JP2014207983A - Acetaminophen injection solution preparation - Google Patents
Acetaminophen injection solution preparation Download PDFInfo
- Publication number
- JP2014207983A JP2014207983A JP2014063758A JP2014063758A JP2014207983A JP 2014207983 A JP2014207983 A JP 2014207983A JP 2014063758 A JP2014063758 A JP 2014063758A JP 2014063758 A JP2014063758 A JP 2014063758A JP 2014207983 A JP2014207983 A JP 2014207983A
- Authority
- JP
- Japan
- Prior art keywords
- acetaminophen
- oxygen
- aqueous solution
- container
- injection solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940050447 acetaminophen injection Drugs 0.000 title claims abstract description 86
- 239000000243 solution Substances 0.000 title claims abstract description 84
- 238000002360 preparation method Methods 0.000 title claims abstract description 78
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 182
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Classifications
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- A—HUMAN NECESSITIES
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- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Engineering & Computer Science (AREA)
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Abstract
Description
本発明は、アセトアミノフェン注射液製剤に関する。より詳細には、本発明は、長期間室温で保存してもアセトアミノフェンが液中に安定に存在する保存安定性に優れるアセトアミノフェン注射液製剤に関する。 The present invention relates to an acetaminophen injection solution preparation. More specifically, the present invention relates to an acetaminophen injection solution preparation having excellent storage stability in which acetaminophen is stably present in a solution even when stored at room temperature for a long period of time.
アセトアミノフェン（別名：パラセタモール）は、胃を刺激せず、血液凝固や腎臓への影響がなく、興奮や眠気などの副作用がなく、しかも依存性や禁断症状などの問題のない、穏やかな解熱・鎮痛剤である。かかる点から、アセトアミノフェンの経口剤と坐剤は、世界で最も使用されている鎮痛・解熱薬剤の１つとなっている。
また、アセトアミノフェンの水溶液を容器に充填したアセトアミノフェン注射液製剤は、海外で２００２年に発売開始されて以来、現在では米国および欧州諸国を含む、日本以外の約８０カ国で製造販売が承認されて、術後疼痛の標準的療法で用いられている。
Acetaminophen (also known as paracetamol) is a mild antipyretic that does not irritate the stomach, does not affect blood clotting and kidneys, has no side effects such as excitement and sleepiness, and has no problems such as dependence or withdrawal.・ It is an analgesic. In this respect, acetaminophen oral preparations and suppositories have become one of the most used analgesic / antipyretic drugs in the world.
In addition, acetaminophen injectable preparations filled with acetaminophen aqueous solutions in containers have been manufactured and sold in about 80 countries other than Japan, including the US and European countries, since it was launched overseas in 2002. Approved and used in standard therapy for postoperative pain.
アセトアミノフェン注射液製剤としては、長期間安定に保存できるようにするために、アセトアミノフェンの水溶液に不活性ガスを吹き込んで脱酸素し、それを窒素ガス雰囲気中でガラス瓶に充填して密封し、高圧蒸気滅菌したものが知られており（特許文献１を参照）、またアセトアミノフェン水溶液中の酸素含量を０．４〜４ｍｇ／Ｌのオーダーにするために、アセトアミノフェン水溶液を、超音波作用と、吸引およびマイクロバブリングの少なくとも１つの作用とにかける方法が提案されている（特許文献２を参照）。 As an acetaminophen injection solution formulation, an inert gas was blown into an aqueous solution of acetaminophen to deoxygenate it so that it could be stored stably for a long period of time, and it was sealed in a glass bottle in a nitrogen gas atmosphere. In order to make the oxygen content in the acetaminophen aqueous solution on the order of 0.4 to 4 mg / L, an acetaminophen aqueous solution is used. A method of applying an ultrasonic action and at least one action of suction and micro bubbling has been proposed (see Patent Document 2).
しかし、本発明者らが、前記した特許文献１および２に記載されている技術を参考にして、アセトアミノフェン水溶液に不活性ガスを吹き込んで脱酸素し、それを不活性ガス雰囲気中で容器、特に有機重合体製シートから形成したバッグに充填して密封した後、窒素ガスなどの不活性ガスを加圧媒体として用いて高圧蒸気滅菌して、バッグ入りのアセトアミノフェン注射液製剤を製造し、当該アセトアミノフェン注射液製剤の保存安定性試験を行ったところ、各工程で脱酸素処理を行ったにも拘わらず、長期保存安定性が不十分であった。 However, the present inventors refer to the techniques described in Patent Documents 1 and 2 described above and blow off an inert gas into an acetaminophen aqueous solution to deoxygenate the solution in a container in an inert gas atmosphere. In particular, after filling and sealing a bag formed from an organic polymer sheet, autoclaving using an inert gas such as nitrogen gas as a pressurized medium to produce a bag of acetaminophen injection preparation And when the storage stability test of the said acetaminophen injection solution formulation was conducted, long-term storage stability was inadequate in spite of having performed a deoxygenation process at each process.
本発明の目的は、室温下で３年間以上保存したときにもアセトアミノフェンの残存率が極めて高くて、長期間にわたって安全に保存することのできる、長期保存安定性に優れるアセトアミノフェン注射液製剤を提供することである。
本発明の目的は、室温下で長期間安定に保存することのできると共に、破損が生じず、軽量で取り扱い性に優れる、有機重合体製のフィルムまたはシートから形成した容器、特にバッグ状容器に収容したアセトアミノフェン注射液製剤を提供することである。
An object of the present invention is an acetaminophen injection solution that has a very high residual ratio of acetaminophen even when stored at room temperature for 3 years or more, and can be stored safely for a long period of time, and has excellent long-term storage stability. It is to provide a formulation.
An object of the present invention is a container formed from an organic polymer film or sheet, particularly a bag-shaped container, which can be stably stored at room temperature for a long period of time, is not damaged, is lightweight and excellent in handleability. It is to provide a stored acetaminophen injection solution formulation.
本発明者らは上記の目的を達成すべく研究を重ねてきた。その研究過程において、アセトアミノフェン注射液製剤の製造時の酸素管理は長期保存安定性に貢献していないのではないかという疑問が生じた。そこで、容器充填前のアセトアミノフェン水溶液の調製工程、アセトアミノフェン水溶液の容器への充填工程およびアセトアミノフェン水溶液を充填した容器の高圧蒸気滅菌工程を不活性ガスの導入下または不活性雰囲気中で行なってアセトアミノフェン注射液製剤を製造する前記した方法と共に、いずれか１つまたは２つの工程或いは全ての工程を不活性ガスを用いずに空気中で行なってアセトアミノフェン注射液製剤を製造する方法を併せて実施し、それにより得られたアセトアミノフェン注射液製剤の保存安定性について調査した。
その結果、容器充填前のアセトアミノフェン水溶液の調製、アセトアミノフェン水溶液の容器への充填およびアセトアミノフェン水溶液を充填した容器の高圧蒸気滅菌というアセトアミノフェン注射液製剤の製造段階での酸素被爆は、上記した特許文献１および２に記載されている従来の知見とは異なり、アセトアミノフェン注射液製剤の長期保存安定性に与える影響が少ないことが判明した。
The inventors of the present invention have been researched to achieve the above object. In the course of the research, the question arises that oxygen management during the manufacture of an acetaminophen injection preparation may not contribute to long-term storage stability. Therefore, the preparation process of the acetaminophen aqueous solution before filling the container, the filling process of the acetaminophen aqueous solution into the container, and the high-pressure steam sterilization process of the container filled with the acetaminophen aqueous solution were conducted under the introduction of an inert gas or in an inert atmosphere. The acetaminophen injection preparation is prepared by performing any one or two steps or all steps in the air without using an inert gas, together with the above-described method for producing an acetaminophen injection preparation by performing in The storage stability of the acetaminophen injection solution thus obtained was investigated.
As a result, preparation of acetaminophen aqueous solution before filling the container, filling of the acetaminophen aqueous solution into the container, and high pressure steam sterilization of the container filled with the acetaminophen aqueous solution at the production stage of the acetaminophen injection solution formulation Unlike the conventional findings described in Patent Documents 1 and 2 above, it has been found that there is little effect on the long-term storage stability of an acetaminophen injection solution formulation.
上記のような状況下において、本発明者らは、アセトアミノフェン注射液製剤の変質・劣化は、短期間で実行されるアセトアミノフェン注射液製剤の製造段階での酸素管理にはあまり依存せず、製造後の保存中に起こると考え、かかる点から、アセトアミノフェンは酸素と急激に反応するのではなく、酸素との反応が遅いタイプの化合物であると推測した。そこで、本発明者らは、アセトアミノフェン水溶液の調剤時の酸素管理（窒素ガスなどの不活性ガスバブリング）、アセトアミノフェン水溶液の容器への充填時の酸素管理（不活性ガス雰囲気中での充填）および高圧蒸気滅菌時の酸素管理（不活性ガスを加圧媒体とする高圧蒸気滅菌）は必ずしも重要ではなく、寧ろアセトアミノフェン注射液製剤を販売可能な包装形態とした後において当該包装形態の内部やアセトアミノフェン水溶液中に残存している酸素を徐々にでも確実に除去することが重要であり、それによってアセトアミノフェン水溶液中のアセトアミノフェンが保存中に変質・劣化することを抑制して、長期保存安定性を優れるアセトアミノフェン注射液製剤が得られるのではないかと考え、そのための方策について種々検討を重ねた。
そして、アセトアミノフェン水溶液を収容する容器を、酸素透過性の内側容器と酸素難透過性の包装容器からなる二重容器とし、両容器の間に脱酸素剤を収容すれば、アセトアミノフェン水溶液中に含まれている酸素およびアセトアミノフェン水溶液を充填した内側容器のヘッドスペースおよび水溶液中に存在する酸素が保存中に徐々に除去されて内側容器内に存在する酸素量が大幅に低減し、それによって長期保存安定性に優れるアセトアミノフェン注射液製剤が得られることを見出した本発明を完成した。
Under the circumstances as described above, the present inventors have found that alteration / degradation of an acetaminophen injection liquid formulation is not very dependent on oxygen management at the manufacturing stage of an acetaminophen injection liquid drug product that is performed in a short period of time. Therefore, it was assumed that it occurred during storage after production, and from this point, acetaminophen was presumed to be a type of compound that does not react rapidly with oxygen but reacts slowly with oxygen. Therefore, the present inventors managed oxygen during preparation of an acetaminophen aqueous solution (inert gas bubbling such as nitrogen gas), oxygen management during filling of an acetaminophen aqueous solution into a container (in an inert gas atmosphere) Filling) and oxygen management during autoclaving (high-pressure steam sterilization using an inert gas as a pressurized medium) are not necessarily important. It is important to gradually and surely remove the oxygen remaining in the inside of the acetaminophen solution and the acetaminophen solution in the acetaminophen solution to prevent the acetaminophen in the acetaminophen solution from being altered or deteriorated during storage. Therefore, it is thought that an acetaminophen injection solution with excellent long-term storage stability can be obtained, and various studies have been conducted on measures for that purpose. Proof.
If the container containing the acetaminophen aqueous solution is a double container comprising an oxygen permeable inner container and an oxygen poorly permeable packaging container, and an oxygen scavenger is contained between the two containers, the acetaminophen aqueous solution The oxygen contained in the inner container filled with oxygen and the acetaminophen aqueous solution and the oxygen present in the aqueous solution are gradually removed during storage, greatly reducing the amount of oxygen present in the inner container, Thus, the present invention has been completed, which has been found that an acetaminophen injection solution preparation excellent in long-term storage stability can be obtained.
