JPH119655A - Injection agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To restrict the increase of the number of particulates at the time of preserving an injection liquid formulation filled in a plastic container and to reduce an insoluble foreign matter and the particulates by permitting the density of oxigen gas inside a head space part and/or a secondary wrapping material to be equal to below specified vol.%. SOLUTION: The density of oxigen gas with a gas composition inside the head space part and/or the secondary wrapping material is adjusted to be equal to below 10 vol in an injecting agent which is filled in a gas transmissive plastic container and wrapped by an oxigen gas non-transmissive and secondary wrapping material. It is favorable that it is adjusted to be equal to below 7 vol. The adjusting method is the one, for example, for sealing inert gas such as nitrogen gas, etc., which does not contain oxigen gas between the plastic container and the secondary wrapping material or for sealing a disoxidizer. Or, the method is the one for bubbling the injecting liquid by inert gas or for replacing the head space part with inert gas. Thus, the increase of the number of the particulates at the time of preservation is restricted.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an injection.

[0002]

2. Description of the Related Art Injections used as pharmaceuticals are:
Conventionally, glass containers have been provided in a filled state. However, in recent years, due to the weight of the container and the risk of breakage, it has been increasingly provided to be filled in a plastic container. In particular, for a transfusion agent or the like having a large capacity and heavy weight, products provided using a plastic container such as a plastic bottle or a plastic bag are increasing.

[0003]

[0005] Such pharmaceuticals are:
During transportation and storage, they may be exposed to so-called hard conditions such as high temperature and high humidity. Under these conditions, in a plastic container filled drug,
The generation of insoluble foreign matter and / or the increase of fine particles, which are not observed in the conventional glass container, may be observed.

The present invention has been made in view of the above problems and has been completed as a result of intensive studies. It is an object of the present invention to provide a pharmaceutical composition filled in a plastic container, particularly an injection liquid formulation filled in a plastic container. An object of the present invention is to provide an injection which suppresses an increase in the number of fine particles and has few insoluble foreign substances and fine particles.

[0005]

The present inventors have studied the gas composition in the headspace portion and / or the secondary packaging material of the plastic container and found that the headspace portion and / or the secondary packaging material have been obtained. Oxygen gas concentration within a predetermined range (10
(% by volume or less), it has been found that an increase in the amount of fine particles can be suppressed, thereby providing the intended injection.

In an injection containing bicarbonate ions, the oxygen gas concentration in the headspace portion and / or the secondary packaging material is adjusted within the above range, and the carbon dioxide gas concentration is adjusted to 2 to 35 vol%. By doing so, a stable injection with few fine particles is provided.

That is, the present invention relates to (1) an injection which is filled in a gas-permeable plastic container and packaged with an oxygen gas-impermeable secondary packaging material. Composition is oxygen gas concentration 10vol
% Or less, (2) the injection according to (1), which contains bicarbonate ions,
(3) Bicarbonate ions are contained, and the gas composition in the head space portion and / or the secondary packaging material has a carbon dioxide gas concentration of 2 to 35 v
(1) to (3), wherein the injection is described in (1) or (2), and (4) an oxygen scavenger is enclosed in the secondary packaging material. The injection described in the above.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION As described above, an injection according to the present invention is intended to be filled in a gas-permeable plastic container and packaged with an oxygen-impermeable secondary packaging material. In the present invention, the gas composition in the head space portion and / or the secondary packaging material is adjusted to an oxygen gas concentration of 10 vol.
Adjust to less than%. Preferably, the gas composition in the headspace portion and / or the secondary packaging material is adjusted to an oxygen gas concentration of 7 vol.
%, More preferably, the oxygen gas concentration is adjusted to 5 vol% or less.

As a method for reducing the gas composition in the head space portion and / or the secondary packaging material to an oxygen gas concentration of 10 vol% or less, for example, a method in which oxygen gas is not contained between the plastic container and the secondary packaging material. The method of enclosing the active gas, and in this case, the inert gas includes, for example, nitrogen gas, carbon dioxide gas and the like. A method of encapsulating a deoxidizer between the container and the secondary packaging material, a method of bubbling the injection solution with the above-mentioned inert gas, a method of replacing the headspace portion with the above-mentioned inert gas, etc. This can be achieved by adopting the means described above.

