TW201603801A - Packaged acetaminophen injection solution preparation - Google Patents

Abstract

A packaged acetaminophen injection solution preparation (1) comprises an oxygen-impermeable packaging container (2) and an acetaminophen injection solution preparation including acetaminophen aqueous solution of pH 4 to 8 containing acetaminophen as an active ingredient and a sealed oxygen-permeable container (3) filling the acetaminophen aqueous solution. The acetaminophen injection solution preparation is sterilized by moist heat sterilization. The oxygen-impermeable packaging container (2) encloses the acetaminophen injection solution preparation and is sealed. The packaged acetaminophen injection solution preparation has an oxygen scavenger (4) to absorb oxygen within the oxygen-impermeable packaging container.

Description

Packaged acetaminophen injection solution preparation

This invention relates to a packaged acetaminophen injection solution formulation. More particularly, the present invention relates to a packaged acetaminophen phenol injection solution formulation which is excellent in storage stability, which permits acetaminophen to remain stable in the solution even after storage for a long period of time at room temperature.

Acetaminophen (synonymous with paracetamol) is a mild antipyretic/analgesic that does not have stomach irritation, inhibits blood clotting, kidney disease, and side effects such as excitement and lethargy. Furthermore, it does not include the symptoms of drug addiction and withdrawal symptoms. This is why the acetaminophen in the form of oral drugs and suppositories is one of the most popular antipyretics/analgesics in the world.

Acetaminophen can also be obtained in the form of an injection solution formulation which is an aqueous solution of acetaminophen in a container. Because it appeared in overseas markets in 2002, it has been approved for manufacturing and sale in about 80 countries (except Japan), including the US and European countries. It is now used for standard treatment of post-operative pain.

In the known acetaminophen phenol injection solution preparation, in order to maintain stability during long-term storage, the aqueous solution of acetaminophen is filled and sealed in a nitrogen atmosphere after deoxygenation (blowing by an inert gas). In a glass bottle, and then subjected to moist heat sterilization (see USP 6028222, hereafter referred to as Patent Document 1). There has been proposed a method of maintaining the oxygen content in an aqueous solution of acetaminophen at a low level of 0.4 to 4 mg/liter by subjecting the aqueous solution to ultrasonication and either or both of filtration and micro-blowing. (See US 2009044700A, hereafter referred to as Patent Document 2).

Following the techniques described in the above-referenced USP 6028222 and US 2009044700A, the present inventors prepared an acetaminophen phenol injection solution formulation filled in a bag by subjecting an aqueous solution of acetaminophen to deoxygenation ( It is filled and sealed in a container (particularly, a bag of an organic polymer sheet) in an inert gas atmosphere by an inert gas blowing, and subjected to moist heat sterilization (pressurization with an inert gas such as nitrogen). Due to the storage stability test, it has been found that although the deoxygenation treatment is carried out in each step, the acetaminophen phenol injection solution preparation is not satisfactory in long-term storage stability.

It is an object of the present invention to provide a packaged acetaminophen phenol injection solution preparation which is excellent in long-term storage stability, which retains an extremely high ratio of acetaminophen even after storage for three years or longer at room temperature, Therefore, it can be safely stored for a long period of time.

Another object of the present invention is to provide a packaged acetaminophen phenol injection solution formulation which is held in a container formed from an organic polymer film or sheet, particularly a bag-shaped container, which is suitable for use at room temperature It is safe to store for a long time and is light in weight and has good operability without damage.

In order to achieve the foregoing objectives, the inventors conducted extensive research and have suggested that the long-term storage stability is not attributable to the oxygen control contained in the manufacture of the acetaminophen injection solution formulation. In order to clarify whether this is true, the inventors made samples of the acetaminophen phenol injection solution preparation in the following different ways, and tested their storage stability.

That is, the present inventors manufactured the acetaminophen phenol injection solution preparation in the above-mentioned manner, which comprises the steps of preparing an aqueous solution of acetaminophen phenol before filling in a container, and filling the aqueous solution of acetaminophen phenol in The step in the vessel, the step of moist heat sterilization (in other words, high pressure steam sterilization and hot press sterilization) in a vessel filled with the aqueous solution of acetaminophen; all steps are carried out by introducing an inert gas or in an inert gas atmosphere. In addition, the inventors have prepared the acetaminophen phenol injection solution formulation in such a manner that one or two or all of the steps are carried out in air (instead of an inert atmosphere).

The results of the foregoing experiments indicate that, unlike the known materials described in the above-mentioned Patent Documents 1 and 2, the long-term storage stability of the acetaminophen phenol injection solution preparation is only slightly affected by exposure to oxygen. The step of preparing the aqueous solution of the acetaminophen phenol before filling the container, the step of loading the aqueous solution of the acetaminophen phenol in the container, and applying the moist heat sterilization to the container filled with the aqueous solution of the acetaminophen phenol. step.

The present inventors have speculated from the foregoing that the deterioration and decomposition of the acetaminophen phenol injection solution formulation are slightly affected by the short-term oxygen control performed in the manufacturing stage thereof, but the effect occurs during storage after manufacture. As a result, the inventors have understood that acetaminophen phenol reacts with oxygen not rapidly but rather slowly.

The inventors have assumed the following.

Oxygen control (inhalation by an inert gas such as nitrogen) at the time of preparation of an aqueous solution of acetaminophen, oxygen control (in an inert gas atmosphere) at the time of loading an aqueous solution of acetaminophen into a container, and Oxygen control (pressurization with inert gas) at the time of moist heat sterilization is not essential. Any gradual removal of the oxygen in the acetaminophen formulation packaged for sale is important. Long-term storage stability can be obtained if the acetaminophen in its aqueous solution is protected from deterioration and decomposition during storage by removing oxygen in the acetaminophen formulation that is packaged for sale. Excellent formulation of acetaminophen injection solution. The inventors have noted the foregoing for reviewing a variety of possible methods.

Finally, the inventors have found that the above object is achieved by filling an aqueous solution of acetaminophen in a two-container form consisting of an oxygen permeable inner container and an oxygen-impermeable outer container, wherein the space between the two containers is Store an oxygen scavenger. The two-layer container permits the gradual removal of oxygen from the apex space of the aqueous solution of acetaminophen and the inner vessel containing the aqueous solution of acetaminophen during storage. In this way, a considerable reduction in oxygen from the inner container is achieved to promote long-term storage stability of the acetaminophen phenol injection solution formulation. This finding led to the present invention.

The method used to achieve the goal is as described below.

The packaged acetaminophen phenol injection solution preparation comprises an oxygen-impermeable packaging container, and an acetaminophen phenol injection solution preparation comprising an aqueous solution of acetaminophen having pH 4 to 8 containing acetaminophen phenol as an active ingredient, And one a sealed oxygen permeable container filled with the aqueous solution of acetaminophen phenol, wherein the acetaminophen phenol injection solution preparation is sterilized by moist heat sterilization, and the oxygen-impermeable packaging container surrounds the acetaminophen phenol injection solution preparation and The seal, and the packaged acetaminophen injection solution formulation, has an oxygen scavenger to absorb oxygen in the sealed oxygen-impermeable packaging container.