すなわち、本発明は、
（１） 有効成分としてアセトアミノフェンを含有するｐＨ４〜８のアセトアミノフェン水溶液を酸素透過性容器に充填して高圧蒸気滅菌したアセトアミノフェン水溶液入り容器を、脱酸素剤と共に、酸素難透過性の包装容器内に収容して密封してなることを特徴とするアセトアミノフェン注射液製剤である。
That is, the present invention
(1) A container containing an acetaminophen aqueous solution, which is filled with an acetaminophen aqueous solution of pH 4 to 8 containing acetaminophen as an active ingredient in an oxygen permeable container and sterilized under high pressure steam, together with an oxygen scavenger, and a poor oxygen permeability An acetaminophen injection solution characterized by being housed in a packaging container and sealed.
そして、本発明は、
（２） アセトアミノフェン水溶液が、調製時に酸素管理されたものであるかまたは酸素管理されていないものである、前記（１）のアセトアミノフェン注射液製剤；
（３） アセトアミノフェン水溶液の酸素透過性容器への充填が、不活性ガスの雰囲気中または不活性ガスと空気の混合ガスの雰囲気中で行われたか或いは空気中で行われたものである、前記（１）または（２）のアセトアミノフェン注射液製剤；および、
（４） アセトアミノフェン水溶液入り酸素透過性容器の高圧蒸気滅菌が、加圧媒体として、不活性ガス、不活性ガスと空気の混合ガスまたは空気を用いて行われたものである、前記（１）〜（３）のいずれかのアセトアミノフェン注射液製剤；
である。
And this invention,
(2) The acetaminophen injection solution preparation according to the above (1), wherein the acetaminophen aqueous solution is oxygen-controlled or not oxygen-controlled at the time of preparation;
(3) The filling of the acetaminophen aqueous solution into the oxygen permeable container was performed in an atmosphere of an inert gas, an atmosphere of a mixed gas of an inert gas and air, or performed in the air. The acetaminophen injection solution preparation of (1) or (2); and
(4) High-pressure steam sterilization of an oxygen-permeable container containing an acetaminophen aqueous solution is performed using an inert gas, a mixed gas of an inert gas and air, or air as a pressurized medium (1) ) To (3) acetaminophen injection solution formulation;
It is.
さらに、本発明は、
（５） アセトアミノフェン水溶液中のアセトアミノフェンの濃度が、２〜５０ｍｇ／ｍＬである前記（１）〜（４）のいずれかのアセトアミノフェン注射液製剤；
（６） 酸素透過性容器の酸素透過度が、２３℃、９０％ＲＨおよび１気圧（１０１３ｈＰａ）で測定したときに、２００ｃｍ3／ｍ2・ｄａｙ以上で前記（１）〜（５）のいずれかのアセトアミノフェン注射液製剤；
（７） 酸素難透過性の包装容器の酸素透過度が、２３℃、９０％ＲＨおよび１気圧（１０１３ｈＰａ）で測定したときに、１．０ｃｍ3／ｍ2・ｄａｙ以下である、前記（１）〜（６）のいずれかのアセトアミノフェン注射液製剤；および、
（８） 酸素透過性容器が有機重合体製の酸素透過性のフィルムまたはシートから形成され、酸素難透過性の包装容器が有機重合体を用いた酸素難透過性のフィルムまたはシートから形成されている前記（１）〜（７）のいずれかのアセトアミノフェン注射液製剤；
である。
Furthermore, the present invention provides
(5) The acetaminophen injection solution formulation according to any one of (1) to (4), wherein the concentration of acetaminophen in the acetaminophen aqueous solution is 2 to 50 mg / mL;
(6) When the oxygen permeability of the oxygen permeable container is measured at 23 ° C., 90% RH and 1 atm (1013 hPa), any of the above (1) to (5) is 200 cm 3 / m 2 · day or more. Acetaminophen injection formulation;
(7) The oxygen permeability of the poorly oxygen permeable packaging container is 1.0 cm 3 / m 2 · day or less when measured at 23 ° C., 90% RH and 1 atm (1013 hPa), (1 ) To (6) acetaminophen injection solution formulation; and
(8) The oxygen permeable container is formed from an oxygen permeable film or sheet made of an organic polymer, and the poor oxygen permeable packaging container is formed from an oxygen permeable film or sheet using an organic polymer. Acetaminophen injection solution preparation according to any one of (1) to (7) above;
It is.
そして、本発明は、
（９） アセトアミノフェン水溶液が、ｐＨ調整剤、等張化剤、抗酸化剤および緩衝剤の少なくとも１種を含有する前記（１）〜（８）のいずれかのアセトアミノフェン注射液製剤；
（１０） ｐＨ調整剤が、水酸化ナトリウムおよび／または塩酸である前記（９）のアセトアミノフェン注射液製剤；
（１１） 等張化剤が、マンニトールである前記（９）または（１０）のアセトアミノフェン注射液製剤；
（１２） 抗酸化剤が、システイン塩酸塩水和物である前記（９）〜（１１）のいずれかのアセトアミノフェン注射液製剤；および、
（１３） 緩衝剤が、リン酸水素ナトリウム水和物である前記（９）〜（１２）のいずれかのアセトアミノフェン注射液製剤；
である
And this invention,
(9) The acetaminophen aqueous solution preparation according to any one of (1) to (8), wherein the acetaminophen aqueous solution contains at least one of a pH adjuster, an isotonic agent, an antioxidant, and a buffer;
(10) The acetaminophen injection solution preparation according to (9), wherein the pH adjuster is sodium hydroxide and / or hydrochloric acid;
(11) The acetaminophen injection solution preparation according to (9) or (10), wherein the tonicity agent is mannitol;
(12) The acetaminophen injection solution preparation according to any one of (9) to (11), wherein the antioxidant is cysteine hydrochloride hydrate; and
(13) The acetaminophen injection solution preparation according to any one of (9) to (12), wherein the buffer is sodium hydrogenphosphate hydrate;
Is
本発明のアセトアミノフェン注射液製剤は、アセトアミノフェン水溶液を酸素透過性容器に充填して高圧蒸気滅菌したアセトアミノフェン水溶液入り容器を、脱酸素剤と共に、酸素難透過性の包装容器内に収容して密封したという構成を有していることによって、従来のガラス瓶入りアセトアミノフェン注射液製剤において必要であるとされていたアセトアミノフェン水溶液の調製時、アセトアミノフェン水溶液の容器への充填時およびその後の高圧蒸気滅菌時における不活性ガス置換などの厳密な酸素管理が必ずしも必要でなく、容器充填前のアセトアミノフェン水溶液の調製、アセトアミノフェン水溶液の容器への充填および高圧蒸気滅菌のうちの１つ以上または全てを大気中で行なうこともでき、また不活性ガスを用いて行う場合であっても従来のような厳密な管理が不要であり、それにも拘らず、長期保存安定性に優れていて、室温で３年間以上保存しても、アセトアミノフェン注射液製剤中にアセトアミノフェンが極めて高い残存率で安定に維持される。
本発明のアセトアミノフェン注射液製剤のうちで、酸素透過性容器が有機重合体製の酸素透過性のフィルムまたはシートから形成され、酸素難透過性の包装容器が有機重合体を用いた酸素難透過性のフィルムまたはシートから形成されているアセトアミノフェン注射液製剤は、落下や転倒しても破損せず、輸送も容易であり、取り扱い性に優れている。
しかも、アセトアミノフェン水溶液の調製時、アセトアミノフェン水溶液の容器への充填時およびその後の高圧蒸気滅菌時に不活性ガス置換などによって厳密な酸素管理を行い且つアセトアミノフェン水溶液を酸素難透過性有機重合体製の容器に充填して得られるものは、アセトアミノフェン水溶液の調製、容器への充填および高圧蒸気滅菌のすべての工程を厳密に酸素管理しても、前記各工程での酸素混入の可能性は否定し切れないが、それに対して本発明による場合は、より安全に長期間保存することのできる優れた長期間保存安定性をアセトアミノフェン注射液製剤に付与することができる。
The acetaminophen injection solution preparation of the present invention comprises a container containing an acetaminophen aqueous solution filled with an acetaminophen aqueous solution in an oxygen permeable container and sterilized under high-pressure steam in a poorly oxygen permeable packaging container together with an oxygen scavenger. The container is filled with an acetaminophen aqueous solution at the time of preparation of an acetaminophen aqueous solution, which has been said to be necessary in the conventional glass bottle acetaminophen injection liquid formulation by having a constitution of containing and sealing. Strict oxygen control such as inert gas replacement at the time of and after high-pressure steam sterilization is not always necessary, preparation of acetaminophen aqueous solution before filling the container, filling of the acetaminophen aqueous solution into the container and high-pressure steam sterilization One or more or all of them can be carried out in the atmosphere, or with an inert gas. However, strict management as in the past is unnecessary, and despite this, it is excellent in long-term storage stability, and even if it is stored at room temperature for 3 years or more, acetaminophen is not contained in an acetaminophen injection formulation. It remains stable with an extremely high survival rate.
Among the acetaminophen injection liquid preparations of the present invention, the oxygen permeable container is formed from an oxygen permeable film or sheet made of an organic polymer, and the oxygen permeable packaging container is an oxygen refractory using an organic polymer. An acetaminophen injection solution formulation formed from a permeable film or sheet does not break even when dropped or falls, is easy to transport, and has excellent handling properties.
In addition, when preparing an acetaminophen aqueous solution, filling the container with an acetaminophen aqueous solution, and subsequent high-pressure steam sterilization, strict oxygen management is performed by inert gas replacement, etc. What is obtained by filling a container made of a polymer does not contain oxygen in each step even if all steps of preparation of acetaminophen aqueous solution, filling of the container and high-pressure steam sterilization are strictly controlled by oxygen. The possibility cannot be denied, but in the case of the present invention, excellent long-term storage stability that can be stored safely for a long time can be imparted to the acetaminophen injection preparation.
以下に、本発明について詳細に説明する。
本発明は、アセトアミノフェンを含有するアセトアミノフェン水溶液を酸素透過性容器に充填して高圧蒸気滅菌したアセトアミノフェン水溶液入り容器を、脱酸素剤と共に、酸素難透過性の包装容器内に収容して密封したアセトアミノフェン注射液製剤である。
アセトアミノフェンとしては、アセトアミノフェン注射液製剤やアセトアミノフェン経口製剤、アセトアミノフェン坐剤などにおいて用いられているアセトアミノフェンであればいずれも使用することができ、アセトアミノフェンあるいはアセトアミノフェンの生理学的に許容される塩のいずれもが使用できる。
The present invention is described in detail below.
The present invention accommodates an acetaminophen aqueous solution containing acetaminophen containing an acetaminophen aqueous solution in an oxygen permeable container and sterilized under high pressure steam together with an oxygen scavenger in a poorly oxygen permeable packaging container. The sealed acetaminophen injection solution preparation.
As acetaminophen, any acetaminophen used in acetaminophen injection preparation, acetaminophen oral preparation, acetaminophen suppository, etc. can be used. Any of the physiologically acceptable salts of phen can be used.
本発明のアセトアミノフェン注射液製剤では、酸素透過性容器に充填されているアセトアミノフェン水溶液のｐＨは４〜８であり、ｐＨが５〜６であることが好ましい。アセトアミノフェン水溶液のｐＨが４よりも低いと、アセトアミノフェンの保存安定性が低下し、一方ｐＨが８より高いと、注射液として血管に投与した場合に血管に刺激を与えて血管痛や炎症を起こし易くなる。
アセトアミノフェン水溶液のｐＨ調整は、注射液において従来から用いられているｐＨ調整剤を用いて行なうことができ、ｐＨ調整剤としては、例えば水酸化ナトリウム、水酸化カリウムなどの塩基、塩酸などの無機酸、生体内に投与される塩を考慮する際、最小限に抑えられるクエン酸、乳酸、酢酸、コハク酸、リンゴ酸などの有機酸を挙げることができる。そのうちでも、本発明のアセトアミノフェン注射液製剤は、水酸化ナトリウムおよび／または塩酸を用いてｐＨ調整されていることが、生体内に投与される塩を考慮する際、最小限に抑えられる点から好ましい。
In the acetaminophen injection solution preparation of the present invention, the pH of the acetaminophen aqueous solution filled in the oxygen permeable container is 4 to 8, and preferably 5 to 6. When the pH of the acetaminophen aqueous solution is lower than 4, the storage stability of acetaminophen is lowered. On the other hand, when the pH is higher than 8, vascular pain or Prone to inflammation.
