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TW201603801A - Packaged acetaminophen injection solution preparation - Google Patents

Packaged acetaminophen injection solution preparation Download PDF

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TW201603801A
TW201603801A TW103126100A TW103126100A TW201603801A TW 201603801 A TW201603801 A TW 201603801A TW 103126100 A TW103126100 A TW 103126100A TW 103126100 A TW103126100 A TW 103126100A TW 201603801 A TW201603801 A TW 201603801A
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oxygen
acetaminophen
injection solution
phenol
container
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TW103126100A
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Chinese (zh)
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TWI623310B (en
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下田雅美
矢後誠司
坂口千春
岩切智佐都
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泰爾茂股份有限公司
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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

被包裝的乙醯胺苯酚注射溶液製劑 Packaged acetaminophen injection solution preparation

本發明係關於一種被包裝的乙醯胺苯酚注射溶液製劑。更特別的是,本發明係關於一種儲存穩定性傑出之被包裝的乙醯胺苯酚注射溶液製劑,其准許乙醯胺苯酚甚至在室溫下儲存一段長時間後於該溶液中保持安定。 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.

乙醯胺苯酚(與撲熱息痛(paracetamol)同義)係一種溫和的退熱劑/止痛劑,其並無胃部刺激、抑制血液凝結、腎臟病及諸如興奮及嗜睡等副作用。再者,其不包括藥癮及脫癮症狀的問題。此係為何呈口服藥物及栓劑形式的乙醯胺苯酚係遍及世界最受歡迎欲使用的退熱劑/止痛劑的理由之一。 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.

乙醯胺苯酚亦可以注射溶液製劑形式(其係裝填在容器中的乙醯胺苯酚水溶液)獲得。因為其在2002年時出現於海外市場,其已經在約80個國家(除了日本外)中批准製造及出售,包括美國及歐洲國家。其現在係使用於手術後疼痛的標準治療。 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.

在已知的乙醯胺苯酚注射溶液製劑當中,為了在長時間儲存期間的穩定性,係將乙醯胺苯酚水溶液在去氧(藉由惰性氣體吹氣)後,於氮氣環境中填充及密封於玻璃瓶中,及隨後進行濕熱滅菌(參見USP 6028222,於此之後指為專利文件1)。於此已經提出一種藉由讓水溶液接受超音波作用及抽濾與微吹氣之任一種或二者,將在乙醯胺苯酚水溶液中的氧含量保持在低如0.4至4毫克/升之方法(參見US 2009044700A,於此之後指為專利文件2)。 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).

遵循在上述提及的USP 6028222及US 2009044700A中所描述之技術,本發明家製備一種裝填在袋子中的乙醯胺苯酚注射溶液製劑,其係藉由讓一乙醯胺苯酚水溶液接受去氧(藉由惰性氣體吹氣),在惰性氣體環境中將其填充及密封在一容器(特別是,有機聚合物薄片的袋子)中,及進行濕熱滅菌(以惰性氣體諸如氮加壓)。由於儲存穩定性測試,已發現雖然在每個步驟中皆有去氧處理,該乙醯胺苯酚注射溶液製劑在長時間儲存穩定性上並不令人滿意。 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.

本發明的目標為提供一種在長時間儲存穩定性上如此優異之被包裝的乙醯胺苯酚注射溶液製劑,其甚至在室溫下儲存三年或較長後保留極高比率的乙醯胺苯酚,因此,其可安全地儲存超過一段長時間。 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.

本發明的另一個目標為提供一種被包裝的乙醯胺苯酚注射溶液製劑,其係保持在從有機聚合物膜或薄片形成的容器,特別是袋狀容器中,該容器係合適於在室溫下長時間安全儲存且重量輕及具有好的操作性沒有破損。 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.

為了達成前述目標,本發明家進行大量研究,已建議該長時間儲存穩定性不可歸因於包含於乙醯胺苯酚注射溶液製劑之製造中的氧控制。為了清楚此是否為真實,本發明家以如下之不同方法製造乙醯胺苯酚注射溶液製劑的樣品,及測試其儲存穩定性。 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.

也就是說,本發明家以上述提及的方式製造該乙醯胺苯酚注射溶液製劑,其包括在裝填於容器中之前製備一乙醯胺苯酚水溶液的步驟、將該乙醯胺苯酚水溶液裝填在容器中之步驟、在裝填該乙醯胺苯酚水溶液的容器中進行濕熱滅菌(換句話說,高壓蒸氣殺菌及熱壓消毒)之步驟;全部步驟係以引進惰性氣體或在惰性氣體環境中進行。除此之外,本發明家以該等步驟之一個或二個或全部皆在空氣中(取代惰性氣體環境)進行的方式來製造該乙醯胺苯酚注射溶液製劑。 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).

前述實驗的結果指示出,不像在上述提及的專利文件1及2中所描述之已知資料,該乙醯胺苯酚注射溶液製劑的長時間儲存穩定性係受曝露至氧僅有些微影響,其中該曝露係發生在裝填於容器之前製備該乙醯胺苯酚水溶液的步驟、將該乙醯胺苯酚水溶液裝填在容器中之步驟、及對裝填該乙醯胺苯酚水溶液的容器施用濕熱滅菌之步驟。 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.

