JP2008068900A - Package - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To keep constant a pH value of a medical fluid containing hydrogen carbonate which a gas-permeable plastic container is filled with. <P>SOLUTION: A gas-impermeable package 3 stores the gas-permeable plastic container 2 in which the medical fluid 1 containing hydrogen carbonate is sealed. A deoxidizer 5 of a carbon dioxide gas absorption type is disposed in a space 6 around the plastic container 2 in the package. Using a gas injector, a carbon dioxide gas is added. Thereby, the space is substantially set to a gas atmosphere in which only a carbon dioxide gas and a nitrogen gas are present. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention mainly relates to a package for storing a medical drug for a long period of time, and can be suitably used particularly when it contains contents whose quality is impaired by the generation of carbon dioxide.

  The bicarbonate-containing chemical solution is normally sealed in a glass container, but replacement with a plastic container is progressing because glass flakes may be mixed into the chemical solution when opened. However, the plastic container has a low gas barrier property, and there is a problem that when the hydrogen carbonate-containing chemical solution is filled and left in the atmosphere, carbon dioxide gas is generated from the chemical solution and the pH of the aqueous solution increases. In response to such a problem, by disposing the carbon dioxide generating oxygen scavenger in the space between the package and the container, the inside of the package is replaced with carbon dioxide, thereby suppressing the generation of carbon dioxide from the contents. A technique for stabilization is disclosed (see, for example, Patent Document 1).

  When such a technique is used, the amount of carbon dioxide generated depends on the amount of oxygen in the space, so the amount of gas generated cannot be set arbitrarily, and the pH of the chemical solution is lowered and the bicarbonate content increases. Sometimes.

Further, even when a gas-impermeable package is used, if pinholes or the like are vacated in the package and the hermeticity of the package cannot be maintained, carbon dioxide gas is generated from the plastic container, and the pH of the chemical solution increases. However, it is difficult to visually confirm such changes from the outside.
Japanese Patent No. 2505329

  The present invention has been made in view of such background art, and an object thereof is to realize at least one of the following (A) or (B).

  (A) The pH value of the bicarbonate-containing chemical solution filled in the gas permeable plastic container is kept constant.

  (B) The increase in PH value of the bicarbonate-containing chemical solution filled in the gas permeable plastic container is made visible.

  In order to achieve the above object in the present invention, first, in the invention of claim 1, a gas non-permeable packaging body in which a gas permeable plastic container sealed with a hydrogen carbonate-containing chemical solution is stored, the plastic container A carbon dioxide absorbing oxygen scavenger is disposed in the surrounding space in the package, and carbon dioxide is added by a gas filling device, so that the space is substantially made up of only carbon dioxide and nitrogen gas. The package is characterized by being set to an existing gas atmosphere.

  According to a second aspect of the present invention, there is provided the package according to the first aspect, wherein an oxygen indicator is disposed on the package.

According to the first aspect of the present invention, a bicarbonate-containing chemical solution is obtained by the balance between the amount of carbon dioxide filled in the space inside the package around the plastic container by the gas filling device and the amount of carbon dioxide absorbed by the carbon dioxide-absorbing oxygen absorber. According to the PH value, the package body has an appropriate carbon dioxide gas concentration, so that the pH value of the bicarbonate-containing chemical solution can be suppressed and kept constant.

  In the invention of claim 2, in addition to the effect of claim 1, the carbon dioxide absorption deoxygenating agent can substantially reduce the oxygen concentration in the space portion to 0%. Later, when the pH value of the bicarbonate-containing chemical solution increases over time, the color tone of the oxygen indicator arranged in the package changes according to the increase, and this change not only reduces the gas barrier properties of the package. The increase can be visually recognized, and there is an effect that it is possible to prevent the use of a chemical solution having an increased PH value.

  The best embodiment of the present invention will be described below.