1‧‧‧Packed acetaminophen injection solution preparation

2‧‧‧Oxygen-impermeable packaging containers

3‧‧‧ Sealed oxygen permeable container

4‧‧‧Deoxidizer

31‧‧‧ container body

32‧‧‧Sealing components

Fig. 1 is a plan view showing a specific example of the preparation of the acetaminophen injection solution of the present invention.

The following is a detailed description of the invention.

The packaged acetaminophen injection solution preparation of the present invention comprises an acetaminophen phenol injection solution preparation and an oxygen-impermeable packaging container. The acetaminophen phenol injection solution preparation is sterilized by a moist heat sterilization method (in other words, high pressure steam sterilization or hot pressure sterilization). The oxygen-impermeable packaging container surrounds the acetamide phenol injection solution formulation and is sealed. The packaged acetaminophen phenol injection solution formulation has an oxygen scavenger to absorb oxygen in the sealed oxygen-impermeable packaging container.

In other words, the present invention relates to an acetaminophen phenol injection solution preparation which comprises the following: an aqueous solution of acetaminophen phenol containing acetaminophen as an active ingredient; and an oxygen permeable inner container in which the aqueous solution is accommodated , which has been subjected to moist heat sterilization after filling; and a tightly sealed oxygen-impermeable An outer container (in other words, a packaging container) that houses the inner container together; and an oxygen scavenger placed between the inner and outer containers.

The acetaminophen phenol injection solution formulation comprises the sealed oxygen permeable container and the aqueous acetaminophen phenol solution in the sealed oxygen permeable container. In particular, in the embodiment shown in Figure 1, the packaged acetaminophen injection solution formulation comprises the acetaminophen phenol injection solution formulation, the oxygen-impermeable packaging container, and the oxygen scavenger. The oxygen-impermeable packaging container surrounds the acetaminophen phenol injection solution formulation and the oxygen scavenger. Further, the oxygen scavenger is disposed in a space between the packaging container and the sealed oxygen permeable container filled with the aqueous solution of acetaminophen. However, the oxygen-impermeable packaging container or the sealed oxygen-permeable container may have the oxygen scavenger. The acetaminophen phenol can be any type which is usually used in an injection solution, an oral drug, and a suppository. It can also be used in the form of a physiologically acceptable salt.

The acetaminophen phenol injection solution preparation of the present invention comprises the aqueous acetaminophen phenol solution filled in an oxygen permeable container having a pH of 4 to 8, preferably pH 5 to 6. If the pH is lower than 4, the aqueous solution of acetaminophen phenol is poor in storage stability; if the pH is higher than 8, the aqueous solution of acetaminophen tends to stimulate blood vessels when administered by injection (causing vascular pain) And inflammation).

The aqueous solution of acetaminophen can be adjusted to pH by any of the conventional pH adjusting agents for injecting solutions. Examples of the pH adjusting agent include a base such as sodium hydroxide and potassium hydroxide; an inorganic acid such as hydrochloric acid; and an organic acid such as citric acid, lactic acid, acetic acid, succinic acid, and malic acid. What is desired is that less salt is formed when the pH adjustment is completed. Therefore, as the pH adjustment, sodium hydroxide (strong base) and hydrochloric acid (strong acid) are preferred.

The aqueous solution of acetaminophen to be filled in the oxygen permeable container should Prepared from pharmacologically and physiologically acceptable waters such as distilled water, water, purified water, sterile pure water, water for injection, and distilled water for injection. These types of water systems are defined in Japanese Pharmacopoeia, 16th Edition.

When used as an intravenous injection solution, the aqueous solution of acetaminophen should include an amount of 2 to 50 mg/ml of acetaminophen, preferably 5 to 5, from the viewpoint of desired solubility and efficiency and dosage. 10 mg / ml.

If the concentration is too low, it is necessary to administer the aqueous solution of acetaminophen in a large amount to the patient. If the concentration is too high, the aqueous acetaminophen phenol tends to precipitate at a low temperature due to the low solubility of acetaminophen.

In addition to the aforementioned pH adjusting agent, the aqueous solution of acetaminophen should preferably include one or two or more tonicity agents, antioxidants, and buffer species.

The tonicity agent may be selected from any of the existing use solutions for injection. It includes, for example, nonionics such as mannitol, sorbitol, inositol, glucose, propylene glycol, and glycerin; and ionic, such as sodium chloride. One or two or more of them may be used. Among these examples, mannitol is preferred from the viewpoint of sterilization safety and stability.

The tonicity agent should be added in an amount sufficient to cause the acetaminophen phenol injection solution to have an osmotic pressure which is approximately or exactly the same as the serum (so the ratio of the osmotic pressure is 0.9 to 1.1).

The antioxidant may be selected from any of the existing use solutions for injection. It includes, for example, an organic compound having a thiol functional group (such as cysteine), a salt form thereof, and a hydrate thereof (for example, cysteine acid hydrate); a sulfite such as sodium hydrogen sulfite; ascorbic acid. Or a salt thereof; and dibutylhydroxyl Toluene. Among these examples, cysteine acid hydrate (typically cysteine acid monohydrate) is preferred from a physiological point of view.

The buffer may be selected from any of the existing solutions for injection. It includes, for example, phosphoric acid or a salt thereof or a hydrate thereof (for example, sodium hydrogen phosphate hydrate), citric acid or a salt thereof or a hydrate thereof, and acetic acid or a salt thereof or a hydrate thereof. In these examples, anhydrous sodium hydrogen phosphate or a hydrate thereof is preferred from the viewpoint of stability and solubility of the drug substance. The sodium hydrogen phosphate should preferably be in the form of a disodium salt. The sodium hydrogen phosphate hydrate should preferably be in the form of a dihydrate, heptahydrate or dodecahydrate.

The aqueous solution of acetaminophen may optionally include one or two or more additional medicinal active ingredient species such as analgesics, anti-inflammatory agents, antiemetics, anti-epileptics, antidepressants, and antivirals; or Agents such as polyols, complexing agents, alkanols and vitamins.

The aqueous acetaminophen phenol solution can be prepared in any manner without particular limitation as long as a homogeneous solution is obtained without acetaminophen and the aforementioned components are deteriorated and decomposed.

The method for preparing an aqueous solution of acetaminophen phenol can be carried out in the air or in an inert gas atmosphere or in an atmosphere of air and an inert gas.

In the case where the environment is a mixture of air and an inert gas, the mixing ratio (air to inert gas) should be from 1:99 to 99:1, preferably from 10:90 to 90:10 by volume.

Further, the aqueous solution of acetaminophen may be blown with an inert gas during and/or after its preparation to reduce the oxygen content therein. Furthermore, the aqueous solution of acetaminophen may be such that it does not occur during or after its preparation. It is filled in an oxygen permeable container by blowing with an inert gas.