本發明家從前述推測出該乙醯胺苯酚注射溶液製劑之變質及分解係受在其製造階段中所進行的短時期氧控制些微影響,但是該影響發生在製造後之儲存期間。結果,本發明家理解到乙醯胺苯酚與氧並非快速地而是相當慢地反應。 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.

本發明家已如下假設。 The inventors have assumed the following.

在乙醯胺苯酚水溶液之製備那時的氧控制(藉由惰性氣體諸如氮氣吹氣)、在將乙醯胺苯酚水溶液裝填進容器中那時的氧控制(在惰性氣體環境中)、及在濕熱滅菌那時的氧控制(以惰性氣體加壓)非必需性重要。任何逐漸移除在被包裝適於銷售的乙醯胺苯酚製劑中之氧係重要的。若藉由移除在被包裝適於銷售的乙醯胺苯酚製劑中之氧,使得在其水溶液中的乙醯胺苯酚於儲存期間免受變質及分解時,將可獲得在長時間儲存穩定性上優異的乙醯胺苯酚注射溶液製劑。本發明家留意到前述而檢閱多種可能的方法。 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.

最後,本發明家發現前述目標係藉由將乙醯胺苯酚水溶液裝填在由透氧的內容器與不透氧的外容器所構成之雙容器形式中達成,其中在二個容器間之空間係儲存一去氧劑。在儲存期間,該雙層容器准許從該乙醯胺苯酚水溶液及容納該乙醯胺苯酚水溶液的內容器之頂端空間中逐漸地移除氧。以此方式達成從該內容器相當大地減少氧而促成該乙醯胺苯酚注射溶液製劑之長時間儲存穩定性。此發現導致本發明。 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.

該用以達成目標的方法係如下列描述。 The method used to achieve the goal is as described below.

該被包裝的乙醯胺苯酚注射溶液製劑包含一不透氧的包裝容器、及一包括pH 4至8包含乙醯胺苯酚作為有效成份之乙醯胺苯酚水溶液的乙醯胺苯酚注射溶液製劑、及一 裝填該乙醯胺苯酚水溶液之經密封的透氧容器,其中該乙醯胺苯酚注射溶液製劑係藉由濕熱滅菌法殺菌,該不透氧的包裝容器包圍該乙醯胺苯酚注射溶液製劑及經密封,及該被包裝的乙醯胺苯酚注射溶液製劑具有一去氧劑以吸收在該經密封之不透氧的包裝容器內的氧。 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‧‧‧被包裝的乙醯胺苯酚注射溶液製劑 1‧‧‧Packed acetaminophen injection solution preparation

2‧‧‧不透氧的包裝容器 2‧‧‧Oxygen-impermeable packaging containers

3‧‧‧經密封的透氧容器 3‧‧‧ Sealed oxygen permeable container

4‧‧‧去氧劑 4‧‧‧Deoxidizer

31‧‧‧容器主體 31‧‧‧ container body

32‧‧‧密封元件 32‧‧‧Sealing components

圖1係本發明的乙醯胺苯酚注射溶液製劑之具體實例的平面圖。 Fig. 1 is a plan view showing a specific example of the preparation of the acetaminophen injection solution of the present invention.

下列係本發明的詳細說明。 The following is a detailed description of the invention.

本發明之被包裝的乙醯胺苯酚注射溶液製劑包含一乙醯胺苯酚注射溶液製劑及一不透氧的包裝容器。該乙醯胺苯酚注射溶液製劑係藉由濕熱滅菌法(換句話說,高壓蒸氣殺菌或熱壓消毒)殺菌。該不透氧的包裝容器包圍該乙醯胺苯酚注射溶液製劑且經密封。該被包裝的乙醯胺苯酚注射溶液製劑具有一去氧劑以吸收在該經密封之不透氧的包裝容器內的氧。 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.

換句話說,本發明係關於一種乙醯胺苯酚注射溶液製劑,其由下列構成:一包含乙醯胺苯酚作為有效成份的乙醯胺苯酚水溶液;一將該水溶液容納在其中的透氧內容器,其在裝填後已進行濕熱滅菌;及一緊緊密封之不透氧的 外容器(換句話說,包裝容器),其一起容納該內容器;及一放置在該內與外容器間之去氧劑。 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.

該乙醯胺苯酚注射溶液製劑包含該經密封的透氧容器及該裝填在該經密封的透氧容器中之乙醯胺苯酚水溶液。特別是,在顯示於圖1的具體實例中,該被包裝的乙醯胺苯酚注射溶液製劑包括該乙醯胺苯酚注射溶液製劑、該不透氧的包裝容器及該去氧劑。該不透氧的包裝容器包圍該乙醯胺苯酚注射溶液製劑與該去氧劑。再者,該去氧劑係配置在該包裝容器與裝填該乙醯胺苯酚水溶液之經密封的透氧容器間之空間中。但是,該不透氧的包裝容器或該經密封的透氧容器可具有該去氧劑。該乙醯胺苯酚可係通常使用於注射溶液、口服藥物及栓劑之任何型式。其亦可以生理學可接受的鹽形式使用。 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.