  As shown in FIG. 1, this embodiment is a gas-impermeable packaging body 3 in which a gas-permeable plastic container 2 sealed with a bicarbonate-containing chemical solution 1 is housed, and the packaging body 3 contains oxygen. An indicator 4 is printed, and a carbon dioxide absorption type oxygen scavenger 5 is disposed in the space portion 6 in the package 3 around the plastic container 2, and the space portion 6 is formed by a gas filling device. By adding carbon dioxide, the space 6 is set to a gas atmosphere in which only carbon dioxide and nitrogen gas are present.

  The bicarbonate-containing chemical solution corresponds to an aqueous solution of a single bicarbonate such as sodium bicarbonate or potassium bicarbonate or a mixture thereof. The compound concentration of the chemical solution containing these is appropriately set depending on the application, and may include other electrolytes.

  As the material of the plastic container for sealing the bicarbonate-containing chemical solution, it may be a gas permeable container that is highly safe and impervious to liquid since the chemical solution is in direct contact, preferably polyethylene, Polypropylene or the like can be suitably used.

  The gas-impermeable packaging body that accommodates the plastic container may have any gas barrier property and does not allow liquid to pass through, and is basically composed of a barrier base material and a sealant layer. As the sealant layer, a material having oxygen permeability and water vapor permeability, such as polyethylene and polypropylene, can be appropriately selected. As a barrier base material, the structure which uses a metal oxide vapor deposition film, an ethylene vinyl alcohol copolymer, polyvinyl alcohol, etc. as a barrier base material can be considered. In order to confirm the color tone of the oxygen indicator, it is desirable to have transparency.

  As the carbon dioxide-absorbing oxygen scavenger, those in which the main component of the oxygen scavenger absorbs carbon dioxide, such as an iron-based oxygen scavenger, can be suitably used. Here, if the oxygen scavenger is only disposed in the space between the plastic container and the gas-impermeable package, carbon dioxide gas is absorbed from the chemical solution sealed in the plastic container, and the pH of the chemical solution increases. However, this can be prevented by filling the carbon dioxide gas, and the pH of the chemical solution can be maintained at an appropriate value depending on the carbon dioxide gas concentration and the filling amount.

  As a redox indicator that is a component of the oxygen indicator, methylene blue, new methylene blue, neutral red, indigo carmine, acid red, safranin T, phenosafranine, capri blue, nile blue, diphenylamine, xylene cyanol, nitrodiphenylamine, ferroin, N-phenylanthranilic acid or the like can be used.

Moreover, as a reducing agent which is a component of the oxygen indicator, ascorbic acid, ascorbate, erythorbic acid, erythorbate, D-arabinose, D-erythrose, D-galactose, D-xylose, D-glucose, Reducing sugars such as D-mannose, D-fructose, and D-lactose, and metal salts such as stannous salts and ferrous salts can be used.

  The substrate on which the oxygen indicator is printed is preferably a substrate that does not react with the oxygen indicator and does not inhibit the coloration of the reagent. As such a substrate, synthetic resin films such as polyester, polyamide, polyvinyl alcohol, cellophane, ethylene vinyl alcohol copolymer, polyethylene, polypropylene, polymethylpentene, and transparent vapor deposition films such as silica and alumina, etc. It can be used according to the purpose and usage. The oxygen indicator can be printed on the aforementioned barrier substrate, or can be printed on the substrate and laminated between the barrier substrate and the sealant layer.

  An anchor coat layer and an overcoat layer can be provided for the purpose of protecting the oxygen indicator layer and preventing appearance defects, peeling, and breakage. The anchor coat layer is a water-insoluble material that has good adhesion between the substrate and the oxygen indicator layer formed thereon, and the overcoat layer is oxygen permeable and has an oxygen indicator layer. And a material having good adhesion to an adhesive layer or other resin layer that can optionally be further provided on the oxygen indicator layer can be preferably used. Two or more anchor coat layers and / or overcoat layers may be provided as necessary.