As the plastic container used in the present invention, any plastic container generally used for medical purposes can be used. For example, polypropylene (PP) bags,
Examples include a polyethylene (PE) bag and an ethylene-vinyl acetate copolymer (EVA) bag.

As the secondary packaging material used in the present invention, a material that blocks the permeation of gas, especially oxygen gas, is suitable. For example, ethylene-vinyl alcohol copolymer (EVOH), polyvinylidene chloride (PVDC) ), Polyethylene terephthalate (PET), a vapor-deposited film of aluminum oxide or silicon oxide, an aluminum foil laminated film, and the like.

Examples of the oxygen scavenger include those utilizing the oxidation reaction of iron powder and iron compounds, those utilizing the action of adsorbing activated carbon, L-ascorbic acid (vitamin C),
Examples thereof include reductones such as reductic acid, and those utilizing an oxidation reaction of sugar, phenol, catechol, and the like.

[0013] Recently, a deoxidizing agent is enclosed in one layer of a multi-layer film, and a film used as a secondary packaging material itself has a deoxidizing function. Can be.

The injection in the present invention includes an injection in the Japanese Pharmacopoeia. In particular, such as infusions that are infused in large quantities, replenishers for filtration-type artificial kidney dialysis, and peritoneal dialysis agents,
It can be suitably applied to so-called electrolyte preparations.
Examples of the electrolyte preparation in this case include those in which sugars such as glucose and fructose or sugar alcohols such as xylitol are simultaneously added. Examples of these electrolyte preparations include so-called physiological saline, glucose injection, electrolyte infusion, high calorie infusion, Ringer's solution and the like.

The present invention is particularly suitable when the injection is a bicarbonate ion-containing injection. Such an injection is prepared, for example, by first dissolving a calcium salt (eg, CaCl 2), sodium hydrogen carbonate and sodium citrate in water, and bubbling carbon dioxide gas into the aqueous solution to adjust the pH to 6.3.
Adjust to ~ 7.3. Alternatively, a calcium salt excluding sodium hydrogen carbonate and citric acid are dissolved in water, the pH of the aqueous solution is adjusted in advance with an alkali (eg, NaOH), sodium hydrogen carbonate is added thereto, and the pH is adjusted by bubbling carbon dioxide gas. Adjust to 6.3 to 7.3. Next, these solutions are filtered and filled in a gas-permeable plastic container. Subsequently, high-pressure steam sterilization is performed. Finally, the container is packaged with an oxygen gas impermeable secondary packaging material, and a deoxidizer is sealed between the container and the secondary packaging material to produce a bicarbonate ion-containing sterile injection.

Further, instead of enclosing an oxygen scavenger,
For example, by filling an inert gas (e.g., carbon dioxide gas) containing no oxygen gas, the concentration can be adjusted so as to be within the oxygen gas concentration range (10 vol% or less) specified in the present invention.

In this case, the concentration of carbon dioxide in the secondary packaging material is preferably 2 to 35 vol%, more preferably 20 to 30 vol%, and the carbon dioxide concentration in the head space at that time. Is 2 to 20 vol
%, More preferably 10 to 15 vol%.

In this case, for example, (1) a step of dissolving each raw material for producing a liquid containing calcium ions and / or magnesium ions and bicarbonate ions and an alkali metal salt of citric acid in water; Filling the aqueous solution into a gas-permeable plastic container, and (3) sterilizing the container with a sterilized can having an appropriate concentration of carbon dioxide gas so that the pH of the liquid content is 6.7 to 7.5. ,
(4) packaging the container with a secondary packaging material and sealing an inert gas containing no oxygen gas between the container and the secondary packaging material to obtain a bicarbonate ion-containing sterile injection. Can be.

[0019]

The present invention will be described below in more detail with reference to Examples and Comparative Examples of the present invention.

