (manufactured by Hosokawa Yoko), PET-Si [PET / SiO _X deposition PET /
After vacuum packaging with CPP] (manufactured by Toppan Printing Co., Ltd.), high pressure steam sterilization (108 ° C., 25 minutes) was performed.

The liquid agent obtained by the above-mentioned production was sterilized for 24 hours or more, and then, coloring and precipitation were observed and pH was measured.
It also serves as an index for the decomposition of glucose and maltose.
The absorbance at 84 nm was measured. The results are shown in Table 1.

(Comparative Examples 1 and 2) A liquid agent filled in a soft plastic container in the same manner as in Examples was used as an unpackaged Comparative Example 1, a packaging material having a low gas barrier property (carbon dioxide gas permeability: 100 ml). / m ² · 24 hr · atm or more, NY [CPP / N
Y / CPP] (manufactured by Fuji Sangyo Co., Ltd.) was vacuum-packed as Comparative Example 2, and high-pressure steam sterilization was performed in the same manner as in Example, and the same evaluation was performed. The results are shown in Table 1.

[0020]

[Table 1]

As shown in the results, in each example, coloring, p
No decomposition of H or reducing sugar was observed, but in each comparative example, coloration, pH, and decomposition of reducing sugar were confirmed.
Further, no precipitation was observed in each of the examples and the comparative examples.

[0022]

As described above, according to the sterilization method of the present invention,
The one-component liquid agent containing reducing sugar and bicarbonate can be subjected to high-pressure steam sterilization or hot water sterilization while preventing decomposition and coloring of reducing sugar and increase in pH. Therefore, the present invention is mainly effective as a sterilization method for medical fluids in which reducing sugar and bicarbonate are combined into a single solution, such as infusion solution, artificial kidney perfusion solution, filtration type artificial kidney replenisher solution, and peritoneal dialysis solution. Can be used.

Claims (1)

[Claims] 1. A method for sterilizing a one-part liquid preparation containing reducing sugar and bicarbonate, wherein the liquid preparation is contained in a soft plastic bag, and then the soft plastic bag containing the liquid preparation is provided with a gas barrier property. A liquid agent sterilization method characterized by wrapping in a high packaging material and heat sterilization.