The inert gas to be used for blowing into the aqueous solution of acetaminophen may be any of nitrogen, argon and carbon dioxide gas, and nitrogen is preferred because of its low availability.

Subsequently, the aqueous solution of acetaminophen was filled in an oxygen permeable container. The oxygen permeable container is not particularly limited as long as it is made of any material which is permeable to oxygen but non-toxic, does not adsorb acetaminophen, and is impermeable to hot liquid (water) resistant to moist heat sterilization.

The oxygen permeable container should have an oxygen permeability of not less than 200 cubic centimeters per square meter per day measured at 23 ° C and 90% RH at atmospheric pressure (1013 hPa). The oxygen permeability should preferably be not less than 500 cubic centimeters per square meter per day, more preferably not less than 700 cubic centimeters per square meter per day, and most desirably 700 to 10,000 cubic centimeters per square centimeter. Ruler/day.

As long as the oxygen permeable container has oxygen permeability at 23 ° C and 90% RH and is not less than 200 cubic centimeters per square meter per day at atmospheric pressure (1013 hPa), it is permitted to be brought into the oxygen permeable container when filled. The oxygen contained in the aqueous solution of the aqueous solution of acetaminophen and the container and through the oxygen permeable container is sufficiently absorbed and removed by the oxygen scavenger.

The oxygen permeable container should preferably have as high an oxygen permeability as possible in order to permit the aqueous solution of acetaminophen contained therein and the oxygen in the headspace therein to be easily absorbed and removed by the oxygen scavenger.

The oxygen permeable container can be a flexible container or a solid container. Preferably, it is formed from an organic polymer that is permeable to oxygen but impermeable to liquid (water). It should be better that it is permeable to oxygen but not to liquid (water). The organic polymer is formed and is in the form of a film or a sheet. It should be preferred that it is formed from an organic polymer that is permeable to oxygen but impermeable to liquid (water) and is in the form of a soft (flexible) film or sheet.

The organic polymer permeable to oxygen but not liquid (water) forming the oxygen permeable container may include, for example, a polyethylene resin, a polypropylene resin, a mixture of a polyethylene resin and a polypropylene resin, and an ethylene-vinyl acetate copolymer. , PVC resin and a variety of thermoplastic elastomers. The oxygen permeable flexible container can be formed from an organic polymer composition, wherein a solid organic polymer as a substrate is incorporated into a plasticizer or a compatible soft organic polymer (such as a thermoplastic elastomer, including styrene). A thermoplastic elastomer of the substrate and a thermoplastic elastomer based on an olefin).

The oxygen permeable container may be a single layer structure formed of the foregoing organic polymer or a multilayer structure having two or more layers.

The oxygen permeable container formed from the oxygen permeable organic polymer film or sheet should have a wall thickness of 50 to 500 μm, preferably 100 to 300 μm, in order to satisfy the requirements for oxygen permeability and container performance. For containers having sufficient strength and sufficient resistance to moist heat sterilization, a thickness equal to or greater than 50 microns is sufficient. Similarly, for a desired oxygen permeability and for a pouch type container for an acetamide phenol injection solution formulation having a suitable elasticity, a thickness of 500 μm or less is desirable.

The oxygen permeable container should preferably have a crucible in which an aqueous solution of acetaminophen (or an injection solution) filled in the container is discharged from the container and administered to the patient. In the case of using an injection needle for discharge, the crucible can provide a resilient plug. The elastic plug is made of an elastomer or rubber, which is preferably The needle is pierced and the piercing is closed (resealed) after the needle has been removed. The material of the elastic plug includes butyl rubber, isoprene rubber, chlorinated butyl rubber (chloroprene), and the like. Furthermore, the elastic plug may have a surface (at least in contact with the aqueous solution of acetaminophen) coated with a fluorine-based resin, parylene, DLC (Drilling Carbon), polypropylene, polyethylene or An analog layer attached thereto or deposited thereon so that any components contained in the elastic plug are not dissolved in the aqueous solution of acetaminophen.

The shape of the oxygen permeable container is not particularly limited and may be in the form of a bag, a bottle, a syringe, a blister or the like.

The oxygen permeable container can be formed in any manner without particular limitation. Any suitable manufacturing method can be employed depending on the type of material used and the shape of the container. Embodiments of the manufacturing method include extrusion blow molding, injection blow molding, inflation molding, injection molding, casting, flat film or sheet heat sealing by folding a closed heat seal, a cylindrical film or a sheet to close the top end And a cylindrical body having a bottom and an end cap.

The size of the oxygen permeable container is not particularly limited. The appropriate size depends on the form and concentration of the acetaminophen phenol injection solution formulation, which is typically such that the internal volume is from 20 to 500 cubic centimeters, preferably from 50 to 100 cubic centimeters. This size is convenient for handling and patient water control.

The aqueous acetaminophen phenol can be loaded into the oxygen permeable container in air, in an inert gas atmosphere, or in an environment of a mixture of air and an inert gas. The inert gas may be, for example, nitrogen, argon, carbon dioxide gas or the like. Nitrogen is preferred because of its low availability. Again, the filling step can be followed by degassing.

In the case where an aqueous solution of acetaminophen is filled in an oxygen permeable container in an environment of a mixture of air and an inert gas, the mixing ratio of the air to the inert gas should preferably be 1:99 to 99:1 (by volume) ), more preferably 10:90 to 90:10 (by volume).

The oxygen permeable container filled with the aqueous acetamide phenol solution is then subjected to moist heat sterilization. This procedure can be achieved by using steam as a sterilizing medium and air as a pressurized medium, or using steam as a sterilizing medium and an inert gas as a pressurized medium, or using steam as a sterilizing medium and a mixture of air and an inert gas as a pressurized medium. The inert gas used for this purpose may be, for example, nitrogen, argon, carbon dioxide gas or the like. Nitrogen is preferred because of its low availability.

In the case where a mixture of air and an inert gas is used as the pressurized medium, the mixing ratio of the air to the inert gas should preferably be 1:99 to 99:1 (by volume), more preferably 10:90 to 90: 10 (by volume).

The moist heat sterilization method can be carried out under any conditions (temperature, pressure, time, etc.) which are normally used in the preparation of the bactericidal injection solution. For example, the temperature should be from 100 to 129 ° C, preferably from 115 to 124 ° C.

According to the present invention, the step of preparing an aqueous solution of acetaminophen before filling in a container, the step of loading an aqueous solution of acetaminophen in an oxygen permeable container, and at least one step of moist heat sterilization Either two or all of them can be carried out in an environment where an inert gas is introduced or in an inert gas atmosphere. Furthermore, all steps can be carried out in an air environment. The combination of these modes is set forth below.

(1) The aqueous solution of the acetaminophen phenol (implemented in an inert gas shed) and the aqueous solution of the acetaminophen phenol are blown with an inert gas in an inert gas atmosphere. The aqueous solution of acetaminophen is filled in an oxygen-permeable container under an inert gas atmosphere, and the oxygen-permeable container containing the aqueous solution of acetaminophen is subjected to moist heat sterilization using an inert gas as a pressurized medium.