Examples of the present invention will be specifically described below.
<Example 1>
After 2.2 g of sodium bicarbonate was dissolved in 500 mL of distilled water, the pH of the solution was adjusted to 7.1 by adding an appropriate amount of potassium citrate and filled into a polyethylene container. The container is housed in a gas-impermeable package together with a carbon dioxide absorption type oxygen absorber, and the space between the container and the package is filled with 150 mL of mixed gas (carbon dioxide: nitrogen gas = 50: 50), and heat sealed. The package of Example 1 which accommodated the plastic container containing a hydrogen carbonate containing chemical | medical solution by sealing was produced.

  As the carbon dioxide absorbing oxygen scavenger, a freshness-preserving agent (F type manufactured by Toppan Printing Co., Ltd.) for head space of 150 mL was used.

  The layer structure of the package is “OPP30 / ONy15 / alumina-deposited PET12 / oxygen indicator layer / LLDPE60”. Here, the OPP 30 is a 30 μm thick film of biaxially stretched polypropylene. ONy15 is a stretched nylon film having a thickness of 15 μm. Alumina-deposited PET12 is a 12 μm thick film of biaxially stretched polyester deposited with alumina. LLDPE60 is a 60 μm film of linear low density polyethylene.

The oxygen indicator layer is printed in advance on the LLDPE side of the alumina-deposited PET film with the following prescription.
Oxygen indicator layer composition:
3 parts by weight of methylene blue, 7.5 parts by weight of L-ascorbic acid, 10 parts by weight of binder resin, 7.5 parts by weight of glycerin, and 0.6 parts by weight of synthetic silica.
Anchor coat layer, overcoat layer composition:
15 parts by weight of urethane resin.

<Example 2>
A package was produced in the same manner as in Example 1 except that the pH was adjusted to 6.8 and the mixed gas was changed to carbon dioxide gas: nitrogen gas = 95: 5.
Oxygen indicator layer composition: the same as in Example 1.
Anchor coat layer, overcoat layer composition: same as in Example 1.

<Example 3>
A package was produced in the same manner as in Example 1 except that the pH was adjusted to 6.8, and the mixed gas was changed to carbon dioxide gas: nitrogen gas = 95: 5 without filling the freshness-keeping agent.
Oxygen indicator layer composition: the same as in Example 1.
Anchor coat layer, overcoat layer composition: same as in Example 1.

<Example 4>
A package was produced in the same manner as in Example 1 except that the pH was adjusted to 8 and the mixed gas was changed to carbon dioxide gas: nitrogen gas = 10: 90.
Oxygen indicator layer composition: the same as in Example 1.
Anchor coat layer, overcoat layer composition: same as in Example 1.

<Example 5>
A package was produced in the same manner as in Example 1 except that degassing packaging was performed without filling the mixed gas.
Oxygen indicator layer composition: the same as in Example 1.
Anchor coat layer, overcoat layer composition: same as in Example 1.

<Example 6>
A package was prepared in the same manner as in Example 1 except that the space was changed to 150 mL of air without filling the mixed gas.
Oxygen indicator layer composition: the same as in Example 1.
Anchor coat layer, overcoat layer composition: same as in Example 1.

<Example 7>
A package was prepared in the same manner as in Example 1 except that the space was changed to 150 mL of nitrogen without filling with the mixed gas.
Oxygen indicator layer composition: the same as in Example 1.
Anchor coat layer, overcoat layer composition: same as in Example 1.

<Example 8>
It was not stored in the exterior body and left in the atmosphere.

<Example 9>
A package was prepared in the same manner as in Example 1 except that the mixed gas was not used and the space portion was 150 mL of air, and the non-carbon dioxide generating oxygen scavenger headspace was used for 150 mL.
Oxygen indicator layer composition: the same as in Example 1.
Anchor coat layer, overcoat layer composition: same as in Example 1.