The pH adjustment of the acetaminophen aqueous solution can be performed using a pH adjusting agent conventionally used in injection solutions. Examples of the pH adjusting agent include bases such as sodium hydroxide and potassium hydroxide, hydrochloric acid and the like. When considering inorganic acids and salts administered in vivo, mention may be made of organic acids such as citric acid, lactic acid, acetic acid, succinic acid and malic acid which are minimized. Among them, the acetaminophen injection solution preparation of the present invention is adjusted to pH using sodium hydroxide and / or hydrochloric acid, which is minimized when considering salts to be administered in vivo. To preferred.
酸素透過性容器に充填されているアセトアミノフェン水溶液は、医薬上で、薬理学的および生理学的に許容されうる「水」を用いて調製されていずれでもよく、当該「水」としては、例えば、蒸留水、常水、精製水、滅菌精製水、注射用水、注射用蒸留水などを挙げることができる。これらの水の定義は第十六改正日本薬局方に基づく。 The acetaminophen aqueous solution filled in the oxygen permeable container may be prepared using pharmaceutically and pharmacologically and physiologically acceptable “water”, and as the “water”, for example, , Distilled water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like. These water definitions are based on the 16th revised Japanese Pharmacopoeia.
アセトアミノフェン水溶液におけるアセトアミノフェンの濃度は、静注剤としての有効性や投与すべき濃度（量）、水溶液としての溶解性の点から、２〜５０ｍｇ／ｍＬであることが好ましく、５〜１０ｍｇ／ｍＬであることがより好ましい。
アセトアミノフェン水溶液におけるアセトアミノフェンの濃度が低すぎると、患者に投与する液量が増えることとなり、一方濃度が高すぎるとアセトアミノフェンの溶解性が低いことから、低温において結晶が析出し易くなる。
The concentration of acetaminophen in the acetaminophen aqueous solution is preferably 2 to 50 mg / mL from the viewpoint of effectiveness as an intravenous injection, concentration (amount) to be administered, and solubility as an aqueous solution. More preferably, it is 10 mg / mL.
If the concentration of acetaminophen in the acetaminophen aqueous solution is too low, the amount of liquid to be administered to the patient will increase. On the other hand, if the concentration is too high, the solubility of acetaminophen will be low, and crystals will easily precipitate at low temperatures. Become.
アセトアミノフェン水溶液は、上記したｐＨ調整剤の他に、等張化剤、抗酸化剤および緩衝剤の１種または２種以上を含有することが好ましい。
等張化剤としては、注射液製剤において従来から用いられている等張化剤を用いることができ、例えば、マンニトール、ソルビトール、イノシトール、グルコース、プロピレングリコール、グリセロールなどの非イオン性等張化剤、塩化ナトリウムなどのイオン性等張化剤などを挙げることができ、これらの１種または２種以上を用いることができる。そのうちでも、マンニトールが安全性や滅菌処理に対する安定性の点から好ましく用いられる。
等張化剤の含有量は、アセトアミノフェン注射液製剤の浸透圧が、血清の浸透圧と等しいかまたはほぼ等しい、浸透圧比が０．９〜１．１となる量とするのがよい。
The acetaminophen aqueous solution preferably contains one or more of an isotonic agent, an antioxidant and a buffering agent in addition to the above-described pH adjuster.
As the isotonic agent, an isotonic agent conventionally used in injection solution preparations can be used, for example, nonionic tonicity agents such as mannitol, sorbitol, inositol, glucose, propylene glycol, glycerol and the like. And ionic tonicity agents such as sodium chloride can be used, and one or more of these can be used. Among these, mannitol is preferably used from the viewpoint of safety and stability to sterilization treatment.
The content of the isotonic agent is preferably such that the osmotic pressure of the acetaminophen injection solution preparation is equal to or substantially equal to the osmotic pressure of serum and the osmotic pressure ratio is 0.9 to 1.1.
抗酸化剤としては、注射液製剤において従来から用いられている抗酸化剤を用いることができ、例えば、システインなどのチオール官能基を有する有機化合物またはその塩、あるいはそれらの水和物（システイン塩酸塩水和物など）、亜硫酸水素ナトリウムなどの亜硫酸塩、アスコルビン酸またはその塩、ジブチルヒドロキシトルエンなどを挙げることができる。そのうちでも、システイン塩酸塩水和物が生体に対してより生理的である点から好ましく用いられる。具体的にはシステイン塩酸塩・一水和物を挙げることができる。 As the antioxidant, an antioxidant conventionally used in injection liquid preparations can be used. For example, an organic compound having a thiol functional group such as cysteine or a salt thereof, or a hydrate thereof (cysteine hydrochloride) Salt hydrates), sulfites such as sodium bisulfite, ascorbic acid or salts thereof, dibutylhydroxytoluene and the like. Among these, cysteine hydrochloride hydrate is preferably used because it is more physiological to the living body. Specific examples include cysteine hydrochloride / monohydrate.
緩衝剤としては、注射液製剤において従来から用いられている緩衝剤を用いることができ、例えば、リン酸またはその塩、あるいはその水和物（リン酸水素ナトリウム水和物など）、クエン酸またはその塩、あるいはその水和物、酢酸またはその塩、或いはその水和物などを挙げることができる。そのうちでも、無水リン酸水素ナトリウムまたはリン酸水素ナトリウム水和物が原薬の安定性や溶解性の点から好ましく用いられる。リン酸水素ナトリウムとしてはリン酸水素二ナトリウムがこのましく、リン酸水素ナトリウムの水和物としては二水和物、七水和物あるいは十二水和物であることが好ましい。 As the buffering agent, a buffering agent conventionally used in an injection solution preparation can be used. For example, phosphoric acid or a salt thereof, or a hydrate thereof (such as sodium hydrogenphosphate hydrate), citric acid or Examples thereof include salts thereof, hydrates thereof, acetic acid or salts thereof, and hydrates thereof. Among them, anhydrous sodium hydrogen phosphate or sodium hydrogen phosphate hydrate is preferably used from the viewpoint of the stability and solubility of the drug substance. The sodium hydrogen phosphate is preferably disodium hydrogen phosphate, and the sodium hydrogen phosphate hydrate is preferably dihydrate, heptahydrate or dodecahydrate.
アセトアミノフェン水溶液は、上記した成分の他に、必要に応じて、鎮痛剤、抗炎症剤、抗嘔吐剤、抗てんかん剤、抗うつ剤、抗ウィルス剤などの医薬有効成分、またはポリオール、錯化剤、アルカノール、ビタミンなどの添加剤の１種または２種以上を含有することができる。 In addition to the above-mentioned components, an aqueous solution of acetaminophen is an active pharmaceutical ingredient such as an analgesic agent, an anti-inflammatory agent, an anti-emetic agent, an antiepileptic agent, an antidepressant, an antiviral agent, or a polyol, complex. One or more additives such as an agent, an alkanol, and a vitamin can be contained.
アセトアミノフェン水溶液の調製方法は特に制限されず、アセトアミノフェンおよび上記した成分が、変質したり分解したりすることなく均一に溶解したアセトアミノフェン水溶液が得られる方法であればいずれの方法で調製してもよい。
アセトアミノフェン水溶液の調製は大気（空気）中で行なってもよいし、不活性ガスの雰囲気中で行なってもよいし、空気と不活性ガスの混合ガスの雰囲気中で行ってもよい。
アセトアミノフェン水溶液の調製を空気と不活性ガスの混合ガスの雰囲気中で行う場合は、空気：不活性ガス＝１：９９〜９９：１（容積比）の混合ガスを用いることができ、１０：９０〜９０：１０（容積比）の混合ガスを用いることが好ましい。
更に、アセトアミノフェン水溶液の調製時および／または調製後にアセトアミノフェン水溶液中に不活性ガスをバブリングして（吹き込んで）、アセトアミノフェン水溶液中の酸素を低減させてもよいし、またはアセトアミノフェン水溶液の調製時および調製後に不活性ガスのバブリングを行わずに、そのまま酸素透過性容器に充填してもよい。
アセトアミノフェン水溶液中にバブリングする不活性ガスとしては、窒素ガス、アルゴンガス、二酸化炭素ガスなどを挙げることができ、そのうちでも窒素ガスが、安価に入手し易い点から好ましく用いられる。
The method for preparing the acetaminophen aqueous solution is not particularly limited, and any method can be used as long as the acetaminophen aqueous solution in which acetaminophen and the above-described components are uniformly dissolved without being altered or decomposed can be obtained. It may be prepared.
The acetaminophen aqueous solution may be prepared in the atmosphere (air), in an inert gas atmosphere, or in a mixed gas atmosphere of air and inert gas.
When the acetaminophen aqueous solution is prepared in an atmosphere of a mixed gas of air and inert gas, a mixed gas of air: inert gas = 1: 99 to 99: 1 (volume ratio) can be used. : It is preferable to use a mixed gas of 90 to 90:10 (volume ratio).
Further, an inert gas may be bubbled (blown) into the acetaminophen aqueous solution during and / or after the preparation of the acetaminophen aqueous solution to reduce oxygen in the acetaminophen aqueous solution, or acetaminophen The oxygen permeable container may be filled as it is without bubbling the inert gas during and after the preparation of the aqueous fen solution.
Examples of the inert gas that can be bubbled into the acetaminophen aqueous solution include nitrogen gas, argon gas, carbon dioxide gas, etc. Among them, nitrogen gas is preferably used because it is easily available at low cost.
アセトアミノフェン水溶液を酸素透過性容器に充填する。
酸素透過性容器は、酸素透過性で且つ液体（水）非透過性であって、毒性がなく、アセトアミノフェンを吸着せず、しかも高圧蒸気滅菌時の温度に耐え得る材料からなる容器であればいずれでもよい。
酸素透過性容器の酸素透過度は、２３℃、９０％ＲＨおよび１気圧（１０１３ｈＰａ）で測定したときに、２００ｃｍ3／ｍ2・ｄａｙ以上であることが好ましく、５００ｃｍ3／ｍ2・ｄａｙ以上であることがより好ましく、７００ｃｍ3／ｍ2・ｄａｙ以上であることが更に好ましく、７００〜１００００ｃｍ3／ｍ2・ｄａｙであることが特に好ましい。
２３℃、９０％ＲＨおよび１気圧（１０１３ｈＰａ）で測定したときの酸素透過性容器の酸素透過度が２００ｃｍ3／ｍ2・ｄａｙ以上であれば、酸素透過性容器への充填時に持ち込まれて酸素透過性容器内のアセトアミノフェン水溶液やヘッドスペースに含まれている酸素を、脱酸素剤によって酸素透過性容器を通して十分に吸収して除去することができる。
酸素透過性容器の酸素透過度が高ければ高いほど、酸素透過性容器内に充填されたアセトアミノフェン水溶液中の酸素や酸素透過性容器のヘッドスペースに含まれている酸素が脱酸素剤により吸収されて除かれ易くなることから好ましい。
An acetaminophen aqueous solution is filled into an oxygen permeable container.
The oxygen permeable container should be an oxygen permeable and liquid (water) impermeable, non-toxic, does not adsorb acetaminophen, and is made of a material that can withstand the temperature during autoclaving. Any may be used.