(2) Performing either or both of the aqueous solution of acetaminophen (implemented in an inert gas shed) and the blowing of the aqueous acetamide phenol solution with an inert gas in an inert gas atmosphere. The aqueous solution of acetaminophen is charged in an oxygen-permeable container under an inert gas atmosphere, and the oxygen-permeable container containing the aqueous solution of acetaminophen is subjected to moist heat sterilization using air as a pressurized medium.

(3) Either or both of the aqueous solution of acetaminophen (implemented in an inert gas shed) and the aqueous solution of the acetaminophen phenol are blown with an inert gas in an inert gas atmosphere. On the other hand, the aqueous solution of acetaminophen is charged in an oxygen-permeable container in an inert gas atmosphere, and the oxygen-permeable container containing the aqueous solution of the acetaminophen is subjected to moist heat sterilization using an inert gas as a pressurized medium.

(4) Either or both of the aqueous solution of acetaminophen (implemented in an inert gas shed) and the aqueous solution of the acetaminophen phenol are blown with an inert gas in an inert gas atmosphere. Further, the aqueous solution of acetaminophen was charged in an oxygen-permeable container under an inert gas atmosphere, but the oxygen-permeable container containing the aqueous solution of acetaminophen was subjected to moist heat sterilization using air as a pressurized medium.

(5) Performing either or both of the aqueous solution of acetaminophen (implemented in an inert gas shed) and the blowing of the aqueous acetamide phenol solution with an inert gas in an inert gas atmosphere. The aqueous solution of acetaminophen is filled in air The oxygen permeable container and the oxygen permeable container containing the aqueous acetamide phenol solution are subjected to moist heat sterilization using an inert gas as a pressurized medium.

(6) The aqueous solution of acetaminophen is prepared in the absence of an inert gas atmosphere (achieved in an inert gas shed) and the aqueous solution of acetaminophen is not blown with an inert gas. The acetaminophen phenol aqueous solution is filled in an oxygen permeable container in the air, and the oxygen permeable container containing the acetaminophen phenol aqueous solution is subjected to moist heat sterilization using air as a pressurizing medium.

(7) In any one of the above-mentioned modes (1) to (6), the aqueous solution of acetaminophen is filled in a mixture of air and an inert gas in an oxygen permeable container, and/or contains the acetamidine. The oxygen permeable container of the aqueous solution of the amine phenol is subjected to moist heat sterilization using a mixture of air and an inert gas as a pressurizing medium.

After the moist heat sterilization, the oxygen permeable container containing the aqueous solution of acetaminophen is placed and sealed in the oxygen-impermeable outer container together with the oxygen scavenger.

The oxygen-impermeable outer container (packaging container) is not particularly limited in its performance as long as it can be filled with an oxygen permeable container containing an aqueous solution of acetaminophen and an oxygen scavenger, and is impermeable to oxygen and non-toxic.

The oxygen-impermeable outer container (packaging container) should have oxygen permeability of not more than 1.0 cubic centimeter/m 2 /day measured at normal pressure (1013 hPa) at 23 ° C and 90% RH. The oxygen permeability should preferably be no more than 0.3 cubic centimeters per square meter per day, and more preferably no more than 0.1 cubic centimeter per square meter per day.

As long as the oxygen-impermeable outer container (packaging container) has oxygen permeability at 23 ° C and 90% RH and is not higher than 1.0 cubic centimeter / square meter / day at normal pressure (1013 hPa), it is permitted therein. The oxygen scavenger sufficiently absorbs and removes the aqueous solution of acetaminophen contained in the oxygen permeable container and in the oxygen permeable container The apex space releases oxygen passing through the oxygen permeable container while obstructing air (oxygen) outside the oxygen permeable outer container.

The oxygen-impermeable outer container (packaging container) should preferably have as low oxygen permeability as possible in order to permit the oxygen scavenger to easily absorb and remove the aqueous solution of acetaminophen contained in the oxygen permeable container. Oxygen released from the headspace in the oxygen permeable container.

The oxygen-impermeable outer container (packaging container) may be a flexible container or a solid container. The oxygen-impermeable outer container is preferably formed from an impermeable organic polymer film or sheet. The impermeable organic polymer film and sheet preferably have elasticity.

The oxygen-impermeable outer container (packaging container) can be made from an oxygen-impermeable metal foil (such as aluminum foil), a deposited film or sheet, an organic polymer film or sheet coated with DLC (drill-like coating), and never penetrated. An oxygen-containing resin such as an oxygen-impermeable film or sheet formed of polyvinyl alcohol or ethylene-vinyl alcohol, a laminated film or sheet, and a multilayer film or sheet are formed. The deposited film or sheet may be composed of a substrate film or sheet made of an organic polymer and a coating layer. The coating layer deposited on the substrate film or sheet may be a ceramic such as cerium oxide, aluminum oxide, and titanium oxide or a metal. The deposited film or sheet comprises an organic polymer film or sheet on which aluminum is deposited, an organic polymer film or sheet on which cerium oxide is deposited, an organic polymer film or sheet on which titanium oxide is deposited. The laminated film or sheet may be composed of an oxygen-impermeable resin layer such as polyvinyl alcohol or ethylene-vinyl alcohol, which is layered on the other layer. The multilayer film or sheet may be composed of one or two or more layers of the above-mentioned oxygen-impermeable film or sheet and a layer made of other organic polymers other than those mentioned above, which layer one layer on the other layer. .

The oxygen-impermeable outer container (packaging container) is never oxygen-permeable. In the case where a polymer film or sheet is formed, the inner layer of the oxygen-impermeable film or sheet should preferably be formed from a heat-sealable organic polymer because the oxygen-impermeable outer container (packaging container) is usually heated. A seal is formed around the folded film or sheet.

The oxygen-impermeable outer container (packaging container) can be formed from any of the materials exemplified below without particular limitation.

The multilayer film or sheet consists of polypropylene (PP), polyethylene terephthalate (PET) and polypropylene (PP) deposited as cerium oxide, which are layered on top of one another in the order mentioned. .

The multilayer film or sheet is composed of biaxially oriented polyamine (OPA), polyethylene (PE), aluminum-deposited PET, and polyethylene, which are layered on top of one another in the order mentioned.

The multilayer film or sheet consists of OPA, PE, aluminum-deposited PET and PE which are layered on top of one another in the order mentioned.

The multilayer film or sheet consists of OPA, PE, aluminum foil, PE and PE which are layered on top of one another in the order mentioned.

The multilayer film or sheet consists of OPA, PE, aluminum foil, PE, PET and PE which are layered on top of one another in the order mentioned.

The multilayer film or sheet consists of PET, PE, aluminum-deposited PET, PE, ethylene-vinyl acetate copolymer (EVA) and PE which are layered on top of one another in the order mentioned.

The multilayer film or sheet consists of polyvinylidene chloride, PE, aluminum-deposited PET and PE which are layered on top of one another in the order mentioned.