<Example 10>
A package was prepared in the same manner as in Example 1 except that the space portion was 150 mL of air without using a mixed gas, and a carbon dioxide-generating oxygen scavenger (C type manufactured by Toppan Printing Co., Ltd.) headspace was used. Produced.
Oxygen indicator layer composition: the same as in Example 1.
Anchor coat layer, overcoat layer composition: same as in Example 1.

[Experiment 1]
With respect to the above prepared sample, the drug pH, the oxygen indicator color tone, the carbon dioxide concentration in the space portion, and the oxygen concentration were confirmed by evaluation at 60 ° C. and 75% RH × 2 weeks.

Before drug pH test After Oxygen indicator color tone Carbon dioxide concentration Oxygen concentration Example 1 7.2 7.2 Pink 20% 0%
Example 2 6.8 6.9 Pink 70% 0%
Example 3 6.8 6.8 Blue 90% 5%
Example 4 8.0 8.0 Pink 7% 0%
Example 5 7.2 7.5 Pink 5% 0%
Example 6 7.2 7.8 Pink 2% 0%
Example 7 7.2 7.8 Pink 2% 0%
Example 8 7.2 8.9 Blue--
Example 9 7.2 7.5 Pink 5% 0%
Example 10 7.2 7.0 Pink 25% 0%

From the above results, when a carbon dioxide absorption deoxidizer is used, it is possible to suppress an increase in pH only when a mixed gas of carbon dioxide and nitrogen gas is used. Further, by using a mixed gas having an appropriate carbon dioxide concentration depending on the initial pH value, an increase in pH can be suppressed.

  When a non-carbon dioxide-generating oxygen scavenger was used, the increase in PH resulted in the same result as when degassing.

  In addition, when a carbonic acid generating oxygen scavenger was used, a slight decrease in pH was observed.

  From the above, it was shown that the chemical PH can be set more accurately by the combination of carbon dioxide replacement and carbon dioxide absorption-type oxygen absorber.

  In addition, when filling a mixed gas of carbon dioxide gas and nitrogen gas into the space around the plastic container with the gas displacement device, the space portion must be filled with a carbon dioxide absorbing oxygen scavenger. The oxygen concentration does not become substantially 0%, and the color tone of the oxygen indicator remains the oxidized blue color.

  On the other hand, the color tone of the oxygen indicator is pink as long as it is in a deoxygenated state. Thereby, it was shown that the oxygen indicator functioned stably over a long period of time.

[Experiment 2]
Regarding the sample of Example 1, after confirming that the oxygen indicator became pink, the package was opened, and the drug pH, oxygen indicator color tone, carbon dioxide concentration, and oxygen concentration were investigated over time.

Drug pH Oxygen indicator color tone Carbon dioxide concentration Immediately after oxygen concentration 7.1 Pink 22% 0%
12 hours later 7.2 Purple 0% 21%
24 hours later 7.4 Blue 0% 21%
48 hours later 7.6 Dark blue 0% 21%
96 hours later 7.8 Dark blue − −

From the above results, the pH gradually increased after the inside of the package became open to the atmosphere. Along with this, the color tone of the oxygen indicator changed, and the increase in pH could be confirmed by the color tone. On the other hand, no increase in pH could be observed from the appearance of the chemical solution.

The front view of the package of this embodiment.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 ... Hydrogen carbonate containing chemical | medical solution 2 ... Plastic container 3 ... Package 4 ... Oxygen indicator 5 ... Carbon dioxide absorption deoxidizer 6 ... Space part

Claims (2)

  A gas-impermeable packaging body in which a gas-permeable plastic container sealed with a hydrogen carbonate-containing chemical solution is housed, and a carbon dioxide-absorbing oxygen scavenger is disposed in a space in the packaging body around the plastic container. The package is characterized in that, by adding carbon dioxide gas with a gas filling device, the space portion is set to a gas atmosphere in which only carbon dioxide gas and nitrogen gas are substantially present.   The package according to claim 1, wherein an oxygen indicator is disposed on the package.