The oxygen permeability of the oxygen permeable container is preferably 200 cm 3 / m 2 · day or more when measured at 23 ° C., 90% RH and 1 atmosphere (1013 hPa), and 500 cm 3 / m 2 · day or more. more preferably, further preferably 700cm 3 / m 2 · day or more, and particularly preferably 700~10000cm 3 / m 2 · day.
If the oxygen permeability of the oxygen permeable container measured at 23 ° C., 90% RH and 1 atm (1013 hPa) is 200 cm 3 / m 2 · day or more, oxygen is brought into the oxygen permeable container when it is filled. Oxygen contained in the acetaminophen aqueous solution and the head space in the permeable container can be sufficiently absorbed and removed through the oxygen permeable container by the oxygen scavenger.
The higher the oxygen permeability of the oxygen permeable container, the more oxygen in the acetaminophen aqueous solution filled in the oxygen permeable container and the oxygen contained in the head space of the oxygen permeable container will be absorbed by the oxygen scavenger. It is preferable because it is easily removed.
酸素透過性容器は、軟質の容器であってもまたは硬質の容器であってもいずれもよいが、酸素透過性で且つ液体（水）を通さない有機重合体から形成されていることが好ましく、酸素透過性で且つ液体（水）を通さない有機重合体製のフィルムまたはシート、特に有機重合体製の軟質（可撓性）のフィルムまたはシートから形成されていることがより好ましい。
酸素透過性容器を形成する、酸素透過性で且つ液体（水）非透過性の有機重合体の好ましい例としては、ポリエチレン系樹脂、ポリプロピレン系樹脂、ポリエチレン系樹脂とポリプロピレン系樹脂の混合物、エチレン−酢酸ビニル共重合体、ポリ塩化ビニル系樹脂、各種熱可塑性エラストマーなどを挙げることができる。硬質の有機重合体をベースとして用いて柔軟性のある酸素透過性容器を製造する場合は、硬質の有機重合体にそれと相溶性の軟質の有機重合体（例えば、スチレン系熱可塑性エラストマー、オレフィン系熱可塑性エラストマーなどの熱可塑性エラストマーなど）や可塑剤などを配合した有機重合体組成物を用いることによって、柔軟性のある酸素透過性容器を製造することができる。
酸素透過性容器は、前記した有機重合体の単層からなっていてもよいし、または２層以上からなる多層構造を有していてもよい。
The oxygen permeable container may be either a soft container or a hard container, but is preferably formed from an organic polymer that is permeable to oxygen and impermeable to liquid (water). It is more preferably formed from an organic polymer film or sheet which is permeable to oxygen and impermeable to liquid (water), particularly a soft (flexible) film or sheet made of an organic polymer.
Preferred examples of the oxygen permeable and liquid (water) non-permeable organic polymer forming the oxygen permeable container include polyethylene resins, polypropylene resins, mixtures of polyethylene resins and polypropylene resins, ethylene- Examples thereof include a vinyl acetate copolymer, a polyvinyl chloride resin, and various thermoplastic elastomers. When producing a flexible oxygen-permeable container using a hard organic polymer as a base, a soft organic polymer compatible with the hard organic polymer (for example, a styrene-based thermoplastic elastomer, an olefin-based container) A flexible oxygen permeable container can be produced by using an organic polymer composition containing a thermoplastic elastomer such as a thermoplastic elastomer) or a plasticizer.
The oxygen permeable container may be composed of a single layer of the above-described organic polymer or may have a multilayer structure composed of two or more layers.
酸素透過性容器が、酸素透過性の有機重合体製のフィルムまたはシートから形成されている場合は、酸素透過性容器の厚さ（壁部の厚さ）は、酸素透過性という性能と容器としての性能を両立させるために、５０〜５００μｍであることが好ましく、１００〜３００μｍであることがより好ましい。酸素透過性容器の厚さが５０μｍ以上であれば、容器として適した強度を得やすく、高圧蒸気滅菌にも耐えやすい、また、酸素透過性容器の厚さが５００μｍ以下であれば、酸素透過性を発現しやすく、またアセトアミノフェン注射液製剤をソフトバッグ形態にものにしたときに適度な柔軟性を付与しやすい。 When the oxygen permeable container is formed of an oxygen permeable organic polymer film or sheet, the thickness of the oxygen permeable container (wall thickness) In order to achieve both of these performances, the thickness is preferably 50 to 500 μm, and more preferably 100 to 300 μm. If the thickness of the oxygen permeable container is 50 μm or more, it is easy to obtain strength suitable as a container and it is easy to withstand high-pressure steam sterilization. If the thickness of the oxygen permeable container is 500 μm or less, oxygen permeability In addition, it is easy to impart moderate flexibility when the acetaminophen injection solution preparation is made into a soft bag form.
酸素透過性容器には、容器に充填したアセトアミノフェン水溶液（アセトアミノフェン注射液）を患者に投与する際に排出するための口部を設けることが望ましい。当該口部には、排出時に穿刺針を使用する場合には弾性栓が設ける。弾性栓はエラストマーやゴムなどで形成され、穿刺針が刺通可能なものとなっており、弾性栓は穿刺針を抜いたときに穿刺痕が閉じるように再シール性を有していることが好ましい。このような弾性栓の材質としては、例えば、ブチルゴム、イソプレンゴム、塩素化ブチルゴム（クロロプレン）などが挙げられる。さらに、弾性栓に含まれる成分がアセトアミノフェン水溶液中に溶け出さないようにするために、弾性栓の少なくともアセトアミノフェン水溶液と接触する接液面を、フッ素系樹脂、ポリパラキシリレン、ＤＬＣ（ダイアモンドドライカーボノン）、ポリプロピレン、ポリエチレンなどの被覆層や蒸着層などによって被覆しておいてもよい。 The oxygen permeable container is desirably provided with a mouth for discharging an acetaminophen aqueous solution (acetaminophen injection solution) filled in the container to a patient. The mouth is provided with an elastic stopper when a puncture needle is used at the time of discharge. The elastic stopper is made of elastomer or rubber so that the puncture needle can be pierced, and the elastic stopper has resealability so that the puncture mark is closed when the puncture needle is removed. preferable. Examples of the material of such an elastic plug include butyl rubber, isoprene rubber, chlorinated butyl rubber (chloroprene), and the like. Further, in order to prevent the components contained in the elastic plug from being dissolved into the acetaminophen aqueous solution, at least the liquid contact surface of the elastic plug that comes into contact with the acetaminophen aqueous solution is made of fluororesin, polyparaxylylene, DLC. (Diamond dry carbonone), a coating layer such as polypropylene or polyethylene, or a vapor deposition layer may be used.
酸素透過性容器の形状は特に制限されず、例えば、袋状（バッグ形状）、ボトル状、シリンジ状、ブリスター状などを挙げることができる。
酸素透過性容器の製法は特に制限されず、酸素透過性容器を形成する材料の種類、酸素透過性容器の形状などに応じて適当な製法を採用することができ、例えば、上記した有機重合体を用いて、押出ブロー成形法、射出ブロー成形法、インフレーション成形法、射出成形法、注型法、平坦なフィルムまたはシートを作製し当該シートまたは折り重ねて周囲を熱などで融着する方法、筒状のフィルムまたはシートを作製し当該筒状フィルムまたはシートの底部となる部分および上部を熱などで融着する方法、筒状体を作製し蓋と底付けを行う方法などを採用して製造することができる。
酸素透過性容器のサイズは特に制限されず、アセトアミノフェン注射液製剤の使用形態、製剤の濃度などに応じて異なり得るが、一般的には、内容積が２０〜５００ｃｍ3、特に５０〜１００ｃｍ3となるようなサイズにしておくことが、取り扱い性、患者の水分管理などの点から好ましい。
The shape of the oxygen permeable container is not particularly limited, and examples thereof include a bag shape (bag shape), a bottle shape, a syringe shape, and a blister shape.
The production method of the oxygen permeable container is not particularly limited, and an appropriate production method can be adopted according to the type of material forming the oxygen permeable container, the shape of the oxygen permeable container, and the like. For example, the organic polymer described above , Extrusion blow molding method, injection blow molding method, inflation molding method, injection molding method, casting method, a method of producing a flat film or sheet, and then fusing the sheet or the surroundings with heat or the like, Manufactured using a method of manufacturing a tubular film or sheet and fusing the bottom and upper part of the tubular film or sheet with heat, a method of manufacturing a tubular body and attaching the lid and bottom can do.
The size of the oxygen permeable container is not particularly limited, and may vary depending on the use form of the acetaminophen injection liquid preparation, the concentration of the preparation, etc., but generally the internal volume is 20 to 500 cm 3 , particularly 50 to 100 cm. A size of 3 is preferable from the viewpoints of handleability and patient moisture management.
酸素透過性容器へのアセトアミノフェン水溶液の充填は、空気中（大気中）で行なってもよいし、不活性ガス雰囲気中で行ってもよいし、空気と不活性ガスの混合ガスの雰囲気中で行なってもよい。不活性ガスを用いる場合は、例えば、窒素ガス、アルゴンガス、二酸化炭素ガスなどの不活性ガスを用いることができ、そのうちでも窒素ガスが、安価に入手できる点から好ましく用いられる。また、充填後に脱気処理を行ってもよい。
酸素透過性容器へのアセトアミノフェン水溶液の充填を空気と不活性ガスの混合ガスの雰囲気中で行う場合は、空気：不活性ガス＝１：９９〜９９：１（容積比）の混合ガスを用いることができ、１０：９０〜９０：１０（容積比）の混合ガスを用いることが好ましい。
Filling the oxygen permeable container with the acetaminophen aqueous solution may be performed in the air (in the atmosphere), in an inert gas atmosphere, or in an atmosphere of a mixed gas of air and inert gas. You may do it. In the case of using an inert gas, for example, an inert gas such as nitrogen gas, argon gas, or carbon dioxide gas can be used, and among these, nitrogen gas is preferably used because it can be obtained at a low cost. Moreover, you may perform a deaeration process after filling.
When filling an oxygen permeable container with an acetaminophen aqueous solution in an atmosphere of a mixed gas of air and inert gas, a mixed gas of air: inert gas = 1: 99 to 99: 1 (volume ratio) is used. It is preferable to use a mixed gas of 10:90 to 90:10 (volume ratio).
アセトアミノフェン水溶液を充填した酸素透過性容器の高圧蒸気滅菌は、滅菌媒体として水蒸気を用い加圧媒体として空気を用いて行なってもよいし、滅菌媒体として水蒸気を用い加圧媒体として不活性ガスを用いて行なってもよいし、または滅菌媒体として水蒸気を用い加圧媒体として空気と不活性ガスの混合ガスを用いて行ってもよい。その際の不活性ガスとしては、窒素ガス、アルゴンガス、二酸化炭素ガスなどの不活性ガスを挙げることができ、そのうちでも窒素ガスが安価に入手できる点から好ましく用いられる。
加圧媒体として空気と不活性ガスの混合ガスを用いる場合は、空気：不活性ガス＝１：９９〜９９：１（容積比）である混合ガスを用いることができ、１０：９０〜９０：１０（容積比）の混合ガスを用いることが好ましい。
高圧蒸気滅菌を行う際の温度・圧力・時間等の滅菌条件は、注射液剤を滅菌する際に通常実施されている条件で良い。例えば、温度は１００〜１２９℃、特に１１５〜１２４℃であることが好ましい。
High-pressure steam sterilization of an oxygen permeable container filled with an acetaminophen aqueous solution may be performed using steam as a sterilization medium and air as a pressurized medium, or using water vapor as a sterilization medium and an inert gas as a pressurized medium. Or water vapor as a sterilizing medium and a mixed gas of air and an inert gas as a pressurized medium. Examples of the inert gas at that time include inert gases such as nitrogen gas, argon gas, and carbon dioxide gas. Among these, nitrogen gas is preferably used because it can be obtained at low cost.