The multilayer film or sheet consists of PET, aluminum-deposited ethylene-vinyl alcohol copolymer (EVOH) and PE are constructed by laminating one layer on another layer in the order mentioned.

In the case where the oxygen-impermeable outer container (packaging container) is formed from an oxygen-impermeable organic polymer film or sheet, the oxygen-impermeable film or sheet should have a thickness of 50 to 150 μm, preferably 65 to 100 microns so that it meets the need for oxygen impermeability and container performance. The thickness of the oxygen-impermeable film or sheet of not less than 50 μm is sufficient to provide an outer container (packaging container) having an appropriate strength. A flexible bag type outer container suitable for the preparation of the acetaminophen phenol injection solution having a thickness of not more than 150 μm has appropriate elasticity and light weight.

The oxygen scavenger is packaged in the oxygen-impermeable outer container (packaging container) together with the oxygen-permeable container containing the aqueous solution of the acetaminophen phenol, and is not particularly limited as long as it is non-toxic and can effectively absorb oxygen to reduce Oxygen concentration in the environment.

Examples of the oxygen scavenger include metal powders (such as iron powder), inorganic substances (such as sulfites and metal halides), and organic substances (such as ascorbic acid and polyphenols) as main materials. Any of them may be used as long as it is non-toxic and excellent in oxygen absorption.

Further, substances which absorb oxygen and carbon dioxide or absorb oxygen and release carbon dioxide can also be used.

The oxygen scavenger may be in various forms, such as a package comprising an oxygen permeable bag and an oxygen scavenging substance contained therein, a film formed by kneading with an oxygen absorbent, a container molded with an oxygen absorbent, and containing no The oxygen permeable outer layer and the oxygen absorbing layer of the inner layer are such that the sides absorb oxygen. Any of them may be used as long as it is non-toxic and has good oxygen absorption.

Among the known commercial products, Ageless (registered trade name) Said) (from Mitsubishi Gas Chemical Company, Inc.) is suitable for the present invention.

The deoxidizer should be a reagent which absorbs not less than 100 cubic centimeters of oxygen at a normal temperature (25 ° C) and atmospheric pressure for 20 hours from 100 ml of an aqueous solution of acetaminophen phenol contained in an oxygen permeable container. Preferably, it is not less than 200 cubic centimeters, and more preferably not less than 400 cubic centimeters.

A preferred embodiment of the oxygen scavenger is Ageless (registered trade name) ZH-200 (from Mitsubishi Gas Chemical Company, Inc.), which absorbs oxygen at atmospheric pressure equal to or more than 200 cubic meters per 20 hours. Centimeters.

An example of a packaged acetaminophen phenol injection solution formulation of the present invention is shown in FIG.

The packaged acetaminophen injection solution preparation 1 of this specific example comprises a sealed oxygen permeable container 3 filled with an aqueous solution of acetaminophen having pH 4 to 8 containing acetaminophen as an active ingredient, and by moist heat Sterilization sterilization; an oxygen scavenger 4; and an oxygen-impermeable packaging container 2 surrounding the sealed oxygen permeable container 3 and the oxygen scavenger 4 filled with an aqueous solution of acetaminophen. The oxygen-impermeable packaging container 2 is sealed and the deoxidizing agent 4 is placed in a space between the packaging container 2 and the sealed oxygen permeable container 3 filled with the aqueous solution of acetaminophen.

The sealed oxygen permeable container 3 comprises a container body 31 having an internal space for storing the aqueous solution of acetaminophen, a crucible connected to the space, and a crucible for closing the container body 31. Sealing element 32. The container body 31 is an oxygen permeable organic polymer sheet or film as described above. Made of a flexible bag. The sealing element 32 is intended to be capable of venting a piercing needle.

The oxygen-impermeable packaging container 2 is in the form of a bag. After the oxygen-impermeable packaging container 2 stores the oxygen absorbent 4 and the container body 3, the opening portion of the oxygen-impermeable packaging container 2 is sealed by heat sealing. The oxygen-impermeable outer container is made of an oxygen-impermeable organic polymer film or sheet as described above. As shown in FIG. 1, the oxygen scavenger 4 can be fixed to the inner surface of the oxygen-impermeable packaging container 2.

The oxygen scavenger can be provided directly on the inner surface of the packaging container. Further, the oxygen scavenger can be provided directly on the outer surface of the sealed oxygen permeable container.

The container body of the sealed oxygen permeable container can be a rigid or semi-rigid container in the form of a bottle.

The container body of the sealed oxygen permeable container can be a syringe. The syringe preferably includes an oxygen permeable outer cylinder, a slidable gasket in the outer cylinder, and a sealing member for sealing the top end of the outer cylinder.

(Example)

The invention will be explained in more detail with reference to the following examples, which are not intended to limit the scope thereof.

In these examples, the following procedure was used to measure the oxygen concentration in the water for injection and the aqueous solution of acetaminophen.

Measurement of oxygen concentration in the water for injection and the aqueous solution of acetaminophen

The oxygen concentration in water and solution was measured using a dissolved oxygen measuring sensor Inlab 605 (from Mettler Toledo).

[Example 1]

(1) An aqueous solution of acetaminophen was prepared as follows. Under a nitrogen atmosphere (or in a nitrogen shed), a suitable amount of water which has been heated to 35 ° C for nitrogen injection is subjected to nitrogen blowing so that the oxygen concentration therein is maintained at not higher than 1 mg / liter. The water for injection provided 1925 g of D-mannitol, 13 g of disodium hydrogen phosphate dodecahydrate and 500 g of acetaminophen phenol, which were dissolved with stirring. After cooling to room temperature, 12.5 g of L-cysteine acid monohydrate was added and dissolved therein. The resulting solution was adjusted to pH 5.5 using sodium hydroxide and hydrochloric acid, and then water for injection was added so that the total amount of the solution became 50 liters.

(2) 100 ml of the aqueous solution of acetaminophen obtained in the above step (1) was each filled in an oxygen-permeable multilayer polypropylene film flexible bag (100 ml of nominal capacity), followed by isoprene Rubber plug seal. The multilayer film was composed of a three-layer polypropylene film having a total thickness of 264 μm. The multilayer film has oxygen permeability at 809 cubic centimeters per square meter per day at 23 ° C, 90% RH at atmospheric pressure. The charging step was carried out in an environment of a mixture of nitrogen and air (at a ratio of 80:20 by volume).

(3) After the acetaminophen phenol aqueous solution is filled in the above step (2), the oxygen permeable flexible bag (or the oxygen permeable multilayer polypropylene flexible bag) is subjected to moist heat sterilization using nitrogen as a pressurizing medium ( 15 minutes at 121 ° C).