Example 1 Reagents (composition components) shown in Table 1 below were dissolved in water, and the volume was increased to 10 liters. Next, after filtering this solution, 500 mL was filled into a gas-permeable plastic container (made of PP). Keep the container at 116 ° C for 14
After performing high-pressure steam sterilization for 2 minutes, the container was packaged with a secondary packaging material (aluminum oxide-deposited film), vacuum-packed or sealed with nitrogen gas to obtain a sterile sugar electrolyte injection.

[0021]

[Table 1]

Example 2 695 g of sodium hydrogen carbonate was dissolved in water, and the volume was adjusted to 50 liters. Next, after filtering this solution, a gas-permeable plastic container (PE
2L). This container was subjected to high-pressure steam sterilization at 112 ° C. for 40 minutes, and then the container was packaged with a secondary packaging material (aluminum oxide-deposited film), vacuum-packaged or filled with nitrogen gas to obtain a sodium hydrogencarbonate injection solution.

(Example 3) The reagents (composition components) shown in Table 2 below were dissolved in water (pH: 8.1), and the volume was increased to 10 liters, bubbling carbon dioxide gas, and adjusting the pH before sterilization to 6.6 to
Adjusted to 6.8. Next, after filtering this solution, 500 mL was filled into a gas-permeable plastic container (made of PP).
This container was subjected to high-pressure steam sterilization at 116 ° C. for 14 minutes. After sterilization, the container was packaged with a gas-impermeable secondary packaging material (aluminum oxide-deposited film), vacuum-packed or sealed with nitrogen gas to obtain a bicarbonate ion-containing aseptic injection.

[0024]

[Table 2]

For the sterile injections of Examples 1 to 3, 60
After storage at 10 ° C. for 10 days, “the number of fine particles (particles / mL), the oxygen gas concentration (vol%) in the secondary packaging material and in the head space” were measured, and the results are shown in Table 3. The number of fine particles (pieces /
mL) in the measurement of "Automatic particle counter in liquid" KL-0
1 "(manufactured by Lion Corporation)" and "gas chromatograph" GC-9A "(manufactured by Shimadzu Corporation)" were used for measuring the oxygen gas concentration (vol%) in the secondary packaging material and in the headspace.

The carbon dioxide gas concentration in the head space in the vacuum packaging of Example 2 was 3.4 vol%, and the carbon dioxide gas concentration in the secondary packaging material and the head space in the nitrogen gas sealing was 5.3 vol% and 2.1 vol%, respectively. %Met. The carbon dioxide gas concentration in the head space in the vacuum packaging of Example 3 was 14.6 vol%, and the carbon dioxide gas concentrations in the secondary packaging material and the head space in the nitrogen gas sealing were 7.9 vol% and 4.6 vol%, respectively.
Met.

[0027]

[Table 3]

Example 4 A product prepared in the same manner as in Example 3 was packaged in a gas-impermeable secondary packaging material (aluminum oxide-deposited film or oxygen-absorbing film), and vacuum-packed or carbonated. A gas containing 30 vol% of gas was sealed to obtain a sterile injection containing bicarbonate ions.

After storage at 60 ° C. for 10 days, the number of fine particles (particles / m
L), the oxygen gas concentration and the carbon dioxide gas concentration (vol%) in the secondary packaging material and the head space "were measured. The number of fine particles (particles / mL), the oxygen gas concentration and the carbon dioxide gas concentration (vol.
%), The same measuring equipment as in Examples 1 to 3 was used.

[0030]

[Table 4]

[0031]

According to the present invention, it is possible to provide a good injection containing few fine particles.

Claims (4)

[Claims] In an injection filled in a gas-permeable plastic container and packaged with an oxygen-impermeable secondary packaging material, the gas composition in the headspace portion and / or the secondary packaging material has an oxygen gas concentration of 10 vol. % Or less. 2. The injection according to claim 1, which contains bicarbonate ions. 3. A gas composition containing bicarbonate ions and having a gas composition in a headspace portion and / or a secondary packaging material having a carbon dioxide gas concentration of 2.
The injection according to claim 1, wherein the amount is −35 vol%. 4. The injection according to claim 1, wherein an oxygen scavenger is enclosed in the secondary packaging material.