When a mixed gas of air and inert gas is used as the pressurizing medium, a mixed gas of air: inert gas = 1: 99 to 99: 1 (volume ratio) can be used, and 10:90 to 90: It is preferable to use a mixed gas of 10 (volume ratio).
The sterilization conditions such as temperature, pressure, and time for autoclaving may be those normally performed when sterilizing an injection solution. For example, the temperature is preferably 100 to 129 ° C, particularly 115 to 124 ° C.
本発明では、容器充填前のアセトアミノフェン水溶液の調製、アセトアミノフェン水溶液の酸素透過性容器への充填および高圧蒸気滅菌のうちの少なくとも１つ、２つまたは全てが不活性ガスの導入下または不活性ガス雰囲気中で行なわれていてもよいし、或いは容器充填前のアセトアミノフェン水溶液の調製、アセトアミノフェン水溶液の酸素透過性容器への充填および高圧蒸気滅菌の全てが空気中で行なわれていてもよい。
具体的には、本発明では、
（１）不活性ガスの雰囲気中（不活性ガスブースなどの使用）でのアセトアミノフェン水溶液の調製およびアセトアミノフェン水溶液の不活性ガスによるバブリングの両方が行われ、アセトアミノフェン水溶液の酸素透過性容器への充填が不活性ガスの雰囲気中で行なわれ且つアセトアミノフェン水溶液入り酸素透過性容器の高圧蒸気滅菌が不活性ガスを加圧媒体として用いて行なわれていてもよいし；
（２）不活性ガスの雰囲気中（不活性ガスブースなどの使用）でのアセトアミノフェン水溶液の調製およびアセトアミノフェン水溶液の不活性ガスによるバブリングのいずれか一方または両方が行なわれ且つアセトアミノフェン水溶液の酸素透過性容器への充填が不活性ガス雰囲気中で行なわれ、その一方でアセトアミノフェン水溶液入り酸素透過性容器の高圧蒸気滅菌が空気を加圧媒体として用いて行なわれていてもよいし；
（３）不活性ガスの雰囲気中（不活性ガスブースなどの使用）でのアセトアミノフェン水溶液の調製およびアセトアミノフェン水溶液の不活性ガスによるバブリングのいずれか一方または両方が行なわれず、その一方でアセトアミノフェン水溶液の酸素透過性容器への充填が不活性ガス雰囲気中で行なわれ且つアセトアミノフェン水溶液入り酸素透過性容器の高圧蒸気滅菌が不活性ガスを加圧媒体として用いて行なわれていてもよいし；
（４）不活性ガスの雰囲気中（不活性ガスブースなどの使用）でのアセトアミノフェン水溶液の調製およびアセトアミノフェン水溶液の不活性ガスによるバブリングのいずれか一方または両方が行なわれず且つアセトアミノフェン水溶液の酸素透過性容器への充填が不活性ガス雰囲気中で行なわれていて、その一方でアセトアミノフェン水溶液入り酸素透過性容器の高圧蒸気滅菌が空気を加圧媒体として用いて行なわれていてもよいし；
（５）不活性ガスの雰囲気中（不活性ガスブースなどの使用）でのアセトアミノフェン水溶液の調製およびアセトアミノフェン水溶液の不活性ガスによるバブリングのいずれか一方または両方が行なわれ、アセトアミノフェン水溶液の酸素透過性容器への充填が空気中で行なわれ、アセトアミノフェン水溶液入り酸素透過性容器の高圧蒸気滅菌が不活性ガスを加圧媒体として用いて行なわれていてもよいし；
（６）不活性ガスの雰囲気中（不活性ガスブースなどの使用）でのアセトアミノフェン水溶液の調製およびアセトアミノフェン水溶液の不活性ガスによるバブリングの両方が行なわれず、アセトアミノフェン水溶液の酸素透過性容器への充填が空気中で行なわれ、且つアセトアミノフェン水溶液入り酸素透過性容器の高圧蒸気滅菌が空気を加圧媒体として用いて行なわれていてもよいし；或いは、
（７）上記（１）〜（６）のいずれかにおいて、アセトアミノフェン水溶液の酸素透過性容器への充填が空気と不活性ガスの混合ガスを用いて行なわれているか、および／またはアセトアミノフェン水溶液入り酸素透過性容器の高圧蒸気滅菌が空気と不活性ガスの混合ガスを加圧媒体として用いて行なわれていてもよい。
In the present invention, at least one, two, or all of the preparation of the acetaminophen aqueous solution before filling the container, the filling of the acetaminophen aqueous solution into the oxygen permeable container and the high-pressure steam sterilization is performed under the introduction of an inert gas or The preparation may be performed in an inert gas atmosphere, or the preparation of the acetaminophen aqueous solution before filling the container, filling of the acetaminophen aqueous solution into the oxygen permeable container, and high-pressure steam sterilization are all performed in the air. It may be.
Specifically, in the present invention,
(1) Both the preparation of an acetaminophen aqueous solution in an inert gas atmosphere (use of an inert gas booth, etc.) and bubbling of the acetaminophen aqueous solution with an inert gas were performed, and oxygen permeation of the acetaminophen aqueous solution Filling of the active container may be performed in an inert gas atmosphere, and high-pressure steam sterilization of the oxygen-permeable container containing the acetaminophen aqueous solution may be performed using an inert gas as a pressurized medium;
(2) Acetaminophen aqueous solution is prepared in an inert gas atmosphere (using an inert gas booth or the like) and bubbling of the acetaminophen aqueous solution with an inert gas is performed, and acetaminophen is used. The filling of the oxygen permeable container with the aqueous solution may be performed in an inert gas atmosphere, while the high pressure steam sterilization of the oxygen permeable container with the acetaminophen aqueous solution may be performed using air as a pressurized medium. And
(3) Either or both of the preparation of an acetaminophen aqueous solution in an inert gas atmosphere (use of an inert gas booth, etc.) and bubbling of the acetaminophen aqueous solution with an inert gas are not performed. Filling the oxygen permeable container with the acetaminophen aqueous solution in an inert gas atmosphere, and high-pressure steam sterilization of the oxygen permeable container with the acetaminophen aqueous solution is performed using an inert gas as a pressurized medium. May be;
(4) Acetaminophen aqueous solution in an inert gas atmosphere (using an inert gas booth or the like) and bubbling of the acetaminophen aqueous solution with an inert gas are not performed, and acetaminophen The oxygen-permeable container is filled with the aqueous solution in an inert gas atmosphere, while the high-pressure steam sterilization of the oxygen-permeable container containing the acetaminophen aqueous solution is performed using air as a pressurized medium. May be;
(5) Either or both of the preparation of an acetaminophen aqueous solution in an inert gas atmosphere (use of an inert gas booth, etc.) and bubbling of the acetaminophen aqueous solution with an inert gas are performed. Filling of the oxygen permeable container with the aqueous solution may be performed in the air, and high-pressure steam sterilization of the oxygen permeable container containing the acetaminophen aqueous solution may be performed using an inert gas as a pressurized medium;
(6) Preparation of an acetaminophen aqueous solution in an inert gas atmosphere (use of an inert gas booth, etc.) and bubbling of the acetaminophen aqueous solution with an inert gas are not performed, and oxygen permeation of the acetaminophen aqueous solution Filling the functional container in air, and high-pressure steam sterilization of the oxygen-permeable container containing the acetaminophen aqueous solution may be performed using air as a pressurized medium;
(7) In any one of the above (1) to (6), the acetaminophen aqueous solution is filled into the oxygen permeable container using a mixed gas of air and an inert gas, and / or acetamino High-pressure steam sterilization of an oxygen-permeable container containing an aqueous phen solution may be performed using a mixed gas of air and an inert gas as a pressurized medium.
高圧蒸気滅菌したアセトアミノフェン水溶液入りの酸素透過性容器を、脱酸素剤と共に、酸素難透過性の包装容器内に収容して密封する。
酸素難透過性の包装容器は、アセトアミノフェン水溶液入りの酸素透過性容器と脱酸素剤を収容できる、酸素難透過性で毒性のない容器であればいずれもよい。
酸素難透過性の包装容器の酸素透過度は、２３℃、９０％ＲＨおよび１気圧（１０１３ｈＰａ）で測定したときに、１．０ｃｍ3／ｍ2・ｄａｙ以下であることが好ましく、０．３ｃｍ3／ｍ2・ｄａｙ以下であることがより好ましく、０．１ｃｍ3／ｍ2・ｄａｙ以下であることが更に好ましい。
２３℃、９０％ＲＨおよび１気圧（１０１３ｈＰａ）で測定したときの酸素難透過性の包装容器の酸素透過度が１．０ｃｍ3／ｍ2・ｄａｙ以下であれば、酸素透過性容器への充填時に持ち込まれて酸素透過性容器内のアセトアミノフェン水溶液やヘッドスペースに含まれている酸素を、包装容器の外部からの包装容器内への空気（酸素）の通過を遮断しながら、脱酸素剤によって酸素透過性容器を通して十分に吸収して酸素透過性容器内の酸素を低減することができる。
酸素難透過性の包装容器の酸素透過度が低ければ低いほど、酸素透過性容器内に充填されたアセトアミノフェン水溶液中の酸素や酸素透過性容器のヘッドスペースに含まれている酸素が脱酸素剤によって吸収されて除かれ易くなるために好ましい。
An oxygen-permeable container containing an acetaminophen aqueous solution sterilized by high-pressure steam is housed in an oxygen-impermeable permeable packaging container together with an oxygen scavenger and sealed.
The oxygen poorly permeable packaging container may be any oxygen permeable container containing an acetaminophen aqueous solution and a deoxygenating agent, as long as it is oxygen permeable and nontoxic.
The oxygen permeability of the poorly oxygen permeable packaging container is preferably 1.0 cm 3 / m 2 · day or less when measured at 23 ° C., 90% RH and 1 atmosphere (1013 hPa), 0.3 cm 3 / m more preferably 2 · day or less, and more preferably not more than 0.1 cm 3 / m 2 · day.
If the oxygen permeability of the poorly oxygen permeable packaging container measured at 23 ° C., 90% RH and 1 atm (1013 hPa) is 1.0 cm 3 / m 2 · day or less, the oxygen permeable container is filled. An oxygen scavenger while blocking the passage of air (oxygen) from outside the packaging container to the acetaminophen aqueous solution in the oxygen permeable container and oxygen contained in the head space, which is sometimes brought in Can be sufficiently absorbed through the oxygen permeable container to reduce oxygen in the oxygen permeable container.
The lower the oxygen permeability of the poorly oxygen permeable packaging container, the more oxygen in the acetaminophen aqueous solution filled in the oxygen permeable container and the oxygen contained in the head space of the oxygen permeable container are deoxygenated. It is preferable because it is easily absorbed and removed by the agent.
酸素難透過性の包装容器は、軟質の容器であってもまたは硬質の容器であってもいずれもよいが、有機重合体を用いた酸素難透過性のフィルムまたはシートから形成されていることが好ましく、特に有機重合体を用いた酸素難透過性の軟質（可撓性）のフィルムまたはシートから形成されていることがより好ましい。
酸素難透過性の包装容器を形成するための材料としては、例えば、アルミ箔などの酸素難透過性金属箔、酸化珪素系、酸化アルミニウム系、酸化チタン系などのセラミックや金属を有機重合体製の基材フィルムやシートに蒸着した蒸着フィルムや蒸着シート（例えば、アルミ蒸着有機重合体フィルムやシート、シリカ蒸着有機重合体フィルムやシート、酸化チタン蒸着有機重合体フィルムやシート）、ＤＬＣ（ダイアモンドライクコーティング）層を有する有機重合体フィルムやシート、ポリビニルアルコールやエチレンビニルアルコールなどのような酸素難透過性を有する樹脂から形成された酸素難透過性フィルムやシート、ポリビニルアルコールやエチレンビニルアルコールなどのような酸素難透過性を有する樹脂層同士を積層した積層フィルムや積層シート、前記した酸素難透過性のフィルムやシートの１つまたは２つ以上を他の有機重合体よりなる層と積層した多層フィルムや多層シートなどを挙げることができる。
酸素難透過性の包装容器が有機重合体を用いた酸素難透過性のフィルムまたはシートから形成されている場合は、当該酸素難透過性のフィルムまたはシートを折りたたんで周囲をヒートシールして包装容器を形成することが多いことから、折りたたんでときに最内面となる部分が少なくともヒートシール性の有機重合体から形成されていることが好ましい。
The oxygen-poor permeable packaging container may be either a soft container or a hard container, but may be formed from a film or sheet having poor oxygen permeability using an organic polymer. In particular, it is more preferably formed from a soft (flexible) film or sheet having poor oxygen permeability using an organic polymer.