(4) After the moist heat sterilization in the above step (3), the oxygen permeable container filled with the aqueous acetaminophen phenol is placed together with a piece of Ageless (registered trade name) ZH-200 (from Mitsubishi Gas Chemical Company, Inc.). In an oxygen-impermeable bag, where the Ageless is absorbed at atmospheric pressure The amount of oxygen is equal to or more than 200 cubic centimeters per 20 hours. The oxygen-impermeable bag is formed from a three-layer film of PP, PET and PP deposited with cerium oxide, and its three sides are sealed and opened on one side, and have a thickness of 66 μm and oxygen permeability at 23 ° C, 90% RH. It is 0.15 cubic centimeters per square meter per day under normal pressure. After the oxygen permeable container and Ageless (registered trade name) ZH-200 have been placed in the oxygen-impermeable bag, the open side of the oxygen-impermeable bag is sealed by heat sealing. In this way, a packaged acetaminophen injection solution formulation as desired is obtained.

[Embodiment 2]

(1) The aqueous solution of acetaminophen was prepared in the same manner as in the above step (1) of Example 1, except that nitrogen gas blowing was not carried out and the entire procedure was carried out in the air without using a nitrogen shed.

(2) 100 ml of the aqueous solution of the acetaminophen obtained in the above step (1) in the air is each filled in the same oxygen permeated container as the user in the step (2) of the embodiment 1 (in the air) It is an oxygen-permeable multilayer polypropylene flexible bag with a nominal capacity of 100 ml). After filling, the flexible bag is sealed with an isoprene rubber stopper.

(3) After the aqueous solution of acetaminophen is filled in the above step (2), the oxygen-permeable flexible bag (or oxygen-permeable multilayer polypropylene flexible bag) is used in the step (3) of the embodiment 1. The same method was used for moist heat sterilization.

(4) After the moist heat sterilization in the above step (3), the oxygen permeable container containing the aqueous solution of the acetaminophen phenol is placed together with a piece of the same oxygen scavenger as the user in the step (4) of the embodiment 1. In the user in step (4) of embodiment 1, The same oxygen-tight bag (with its three sides sealed). After the oxygen permeable container and the oxygen scavenger have been placed in the oxygen-impermeable bag, the open side of the oxygen-impermeable bag is sealed by heat sealing. In this way, a packaged acetaminophen injection solution formulation as desired is obtained.

[Example 3]

(1) The aqueous solution of acetaminophen was prepared in the same manner as in the above step (1) of Example 1, except that nitrogen gas blowing was not carried out and the entire procedure was carried out in the air without using a nitrogen shed.

(2) 100 ml of the aqueous solution of acetaminophen obtained in the above step (1) was each filled in air in the same oxygen permeated container as the user in the step (2) of Example 1. An oxygen permeable multilayer polypropylene flexible bag, nominal capacity 100 ml). After filling, the flexible bag is sealed with an isoprene rubber stopper.

(3) After the aqueous solution of the acetaminophen phenol is filled in the above step (2), the oxygen permeable flexible bag (or oxygen permeable multilayer polypropylene flexible bag) is used in the step of Example 1 ( The same method in 3) is carried out by moist heat sterilization except that air is used as the pressurized medium.

(4) After the moist heat sterilization in the above step (3), the oxygen permeable container containing the aqueous solution of the acetaminophen phenol is placed together with a piece of the same oxygen scavenger as the user in the step (4) of the embodiment 1. In the same oxygen-impermeable bag (the three sides of which are sealed) as in the step (4) of Example 1. After the oxygen permeable container and the oxygen scavenger have been placed in the oxygen-impermeable bag, the open side of the oxygen-impermeable bag is sealed by heat sealing. In this way, you get the wrapped acetamone as you want. Amine phenol injection solution preparation.

[Example 4]

(1) The aqueous solution of acetaminophen was prepared and subjected to nitrogen gas blowing in the same manner as in the above step (1) of Example 1, except that the entire step was carried out in the air without using a nitrogen shed.

(2) 100 ml of the aqueous solution of the acetaminophen obtained in the above step (1) was each filled in the same oxygen permeation container as the user in the step (2) of Example 1 in the air (which) It is an oxygen-permeable multilayer polypropylene flexible bag with a nominal capacity of 100 ml). After filling, the flexible bag is sealed with an isoprene rubber stopper.

(3) After the aqueous solution of the acetaminophen phenol is filled in the above step (2), the oxygen permeable flexible bag (or oxygen permeable multilayer polypropylene flexible bag) is used in the step (3) of the embodiment 1. The same method was used for moist heat sterilization.

(4) after the moist heat sterilization in the above step (3), the oxygen permeable container containing the aqueous solution of the acetaminophen phenol is combined with a piece of the same oxygen scavenger as the user in the step (4) of the first embodiment, It was placed in the same oxygen-impermeable bag (the three sides of which were sealed) as in the step (4) of Example 1. After the oxygen permeable container and the oxygen scavenger have been placed in the oxygen-impermeable bag, the open side of the oxygen-impermeable bag is sealed by heat sealing. In this way, a packaged acetaminophen injection solution formulation as desired is obtained.

[Comparative Example 1]

(1) Repeat steps (1) to (3) in Example 1 to obtain high An oxygen permeable container (or an oxygen permeable multilayer polypropylene flexible bag) containing the aqueous solution of acetaminophen phenol by steam sterilization.

(2) After the moist heat sterilization in the above step (1), the oxygen permeable container (or the oxygen permeable multilayer polypropylene flexible bag) containing the aqueous solution of the acetaminophen phenol is placed in the step (4) of the embodiment 1. In the same oxygen-impermeable bag (the three sides of which are sealed), there is no oxygen scavenger. After the oxygen permeable container has been placed in the oxygen-impermeable bag, the open side of the oxygen-impermeable bag is sealed by heat sealing. In this way, a packaged acetaminophen injection solution formulation as desired is obtained.

[Comparative Example 2]

(1) The step (1) in Example 1 was repeated to obtain the aqueous solution of acetaminophen, except that the method was carried out in the air without using a nitrogen shed and without nitrogen gas blowing.

(2) 100 ml of the aqueous solution of the acetaminophen obtained in the above step (1) in the air is each filled in the same oxygen permeating container as the user in the step (2) of the embodiment 1 (in the air) It is an oxygen-permeable multilayer polypropylene flexible bag with a nominal capacity of 100 ml). After filling, the flexible bag is sealed with an isoprene rubber stopper.

(3) repeating the step (3) in the first embodiment to carry out the oxygen-permeable container (or the oxygen-permeable multilayer polypropylene flexible bag) containing the aqueous solution of acetaminophen obtained in the above step (2). Wet heat sterilization, except that air is used as the pressurized medium.

(4) After the moist heat sterilization of the above step (3), the oxygen permeable container containing the aqueous solution of the acetaminophen phenol is placed in the same manner as the user in the step (4) of the embodiment 1. The same oxygen-tight bag (the three sides are sealed), no deoxidizer. After the oxygen permeable container has been placed in the oxygen-impermeable bag, the open side of the oxygen-impermeable bag is sealed by heat sealing. In this way, a packaged acetaminophen injection solution formulation as desired is obtained.