Examples of materials for forming a low oxygen-permeable packaging container include, for example, a metal foil with low oxygen permeability such as aluminum foil, ceramics and metals such as silicon oxide, aluminum oxide, and titanium oxide made of an organic polymer. Vapor deposition film or vapor deposition sheet (for example, aluminum vapor deposition organic polymer film or sheet, silica vapor deposition organic polymer film or sheet, titanium oxide vapor deposition organic polymer film or sheet), DLC (diamond like film) Organic polymer film or sheet having a coating layer, oxygen poorly permeable film or sheet formed from a resin having poor oxygen permeability such as polyvinyl alcohol or ethylene vinyl alcohol, polyvinyl alcohol or ethylene vinyl alcohol, etc. Layered with resin layers that have low oxygen permeability Irumu or laminate sheet, such as the oxygen-impermeable multi-layer film or multilayer sheet film and one sheet or two or more laminated with a layer made of other organic polymers can be exemplified.
In the case where the poorly oxygen permeable packaging container is formed of an oxygen poorly permeable film or sheet using an organic polymer, the oxygen poorly permeable film or sheet is folded and the surroundings are heat-sealed to wrap the container. Therefore, it is preferable that at least the portion which becomes the innermost surface when folded is formed of an organic polymer having heat sealability.
限定されるものではないが、酸素難透過性の包装容器用の材料として、本発明で用い得る材料の具体例としては、
・ポリプロピレン（ＰＰ）／シリカ蒸着ポリエチレンテレフタレート（ＰＥＴ）／ポリプロピレン（ＰＰ）をこの順に積層した多層フィルムまたは多層シート；
・２軸延伸ポリアミド（ＯＰＡ）／ポリエチレン（ＰＥ）／アルミニウム蒸着ＰＥＴ／ポリエチレン（ＰＥ）をこの順に積層した多層フィルムまたは多層シート；
・ＯＰＡ／ＰＥ／アルミニウム蒸着ＰＥＴ／ＰＥをこの順に積層した多層フィルムまたは多層シート；
・ＯＰＡ／ＰＥ／アルミニウム箔／ＰＥ／ＰＥをこの順に積層した多層フィルムまたは多層シート；
・ＯＰＡ／ＰＥ／アルミニウム箔／ＰＥ／ＰＥＴ／ＰＥをこの順に積層した多層フィルムまたは多層シート；
・ＰＥＴ／ＰＥ／アルミニウム蒸着ＰＥＴ／ＰＥ／エチレン−酢酸ビニル共重合体（ＥＶＡ）／ＰＥをこの順で積層した多層フィルムまたは多層シート；
・ポリ塩化ビニリデン／ＰＥ／アルミニウム蒸着ＰＥＴ／ＰＥをこの順で積層した多層フィルムまたは多層シート；
・ＰＥＴ／アルミニウム蒸着エチレン−ビニルアルコール共重合体（ＥＶＯＨ）／ＰＥをこの順で積層した多層フィルムまたは多層シート；
などを挙げることができる。
As a specific example of a material that can be used in the present invention as a material for a packaging container that is hardly oxygen permeable,
-A multilayer film or multilayer sheet in which polypropylene (PP) / silica vapor-deposited polyethylene terephthalate (PET) / polypropylene (PP) are laminated in this order;
A multilayer film or a multilayer sheet in which biaxially oriented polyamide (OPA) / polyethylene (PE) / aluminum-deposited PET / polyethylene (PE) are laminated in this order;
A multilayer film or multilayer sheet in which OPA / PE / aluminum-deposited PET / PE are laminated in this order;
A multilayer film or multilayer sheet in which OPA / PE / aluminum foil / PE / PE are laminated in this order;
A multilayer film or multilayer sheet in which OPA / PE / aluminum foil / PE / PET / PE are laminated in this order;
A multilayer film or multilayer sheet in which PET / PE / aluminum-deposited PET / PE / ethylene-vinyl acetate copolymer (EVA) / PE are laminated in this order;
A multilayer film or multilayer sheet in which polyvinylidene chloride / PE / aluminum-deposited PET / PE are laminated in this order;
A multilayer film or multilayer sheet in which PET / aluminum-deposited ethylene-vinyl alcohol copolymer (EVOH) / PE is laminated in this order;
And so on.
酸素難透過性の包装容器が、有機重合体を用いた酸素難透過性のフィルムまたはシートから形成されている場合は、酸素難透過性と包装容器としての性能を両立させるために、厚さが５０〜１５０μｍ、特に６５〜１００μｍの酸素難透過性のフィルムまたはシートから形成されていることが好ましい。酸素難透過性の包装容器を形成するフィルムまたはシートの厚さが５０μｍ以上であれば、包装容器として適した強度が得られ易く、また１５０μｍ以下であれば、アセトアミノフェン注射液製剤がソフトバッグタイプの製剤である場合に適度な柔軟性および軽量性を付与し易くなる。 In the case where the oxygen poorly permeable packaging container is formed from an oxygen poorly permeable film or sheet using an organic polymer, in order to achieve both the oxygen permeable and the performance as a packaging container, the thickness is It is preferably formed from a film or sheet having a poor oxygen permeability of 50 to 150 μm, particularly 65 to 100 μm. If the thickness of the film or sheet forming the poorly oxygen permeable packaging container is 50 μm or more, it is easy to obtain strength suitable as a packaging container, and if it is 150 μm or less, the acetaminophen injection solution is a soft bag. Appropriate flexibility and lightness are easily imparted in the case of a type of preparation.
アセトアミノフェン水溶液入り酸素透過性容器と共に酸素難透過性の包装容器内に収容される脱酸素剤としては、使用上で毒性などの問題がなく、酸素を効率的に吸収して雰囲気中の酸素量を低減させるものであれば、いずれのものでも使用することができる。
脱酸素剤としては、鉄粉などの金属粉末を主体とするもの、亜硫酸塩、ハロゲン化金属などの無機物を主体とするもの、アスコルビン酸やポリフェノールなどの有機物を主体とするものなど、色々な種類のものが知られており、毒性がなくかつ酸素吸収性能に優れるものであれば、いずれも使用できる。
また、酸素吸収と共に炭酸ガスを同時に吸収するもの、酸素吸収と共に炭酸ガスを排出するものもあるが、本発明ではいずれも使用可能である。
脱酸素剤の形態としては、酸素透過性の袋に上記した脱酸素性能を有する物質を封入したもの、酸素吸収剤を練りこんだフィルム、酸素吸収剤を使用した成形容器、両方の表面層が酸素難透過性の層でそれらの層の内側に脱酸素性の層が配置された積層構造を有し当該積層体の側面から酸素を吸収するようにしたものなど、種々のものが知られているが、毒性がなく且つ酸素吸収性能に優れるものであれば、いずれも使用できる。
市販のものとしては、三菱ガス化学社製の“エージレス（登録商標）”などが知られており、エージレスは本発明において好適に使用できる。
脱酸素剤の脱酸素性能からは、酸素透過性容器内に充填されたアセトアミノフェン水溶液１００ｍＬに対して、常温（２５℃）および大気圧下で、２０時間で酸素を１００ｃｍ3以上、好ましくは２００ｃｍ3以上、特に４００ｃｍ3以上の量で吸収することのできる脱酸素剤が好ましく用いられる。
具体的には、三菱ガス化学株式会社製「エージレス（登録商標）ＺＨ−２００」、酸素吸収量＝２００ｃｍ3／２０時間以上（大気圧下）を挙げることができる。
As an oxygen scavenger contained in an oxygen permeable container containing an acetaminophen aqueous solution and a poorly oxygen permeable packaging container, there is no problem such as toxicity in use, and oxygen in the atmosphere is absorbed efficiently. Any material can be used as long as the amount is reduced.
There are various types of oxygen scavengers such as those mainly composed of metal powders such as iron powder, those mainly composed of inorganic substances such as sulfites and metal halides, and those mainly composed of organic substances such as ascorbic acid and polyphenols. Any of them can be used as long as they are known and have no toxicity and excellent oxygen absorption performance.
Some of them absorb carbon dioxide gas simultaneously with oxygen absorption, and others absorb carbon dioxide gas together with oxygen absorption, but any of them can be used in the present invention.
As the form of the oxygen scavenger, the oxygen permeable bag is filled with the above-mentioned substance having the oxygen scavenging ability, a film in which the oxygen absorber is kneaded, a molded container using the oxygen absorber, both surface layers are Various types are known, such as a layer having a laminated structure in which a deoxygenating layer is disposed on the inside of these layers, and oxygen is absorbed from the side surface of the laminated body. However, any of them can be used as long as they are not toxic and have excellent oxygen absorption performance.
As commercially available products, “AGELESS (registered trademark)” manufactured by Mitsubishi Gas Chemical Co., Ltd. is known, and AGELESS can be suitably used in the present invention.
From the oxygen scavenging performance of the oxygen scavenger, oxygen is 100 cm 3 or more in 20 hours at room temperature (25 ° C.) and atmospheric pressure with respect to 100 mL of an acetaminophen aqueous solution filled in an oxygen permeable container, preferably An oxygen scavenger capable of absorbing in an amount of 200 cm 3 or more, particularly 400 cm 3 or more is preferably used.
Specifically, manufactured by Mitsubishi Gas Chemical Company, Inc. "Ageless (registered trademark) ZH-200", can be mentioned oxygen absorption amount = 200 cm 3/20 hours or more (under atmospheric pressure).
以下に実施例などによって本発明について具体的に説明するが、本発明は以下の例によって何ら限定されない。
以下の例において、注射用水およびアセトアミノフェン水溶液中の酸素濃度は、以下の方法により測定した。
EXAMPLES The present invention will be specifically described below with reference to examples and the like, but the present invention is not limited to the following examples.
In the following examples, the oxygen concentration in water for injection and acetaminophen aqueous solution was measured by the following method.
［注射用水およびアセトアミノフェン水溶液中の酸素濃度の測定］
溶存酸素測定用センサー（Ｍｅｔｔｌｅｒ Ｔｏｌｅｄｏ社製 Ｉｎｌａｂ６０５）を用いて、溶液中の酸素濃度を測定した。
[Measurement of oxygen concentration in water for injection and acetaminophen aqueous solution]
The oxygen concentration in the solution was measured using a sensor for measuring dissolved oxygen (Inlab 605 manufactured by Mettler Toledo).
《実施例１》
（１） 窒素ガス雰囲気中（窒素ブース中）で、３５℃に加温した注射用水に窒素ガスバブリングして酸素濃度を１ｍｇ／Ｌ以下に保ち、Ｄ−マンニトール１９２５ｇ、リン酸水素二ナトリウム・十二水和物１３ｇ、アセトアミノフェン５００ｇを加えて攪拌溶解し、室温まで冷却した後にＬ−システイン塩酸塩・一水和物１２．５ｇを加えて溶解した。次いで、水酸化ナトリウムおよび塩酸でｐＨを５．５に調整し、注射用水を加えて全量を５０Ｌとして、アセトアミノフェン水溶液を調製した。
（２） 上記（１）で得られたアセトアミノフェン水溶液を、窒素ガスと空気の混合ガス（窒素ガス：空気＝８０：２０の容積比）の雰囲気中で、１００ｍＬ容の酸素透過性の多層ポリプロピレン製ソフトバッグ［２３℃、９０％ＲＨおよび１気圧で測定した酸素透過度＝８０９ｃｍ3／ｍ2・ｄａｙ、層構造＝ポリプロピレン／ポリプロピレン／ポリプロピレンの三層フィルム、厚さ＝２６４μｍ）に、１００ｍＬずつ充填し、イソプレン製ゴム栓によりシールした。
（３） 上記（２）で得られたアセトアミノフェン水溶液入り酸素透過性容器（酸素透過性の多層ポリプロピレン製ソフトバッグ）を、窒素ガスを加圧媒体として高圧蒸気滅菌（１２１℃で１５分間）を行った。
（４） 上記（３）で得られた高圧蒸気滅菌後のアセトアミノフェン水溶液入り酸素透過性容器を、酸素難透過性の三方シール袋［ＰＰ／シリカ蒸着ＰＥＴ／ＰＰからなる三層構造フィルム（２３℃、９０％ＲＨおよび１気圧で測定した酸素透過度＝０．１５ｃｍ3／ｍ2・ｄａｙ、厚さ＝６６μｍ）をから作製した三方をシールし一方を開口した袋］に、脱酸素剤［三菱ガス化学株式会社製「エージレス（登録商標）ＺＨ−２００」、酸素吸収量＝２００ｃｍ3／２０時間以上、大気圧下）１個と共に収容し、ヒートシール機によって袋の開口部を密封して、アセトアミノフェン注射液製剤を製造した。
Example 1
(1) In a nitrogen gas atmosphere (in a nitrogen booth), nitrogen gas was bubbled into water for injection heated to 35 ° C. to keep the oxygen concentration at 1 mg / L or less, and 1925 g of D-mannitol, disodium hydrogen phosphate · 10 13 g of dihydrate and 500 g of acetaminophen were added and dissolved by stirring. After cooling to room temperature, 12.5 g of L-cysteine hydrochloride / monohydrate was added and dissolved. Next, the pH was adjusted to 5.5 with sodium hydroxide and hydrochloric acid, and water for injection was added to bring the total volume to 50 L to prepare an acetaminophen aqueous solution.
(2) The acetaminophen aqueous solution obtained in the above (1) is subjected to 100 mL of oxygen permeable multilayer in an atmosphere of a mixed gas of nitrogen gas and air (nitrogen gas: air = 80: 20 volume ratio). 100 mL in polypropylene soft bag [Oxygen permeability measured at 23 ° C., 90% RH and 1 atm = 809 cm 3 / m 2 · day, layer structure = three layers film of polypropylene / polypropylene / polypropylene, thickness = 264 μm) Each was filled and sealed with a rubber plug made of isoprene.
(3) Oxygen permeable container (oxygen permeable multilayer polypropylene soft bag) containing the acetaminophen aqueous solution obtained in (2) above is autoclaved with nitrogen gas as a pressurized medium (at 121 ° C. for 15 minutes) Went.
(4) The oxygen-permeable container containing the acetaminophen aqueous solution obtained after the high-pressure steam sterilization obtained in the above (3) is used as a three-layer sealed bag made of PP / silica vapor-deposited PET / PP. Oxygen permeability measured at 23 ° C., 90% RH and 1 atm = 0.15 cm 3 / m 2 · day, thickness = 66 μm) [manufactured by Mitsubishi Gas Chemical Co., Inc. "Ageless (registered trademark) ZH-200", the oxygen absorption amount = 200 cm 3/20 hours or more, housed together under atmospheric pressure) 1, to seal the opening of the bag by heat sealing machine Thus, an acetaminophen injection solution preparation was produced.
《実施例２》
（１） 実施例１の（１）において、窒素ブースを用いずに空気中で、窒素ガスバブリングを行わずに、それ以外は実施例１の（１）と同様にしてアセトアミノフェン水溶液を調製した。
（２） 上記（１）で得られたアセトアミノフェン水溶液を、空気中で、実施例１の（２）で用いたのと同じ１００ｍＬ容の酸素透過性の多層ポリプロピレン製ソフトバッグに、１００ｍＬずつ充填し、イソプレン製ゴム栓によりシールした。
（３） 上記（２）で得られたアセトアミノフェン水溶液入り酸素透過性容器（酸素透過性の多層ポリプロピレン製ソフトバッグ）を、実施例１の（３）と同様にして高圧蒸気滅菌した。
（４） 上記（３）で得られた高圧蒸気滅菌後のアセトアミノフェン水溶液入り酸素透過性容器を、実施例１の（４）で用いたのと同じ酸素難透過性の三方シール袋に、実施例１の（４）で用いたのと同じ脱酸素剤１個と共に収容し、ヒートシール機によって袋の開口部を密封して、アセトアミノフェン注射液製剤を製造した。
Example 2
(1) In Example 1 (1), an acetaminophen aqueous solution was prepared in the same manner as in Example 1 (1), except that nitrogen gas bubbling was not performed in the air without using a nitrogen booth. did.
(2) 100 mL each of the acetaminophen aqueous solution obtained in (1) above is placed in the same 100 mL oxygen-permeable multilayer polypropylene soft bag as used in (2) of Example 1 in the air. Filled and sealed with a rubber plug made of isoprene.
(3) The oxygen-permeable container (oxygen-permeable multilayer polypropylene soft bag) containing the acetaminophen aqueous solution obtained in (2) above was autoclaved in the same manner as (3) of Example 1.
(4) The oxygen-permeable container containing an acetaminophen aqueous solution after high-pressure steam sterilization obtained in (3) above is used in the same oxygen-impermeable three-way sealed bag used in (4) of Example 1, The acetaminophen injection solution was prepared by storing together with one oxygen scavenger used in (4) of Example 1 and sealing the opening of the bag with a heat sealer.
《実施例３》
（１） 実施例１の（１）において、窒素ブースを用いずに空気中で、窒素ガスバブリングを行わずに、それ以外は実施例１の（１）と同様にしてアセトアミノフェン水溶液を調製した。
（２） 上記（１）で得られたアセトアミノフェン水溶液を、空気中で、実施例１の（２）で用いたのと同じ１００ｍＬ容の酸素透過性の多層ポリプロピレン製ソフトバッグに、１００ｍＬずつ充填し、イソプレン製ゴム栓によりシールした。
（３） 上記（２）で得られたアセトアミノフェン水溶液入り酸素透過性容器（酸素透過性の多層ポリプロピレン製ソフトバッグ）を、加圧媒体として空気を用いた以外は実施例１の（３）と同様にして高圧蒸気滅菌した。
（４） 上記（３）で得られた高圧蒸気滅菌後のアセトアミノフェン水溶液入り酸素透過性容器を、実施例１の（４）で用いたのと同じ酸素難透過性の三方シール袋に、実施例１の（４）で用いたのと同じ脱酸素剤１個と共に収容し、ヒートシール機によって袋の開口部を密封して、アセトアミノフェン注射液製剤を製造した。
Example 3
(1) In Example 1 (1), an acetaminophen aqueous solution was prepared in the same manner as in Example 1 (1), except that nitrogen gas bubbling was not performed in the air without using a nitrogen booth. did.
(2) 100 mL each of the acetaminophen aqueous solution obtained in (1) above is placed in the same 100 mL oxygen-permeable multilayer polypropylene soft bag as used in (2) of Example 1 in the air. Filled and sealed with a rubber plug made of isoprene.
(3) (3) of Example 1 except that the oxygen permeable container (oxygen permeable multilayer polypropylene soft bag) containing the acetaminophen aqueous solution obtained in (2) above was used as the pressurizing medium. High-pressure steam sterilization was performed in the same manner as described above.
(4) The oxygen-permeable container containing an acetaminophen aqueous solution after high-pressure steam sterilization obtained in (3) above is used in the same oxygen-impermeable three-way sealed bag used in (4) of Example 1, The acetaminophen injection solution was prepared by storing together with one oxygen scavenger used in (4) of Example 1 and sealing the opening of the bag with a heat sealer.
《実施例４》
（１） 実施例１の（１）において、窒素ブースを用いずに空気中で、それ以外は実施例１の（１）と同様にして窒素ガスバブリングを行ってアセトアミノフェン水溶液を調製した。
（２） 上記（１）で得られたアセトアミノフェン水溶液を、空気中で、実施例１の（２）で用いたのと同じ１００ｍＬ容の酸素透過性の多層ポリプロピレン製ソフトバッグに、１００ｍＬずつ充填し、イソプレン製ゴム栓によりシールした。
（３） 上記（２）で得られたアセトアミノフェン水溶液入り酸素透過性容器（酸素透過性の多層ポリプロピレン製ソフトバッグ）を、実施例１の（３）と同様にして高圧蒸気滅菌した。
（４） 上記（３）で得られた高圧蒸気滅菌後のアセトアミノフェン水溶液入り酸素透過性容器を、実施例１の（４）で用いたのと同じ酸素難透過性の三方シール袋に、実施例１の（４）で用いたのと同じ脱酸素剤１個と共に収容し、ヒートシール機によって袋の開口部を密封して、アセトアミノフェン注射液製剤を製造した。
Example 4
(1) An acetaminophen aqueous solution was prepared by performing nitrogen gas bubbling in the same manner as in (1) of Example 1 except that the nitrogen booth was not used in (1) of Example 1 and in the air.
(2) 100 mL each of the acetaminophen aqueous solution obtained in (1) above is placed in the same 100 mL oxygen-permeable multilayer polypropylene soft bag as used in (2) of Example 1 in the air. Filled and sealed with a rubber plug made of isoprene.
(3) The oxygen-permeable container (oxygen-permeable multilayer polypropylene soft bag) containing the acetaminophen aqueous solution obtained in (2) above was autoclaved in the same manner as (3) of Example 1.
(4) The oxygen-permeable container containing an acetaminophen aqueous solution after high-pressure steam sterilization obtained in (3) above is used in the same oxygen-impermeable three-way sealed bag used in (4) of Example 1, The acetaminophen injection solution was prepared by storing together with one oxygen scavenger used in (4) of Example 1 and sealing the opening of the bag with a heat sealer.
《比較例１》
（１） 実施例１の（１）〜（３）と同じに行って、高圧蒸気滅菌したアセトアミノフェン水溶液入り酸素透過性容器（酸素透過性の多層ポリプロピレン製ソフトバッグ）を製造した。
（２） 上記（２）で得られた高圧蒸気滅菌したアセトアミノフェン水溶液入り酸素透過性容器（酸素透過性の多層ポリプロピレン製ソフトバッグ）を、実施例１の（４）で用いたのと同じ酸素難透過性の三方シール袋に、脱酸素剤を用いずに、単独で収容し、ヒートシール機によって袋の開口部を密封して、アセトアミノフェン注射液製剤を製造した。
<< Comparative Example 1 >>
(1) An oxygen-permeable container (oxygen-permeable multilayer polypropylene soft bag) containing an acetaminophen aqueous solution sterilized by high-pressure steam was manufactured in the same manner as in (1) to (3) of Example 1.
(2) The same high pressure steam sterilized oxygen permeable container (oxygen permeable multilayer polypropylene soft bag) obtained in (2) as used in (4) of Example 1 An acetaminophen injection solution was prepared by storing in a poorly oxygen permeable three-way sealed bag without using an oxygen scavenger and sealing the opening of the bag with a heat sealer.