The packaged acetaminophen injection solution preparations obtained in Examples 1 to 4 and Comparative Examples 1 and 2 were found to have the compositions and pH values as shown in Table 1.

Test 1 was used to measure the oxygen concentration in the aqueous solution of acetaminophen after moist heat sterilization and before filling in an outer container (packaging container):

This test is performed to measure in the step (3) of the embodiment 1, in the step (3) of the embodiment 2, in the step (3) of the embodiment 3, and in the step (3) of the embodiment 4 The oxygen concentration of each of the aqueous solutions of the acetaminophen phenol obtained in the step (1) of Comparative Example 1 and the step (3) of Comparative Example 2. All samples were collected after moist heat sterilization and before being filled in an outer container (packaging container). The measurement results are shown in Tables 2 to 4.

Test 2 was used to measure the oxygen concentration in the acetaminophen injection solution formulation:

This test is performed to measure in the step (4) of the embodiment 1, in the step (4) of the embodiment 2, in the step (4) of the embodiment 3, and in the step (4) of the embodiment 4. The oxygen concentration of each of the acetaminophen phenol injection solution preparations obtained in the step (2) of Comparative Example 1 and in the step (4) of Comparative Example 2. All samples are finished products. The aqueous solution of acetaminophen was measured after storage in air for 24 hours and four days at room temperature. The measurement results are shown in Tables 2 to 4.

Test 3 is used for stability:

The appearance, pH, L-cysteine acid hydrate content, and total amount of decomposition products of each of the samples of the acetaminophen phenol injection solution obtained in Examples 1 to 4 and Comparative Examples 1 and 2 were tested. And the residual ratio of acetaminophen. This test was carried out immediately after manufacture and seven days and 21 days after storage at 60 °C. The remaining methods and results are shown in Tables 2 through 4 below.

Test 4 is used for stability:

The appearance, pH, L-cysteine acid hydrate content, total amount of decomposition products, and residual of acetaminophen of each sample of the acetaminophen phenol injection solution preparation obtained in Example 1 were tested. ratio. This test is stored at 40 It is carried out three months and six months after °C. The results are shown in Tables 2 to 4 below.

(1) Evaluation of the appearance of an aqueous solution of acetaminophen in an acetamide phenol injection solution preparation:

Verify the transparency and color of each sample.

(2) pH of an aqueous solution of acetaminophen in an acetamide phenol injection solution preparation:

The pH of each sample was tested using a pH meter.

(3) L-cysteine acid hydrate content in an aqueous solution of acetaminophen in the preparation of acetaminophen injection solution:

Each sample was diluted with water to provide a dilute solution of the specified concentration. The L-cysteine acid hydrate content (in mg/100 ml) of the diluted solution was checked by liquid chromatography.

(4) The total amount of decomposition products in an aqueous solution of acetaminophen in the preparation of acetaminophen injection solution:

The total amount (%) of the respective decomposition products was obtained by liquid chromatography (in terms of the area percentage of the peak area of the chromatogram).

(5) Residual ratio of acetaminophen in an aqueous solution of acetaminophen in the preparation of acetaminophen injection solution:

Each sample was diluted with water to provide a dilute solution of the specified concentration. The acetaminophen content of the diluted solution was examined by liquid chromatography. The residual ratio is expressed as a percentage (%) of the initial content (100%) before the test.

It can be noted from Tables 2 to 4 that the acetaminophen injection solution preparations according to Examples 1 to 4 are extremely excellent in long-term storage stability.

In contrast, the acetaminophen phenol injection solution preparations according to Comparative Examples 1 and 2 were inferior in long-term storage stability.

The acetaminophen phenol injection solution preparation according to the present invention, although in a liquid form, is excellent in long-term storage stability at room temperature. It keeps the acetaminophen phenol with very little deterioration and decomposition, or it retains the high acetamide phenol residual ratio even after storage for a long period of time. Therefore, it can be effectively used for medical treatment, such as treating post-operative pain.

It should be understood by those skilled in the art that various modifications, combinations, sub-combinations and changes may be made depending on the design requirements and other factors, as long as they are within the scope of the appended claims or their equivalents.

[industrial feasibility]

The acetaminophen phenol injection solution formulation of the present invention is constructed as described below.

(1) A packaged acetaminophen phenol injection solution preparation comprising an oxygen-impermeable packaging container, and an acetaminophen injection comprising an aqueous solution of acetaminophen having pH 4 to 8 containing acetaminophen as an active ingredient. a solution preparation, and a sealed oxygen permeable container filled with the aqueous solution of acetaminophen phenol, wherein the acetaminophen phenol injection solution preparation is sterilized by moist heat sterilization, and the oxygen-impermeable packaging container surrounds the acetaminophen phenol The injection solution formulation and the seal, and the packaged acetaminophen injection solution formulation have an oxygen scavenger to absorb oxygen in the sealed oxygen-impermeable packaging container.

The packaged acetaminophen injection solution preparation according to the present invention comprises an aqueous solution of acetaminophen, an oxygen-permeable inner container filled with the same, and an oxygen-impermeable outer container for storing the inner container and the oxygen scavenger together (packaging container) ) constitutes. The filled inner container is subjected to moist heat sterilization, and then placed in an outer container (packaging container) with an oxygen scavenger, and then the outer container (packaging container) is sealed. Unlike the existing acetaminophen phenol injection solution preparation using a small glass bottle, the present invention does not require the aqueous solution of acetaminophen phenol to be filled into the container at the time of preparation of the aqueous solution of acetaminophen phenol and then Strict oxygen control by inert gas replacement at the damp heat sterilization time. Accordingly, the present invention permits at least one or all of the steps of preparing the aqueous solution of the acetaminophen phenol prior to loading into the container, filling the aqueous solution of the acetaminophen in the container, and moisturizing the heat in air. Moreover, even when an inert gas is used for deoxidation, it does not require such strict control as has been practiced in the past. Although the oxygen control method is simplified, the acetaminophen phenol injection solution preparation is excellent in long-term storage stability, which allows acetaminophen phenol therein even in storage at room temperature for three years or longer. Completely maintained at very high ratios.

If the oxygen permeable container is made of an oxygen permeable organic polymer film or sheet and the oxygen permeable packaging container is made of an oxygen-impermeable organic polymer film or sheet, it is easy to transport and handle without Damaged by falling or dumping.

The packaged acetaminophen phenol injection solution preparation according to the present invention is excellent in long-term storage stability, unlike existing ones, although it is used for preparation of an aqueous solution of acetaminophen phenol and is filled in an oxygen-impermeable outer layer. There are strict oxygen controls in the container (packaging container) and in the separate steps of moist heat sterilization in an inert gas environment, but it will inevitably suffer from oxygen contamination.

Specific examples of the invention can be carried out as described below.

(2) The packaged acetaminophen phenol injection solution preparation according to (1) above, wherein the acetaminophen phenol aqueous solution is or is not subjected to oxygen control at the time of preparation.