《比較例２》
（１） 実施例１の（１）において、窒素ブースを用いずに空気中で、窒素ガスバブリングを行わずに、それ以外は実施例１の（１）と同様にしてアセトアミノフェン水溶液を調製した。
（２） 上記（１）で得られたアセトアミノフェン水溶液を、空気中で、実施例１の（２）で用いたのと同じ１００ｍＬ容の酸素透過性の多層ポリプロピレン製ソフトバッグに、１００ｍＬずつ充填し、イソプレン製ゴム栓によりシールした。
（３） 上記（２）で得られたアセトアミノフェン水溶液入り酸素透過性容器（酸素透過性の多層ポリプロピレン製ソフトバッグ）を、加圧媒体として空気を用いた以外は実施例１の（３）と同様にして高圧蒸気滅菌した。
（４） 上記（３）で得られた高圧蒸気滅菌後のアセトアミノフェン水溶液入り酸素透過性容器を、実施例１の（４）で用いたのと同じ酸素難透過性の三方シール袋に、脱酸素剤を用いずに、単独で収容し、ヒートシール機によって袋の開口部を密封して、アセトアミノフェン注射液製剤を製造した。
<< Comparative Example 2 >>
(1) In Example 1 (1), an acetaminophen aqueous solution was prepared in the same manner as in Example 1 (1), except that nitrogen gas bubbling was not performed in the air without using a nitrogen booth. did.
(2) 100 mL each of the acetaminophen aqueous solution obtained in (1) above is placed in the same 100 mL oxygen-permeable multilayer polypropylene soft bag as used in (2) of Example 1 in the air. Filled and sealed with a rubber plug made of isoprene.
(3) (3) of Example 1 except that the oxygen permeable container (oxygen permeable multilayer polypropylene soft bag) containing the acetaminophen aqueous solution obtained in (2) above was used as the pressurizing medium. High-pressure steam sterilization was performed in the same manner as described above.
(4) The oxygen-permeable container containing an acetaminophen aqueous solution after high-pressure steam sterilization obtained in (3) above is used in the same oxygen-impermeable three-way sealed bag used in (4) of Example 1, Without using an oxygen scavenger, it was housed alone, and the opening of the bag was sealed with a heat sealer to produce an acetaminophen injection solution.
上記の実施例１〜４および比較例１〜２で得られたアセトアミノフェン注射液製剤における成分組成およびｐＨは、以下の表１に示すとおりである。 The component composition and pH in the acetaminophen injection solution formulations obtained in Examples 1 to 4 and Comparative Examples 1 and 2 are as shown in Table 1 below.
《試験１》［高圧蒸気滅菌後で包装容器収容前のアセトアミノフェン水溶液中の酸素濃度の測定試験］
上記の実施例１の（３）で得られた高圧蒸気滅菌後のアセトアミノフェン水溶液（高圧蒸気滅菌後で包装容器に収容する前のアセトアミノフェン水溶液、以下同じ）、実施例２の（３）で得られた高圧蒸気滅菌後のアセトアミノフェン水溶液、実施例３の（３）で得られた高圧蒸気滅菌後のアセトアミノフェン水溶液、実施例４の（３）で得られた高圧蒸気滅菌後のアセトアミノフェン水溶液、比較例１の（１）で得られた高圧蒸気滅菌後のアセトアミノフェン水溶液および比較例２の（３）で得られた高圧蒸気滅菌後のアセトアミノフェン水溶液のそれぞれについて、アセトアミノフェン水溶液中の酸素濃度を測定したところ、下記の表２に示すとおりであった。
<< Test 1 >> [Measurement test of oxygen concentration in acetaminophen aqueous solution after high-pressure steam sterilization and before storing in packaging container]
Acetaminophen aqueous solution after high-pressure steam sterilization obtained in (3) of Example 1 above (acetaminophen aqueous solution after high-pressure steam sterilization and before storing in a packaging container, the same shall apply hereinafter), (3 Acetaminophen aqueous solution after high-pressure steam sterilization obtained in (1), acetaminophen aqueous solution after high-pressure steam sterilization obtained in (3) of Example 3, and high-pressure steam sterilization obtained in (3) of Example 4 The acetaminophen aqueous solution after the high pressure steam sterilization obtained in (1) of Comparative Example 1 and the acetaminophen aqueous solution after the high pressure steam sterilization obtained in (3) of Comparative Example 2 When the oxygen concentration in the acetaminophen aqueous solution was measured, it was as shown in Table 2 below.
《試験２》［アセトアミノフェン注射液製剤中の酸素濃度の測定試験］
上記の実施例１の（４）で得られたアセトアミノフェン注射液製剤（最終的に得られたアセトアミノフェン注射液製剤、以下同じ）、実施例２の（４）で得られたアセトアミノフェン注射液製剤、実施例３の（４）で得られたアセトアミノフェン注射液製剤、実施例４の（４）で得られたアセトアミノフェン注射液製剤、比較例１の（２）で得られたアセトアミノフェン注射液製剤および比較例２の（４）で得られたアセトアミノフェン注射液製剤のそれぞれについて、大気中で室温下に２４時間および４日間保存したときのアセトアミノフェン水溶液中の酸素濃度を測定したところ、下記の表２に示すとおりであった。
<< Test 2 >> [Test for measuring oxygen concentration in acetaminophen injection preparation]
Acetaminophen injection solution obtained in (4) of Example 1 above (finally obtained acetaminophen injection solution, the same shall apply hereinafter), acetamino obtained in (4) of Example 2 Fen injection preparation, acetaminophen injection preparation obtained in (4) of Example 3, acetaminophen injection preparation obtained in (4) of Example 4, and (2) of Comparative Example 1 Each of the obtained acetaminophen injection solution preparation and the acetaminophen injection solution preparation obtained in (4) of Comparative Example 2 was stored in an acetaminophen aqueous solution when stored in air at room temperature for 24 hours and 4 days. When the oxygen concentration of was measured, it was as shown in Table 2 below.
《試験３》［安定性試験］
上記の実施例１〜４および比較例１〜２で得られたそれぞれのアセトアミノフェン注射液製剤を６０℃で７日間および２１日間保存し、試験開始時、７日間経過後および２１日間経過後の各時点で、注射液の外観、ｐＨ、注射液中のＬ−システイン塩酸塩水和物の含有量、分解物の総量およびアセトアミノフェンの残存率を下記の方法で評価または測定したところ、下記の表２に示すとおりであった。
<< Test 3 >> [Stability Test]
The respective acetaminophen injection preparations obtained in Examples 1 to 4 and Comparative Examples 1 and 2 above were stored at 60 ° C. for 7 days and 21 days, at the start of the test, after 7 days and after 21 days. At each time point, the appearance of the injection solution, pH, the content of L-cysteine hydrochloride hydrate in the injection solution, the total amount of degradation products and the residual ratio of acetaminophen were evaluated or measured by the following methods. Table 2 shows the results.
《試験４》［安定性試験］
上記の実施例１で得られたアセトアミノフェン注射液製剤を４０℃で３箇月間および６箇月間保存し、注射液の外観、ｐＨ、注射液中のＬ−システイン塩酸塩水和物の含有量、分解物の総量およびアセトアミノフェンの残存率を下記の方法で測定したところ、下記の表２に示すとおりであった。
<< Test 4 >> [Stability Test]
The acetaminophen injection solution preparation obtained in the above Example 1 was stored at 40 ° C. for 3 months and 6 months, appearance of the injection solution, pH, content of L-cysteine hydrochloride hydrate in the injection solution The total amount of decomposition products and the residual ratio of acetaminophen were measured by the following method, and as shown in Table 2 below.
（１）注射液の外観の評価：
製剤溶液の澄明性及び色を観察した。
(1) Evaluation of appearance of injection solution:
The clarity and color of the formulation solution was observed.
（２）アセトアミノフェン注射液製剤のｐＨ：
ｐＨメータを用いて測定した。
(2) pH of acetaminophen injection solution formulation:
Measurement was performed using a pH meter.
（３）アセトアミノフェン注射液製剤中のＬ−システイン塩酸塩水和物の含有量：
アセトアミノフェン注射液製剤に水を加えて一定濃度の希釈液を調製し、液体クロマトグラフィー法によりＬ−システイン塩酸塩水和物の含量（ｍｇ／１００ｍＬ）を測定した。
(3) Content of L-cysteine hydrochloride hydrate in acetaminophen injection liquid preparation:
Water was added to the acetaminophen injection preparation to prepare a diluted solution having a constant concentration, and the content of L-cysteine hydrochloride hydrate (mg / 100 mL) was measured by liquid chromatography.
（４）アセトアミノフェン注射液製剤中の分解物の総量：
アセトアミノフェン注射液製剤を液体クロマトグラフィー法により測定し、得られたクロマトグラムの各分解物ピークのピーク面積の面積百分率(％)を求め、それらの分解物の総量(％)を算出した。
(4) Total amount of degradation products in the acetaminophen injection formulation:
The acetaminophen injection preparation was measured by liquid chromatography, the area percentage (%) of the peak area of each degradation product peak of the obtained chromatogram was determined, and the total amount (%) of these degradation products was calculated.
（５）アセトアミノフェン注射液製剤中のアセトアミノフェンの残存率：
アセトアミノフェン注射液製剤に水を加えて一定濃度の希釈液を調製し、液体クロマトグラフィー法によりアセトアミノフェンの含量を測定し、試験の開始前における含有量を１００％としたときの残存率（％）を求めた。
(5) Acetaminophen residual rate in the acetaminophen injection preparation:
Water is added to the acetaminophen injection preparation to prepare a dilute solution with a constant concentration, the acetaminophen content is measured by liquid chromatography, and the residual rate when the content before the start of the test is 100% (%) Was calculated.
上記の表２にみるように、実施例１〜４のアセトアミノフェン注射液製剤は、長期保存安定性に極めて優れている。
それに対して、比較例１および２のアセトアミノフェン注射液製剤は、実施例１〜３のアセトアミノフェン注射液製剤に比べて、長期保存安定性の点で劣っている。
As seen in Table 2 above, the acetaminophen injection solutions of Examples 1 to 4 are extremely excellent in long-term storage stability.
On the other hand, the acetaminophen injection solution preparations of Comparative Examples 1 and 2 are inferior in terms of long-term storage stability as compared to the acetaminophen injection solution preparations of Examples 1 to 3.
本発明のアセトアミノフェン注射液製剤は、液剤であるにも拘らず、室温で長期間保存した後でもアセトアミノフェンの変質や分解などが極めて少なくて、アセトアミノフェンが高い残存率で液中に維持されていて、長期保存安定性に優れているので、術後疼痛の治療などのために医療現場で有効に用いることができる。 Although the acetaminophen injection solution preparation of the present invention is a liquid agent, it has very little alteration or decomposition of acetaminophen even after long-term storage at room temperature, and acetaminophen has a high residual rate in the liquid. Therefore, it can be effectively used in the medical field for the treatment of postoperative pain and the like.
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| KR20200131225A (en) | 2018-03-20 | 2020-11-23 | 소니 세미컨덕터 솔루션즈 가부시키가이샤 | Distance sensor and distance measuring device |
| JP2021514934A (en) * | 2018-11-14 | 2021-06-17 | エーブイエム・バイオテクノロジー・エルエルシー | Stable glucocorticoid preparation |
| EP4023292A4 (en) * | 2019-08-30 | 2023-09-06 | TERUMO Kabushiki Kaisha | Injection formulation |
| JP7470308B2 (en) | 2021-12-28 | 2024-04-18 | 大日本印刷株式会社 | Container containing liquid, combination container containing liquid, container, stopper, and method of manufacturing container containing liquid |
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| JP7470308B2 (en) | 2021-12-28 | 2024-04-18 | 大日本印刷株式会社 | Container containing liquid, combination container containing liquid, container, stopper, and method of manufacturing container containing liquid |
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