(3) A packaged acetaminophen phenol injection solution preparation according to the above (1) or (2), which is an aqueous solution of acetaminophen phenol by an inert gas, a mixture of an inert gas and air, or an air atmosphere. It is manufactured by being filled in the oxygen permeable container.

(4) The packaged acetaminophen phenol injection solution preparation according to any one of the above (1) to (3), wherein the osmotic sterilization container for the oxygen permeable container filled with the acetaminophen phenol aqueous solution is sterilized by a moist heat sterilization method This is achieved by using an inert gas, a mixture of inert gas and air, or air as a pressurized medium.

(5) The packaged acetaminophen phenol injection solution preparation according to any one of the above (1) to (4), wherein the aqueous solution of acetaminophen phenol comprises acetaminophen in an amount of 2 to 50 mg/ml.

(6) The packaged acetaminophen phenol injection solution preparation according to any one of the above (1) to (5), wherein the oxygen permeable container has oxygen permeability at 23 ° C and 90% RH at atmospheric pressure (1013 hPa) The lower measurement system is not less than 200 cubic centimeters per square meter per day.

(7) The packaged acetaminophen phenol injection solution preparation according to any one of the above (1) to (6), wherein the oxygen-impermeable packaging container has oxygen permeability at 23 ° C and 90% RH. The measurement under pressure (1013 hPa) is not higher than 1.0 cubic centimeters per square meter per day.

(8) The packaged acetaminophen phenol injection solution preparation according to any one of the above (1) to (7), wherein the oxygen permeable container is made of an oxygen permeable organic polymer film or The sheet is made of the oxygen-impermeable packaging container made of an oxygen-impermeable organic polymer film or sheet.

(9) The packaged acetaminophen phenol injection solution preparation according to any one of the above (1) to (8), wherein the aqueous solution of acetaminophen phenol comprises at least one pH adjuster, tonicity agent, antioxidant, and buffer Species.

(10) A packaged acetaminophen injection solution preparation according to the above (9), wherein the pH adjuster is sodium hydroxide and/or hydrochloric acid.

(11) A packaged acetaminophen injection solution preparation according to the above (9) or (10), wherein the tonicity agent is mannitol.

(12) A packaged acetaminophen injection solution preparation according to any one of the above (9) to (11), wherein the antioxidant is cysteine acid hydrate.

(13) A packaged acetaminophen phenol injection solution preparation according to any one of the above (9) to (12), wherein the buffer is sodium hydrogen phosphate hydrate.

(14) The packaged acetaminophen injection solution preparation according to any one of the above (1) to (13), wherein the oxygen-impermeable packaging container surrounds the acetaminophen phenol injection solution preparation and the oxygen scavenger .

(15) The packaged acetaminophen phenol injection solution preparation according to the above (14), wherein the oxygen scavenger is placed in a space between the packaging container and the sealed oxygen permeable container filled with the acetaminophen phenol aqueous solution. .

(16) The packaged acetaminophen injection solution preparation according to any one of the above (1) to (13), wherein the oxygen-impermeable packaging container or the sealed oxygen-permeable container has the oxygen scavenger.

1‧‧‧Packed acetaminophen injection solution preparation

2‧‧‧Oxygen-impermeable packaging containers

3‧‧‧ Sealed oxygen permeable container

4‧‧‧Deoxidizer

31‧‧‧ container body

32‧‧‧Sealing components

Claims (16)

A packaged acetaminophen phenol injection solution preparation comprising: an oxygen-impermeable packaging container; and an acetaminophen phenol injection solution preparation comprising acetamidine having pH 4 to 8 containing acetaminophen phenol as an active ingredient An aqueous solution of amine phenol; and a sealed oxygen permeable container filled with the aqueous solution of acetaminophen phenol; wherein the acetaminophen phenol injection solution preparation is sterilized by moist heat sterilization, and the oxygen-impermeable packaging container surrounds the acetamide The phenol injection solution formulation is sealed and the packaged acetaminophen injection solution formulation has an oxygen scavenger to absorb oxygen in the sealed oxygen barrier packaging container. The packaged acetaminophen phenol injection solution formulation of claim 1 wherein the aqueous acetaminophen phenol solution is or is not oxygen controlled at the time of preparation. The packaged acetaminophen phenol injection solution preparation according to claim 1 or 2, wherein the aqueous solution of acetaminophen is filled in the oxygen permeable container by an inert gas, a mixture of inert gas and air or an air atmosphere. And manufacturing. The packaged acetaminophen phenol injection solution preparation according to any one of claims 1 to 3, wherein the sterilizing by the moist heat sterilization method for the oxygen permeable container filled with the acetaminophen phenol aqueous solution is carried out by using an inert gas, A mixture of inert gas and air, or air is used as a pressurized medium. Packaged acetaminophen injection solution according to any one of claims 1 to 4 A formulation wherein the aqueous solution of acetaminophen comprises an amount of 2 to 50 mg/ml of acetaminophen. The packaged acetaminophen injection solution preparation according to any one of claims 1 to 5, wherein the oxygen permeable container has an oxygen permeability at 23 ° C and 90% RH and is not low at atmospheric pressure (1013 hPa). At 200 cubic centimeters per square meter per day. The packaged acetaminophen injection solution preparation according to any one of claims 1 to 6, wherein the oxygen-impermeable packaging container has oxygen permeability at 23 ° C and 90% RH at atmospheric pressure (1013 hPa). The system is not higher than 1.0 cubic centimeters per square meter per day. The packaged acetaminophen phenol injection solution preparation according to any one of claims 1 to 7, wherein the oxygen permeable container is made of an oxygen permeable organic polymer film or sheet and the oxygen permeable packaging container is Made of an oxygen-impermeable organic polymer film or sheet. The packaged acetaminophen injection solution formulation of any one of claims 1 to 8, wherein the aqueous solution of acetaminophen phenol comprises at least one of a pH adjuster, a tonicity agent, an antioxidant, and a buffer species. The packaged acetaminophen injection solution preparation of claim 9, wherein the pH adjuster is sodium hydroxide and/or hydrochloric acid. A packaged acetaminophen injection solution formulation according to claim 9 or 10, wherein the tonicity agent is mannitol. A packaged acetaminophen phenol injection solution formulation according to any one of claims 9 to 11, wherein the antioxidant is cysteine acid hydrate. A packaged acetaminophen phenol injection solution formulation according to any one of claims 9 to 12, wherein the buffer is sodium hydrogen phosphate hydrate. The packaged acetaminophen injection solution preparation according to any one of claims 1 to 13, wherein the oxygen-impermeable packaging container surrounds the acetaminophen injection solution preparation and the oxygen scavenger. The packaged acetaminophen phenol injection solution formulation of claim 14, wherein the oxygen scavenger is placed in a space between the packaging container and the sealed oxygen permeable container filled with the aqueous acetamide phenol solution. The packaged acetaminophen injection solution formulation of any one of claims 1 to 13, wherein the oxygen-impermeable packaging container or the sealed oxygen-permeable container has the oxygen scavenger.