本發明之乙醯胺苯酚注射溶液製劑包括該裝填於透氧容器中的乙醯胺苯酚水溶液,其具有pH 4至8,較佳為pH 5至6。若pH值低於4,該乙醯胺苯酚水溶液在儲存穩定性上係差的;若pH值高於8,該乙醯胺苯酚水溶液當藉由注射給藥時趨向於刺激血管(造成血管疼痛及發炎)。 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).

該乙醯胺苯酚水溶液能以任何習知用於注射溶液的pH調整劑來調整pH。該pH調整劑的實施例包括鹼,諸如氫氧化鈉及氫氧化鉀;無機酸,諸如鹽酸;及有機酸,諸如檸檬酸、乳酸、醋酸、琥珀酸及蘋果酸。想要的是,完成pH調整時所形成的鹽較少。因此,作為該pH調整,氫氧化鈉(強鹼)及鹽酸(強酸)係較佳。 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.

欲裝填在該透氧容器中的乙醯胺苯酚水溶液應該 從藥理學及生理學可接受的水製備,諸如蒸餾水、水、純水、無菌的純水、用於注射的水、及用於注射的蒸餾水。這些種類的水係在Japanese Pharmacopoeia,第16版中有定義。 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.

當使用作為靜脈內注射溶液時,從想要的溶解度及效率及劑量之觀點來看,該乙醯胺苯酚水溶液應該包括量係2至50毫克/毫升的乙醯胺苯酚,較佳為5至10毫克/毫升。 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.

若濃度過低時,需要對患者大量給藥該乙醯胺苯酚水溶液。若濃度過高時,該乙醯胺苯酚水溶液由於乙醯胺苯酚的低溶解度而趨向於造成在低溫下析出。 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.

除了前述pH調整劑外,該乙醯胺苯酚水溶液應該較佳包括一或二或更多種張力劑、抗氧化劑及緩衝劑物種。 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.

該張力劑可選自於現存使用於注射溶液之任何一種。其包括例如非離子性,諸如甘露醇、山梨糖醇、肌醇、葡萄糖、丙二醇及甘油;及離子性,諸如氯化鈉。可使用其一或二或更多種。在這些實施例當中,從殺菌的安全性及穩定性之觀點來看,甘露醇係較佳。 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.

該張力劑應該以足以使得該乙醯胺苯酚注射溶液具有大約或精確與血清相同的滲透壓(如此該滲透壓的比率係0.9至1.1)之量加入。 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).

該抗氧化劑可選自於現存使用於注射溶液的任何一種。其包括例如具有硫醇官能基的有機化合物(諸如半胱胺酸)、其鹽形式及其水合物(例如,半胱胺酸鹽酸水合物);亞硫酸鹽,諸如亞硫酸氫鈉;抗壞血酸或其鹽;及二丁基羥基 甲苯。在這些實施例當中,從生理學觀點來看,半胱胺酸鹽酸水合物(典型為半胱胺酸鹽酸單水合物)係較佳。 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.

該緩衝劑可選自於現存使用於注射溶液的任何一種。其包括例如磷酸或其鹽或其水合物(例如,磷酸氫鈉水合物)、檸檬酸或其鹽或其水合物、及醋酸或其鹽或其水合物。在這些實施例中,從藥物物質的穩定性及溶解度之觀點來看,無水磷酸氫鈉或其水合物係較佳。該磷酸氫鈉應該較佳為呈二鈉鹽形式。該磷酸氫鈉水合物應該較佳為呈二水合物、七水合物或十二水合物形式。 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.

該乙醯胺苯酚水溶液可選擇性包括一或二或更多種額外的醫藥有效成份物種,諸如止痛劑、消炎藥、止吐劑、抗癲癇藥、抗抑鬱劑及抗病毒藥;或賦形劑,諸如多元醇、錯合劑、烷醇及維他命。 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.

該乙醯胺苯酚水溶液可以任何方式製備而沒有特定的限制,只要可獲得一均勻的溶液而沒有乙醯胺苯酚及前述提及的成份進行變質及分解。 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.

該用以製備乙醯胺苯酚水溶液的方法可在空氣中或在惰性氣體的環境中或在空氣與惰性氣體的環境中進行。 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.

在該環境係空氣與惰性氣體之混合物的情況中,該混合比率(空氣對惰性氣體)以體積計應該係1:99至99:1,較佳為10:90至90:10。 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.

再者,該乙醯胺苯酚水溶液可在其製備期間及/或之後以惰性氣體進行吹氣,以便減少在其中的氧含量。再者,該乙醯胺苯酚水溶液可係如此,在其製備期間或之後不 以惰性氣體吹氣而裝填在透氧容器中。 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.

欲使用來吹入乙醯胺苯酚水溶液中之惰性氣體可係氮氣、氬氣及二氧化碳氣體之任何,而氮氣由於其低價可利用性係較佳。 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.

隨後,將該乙醯胺苯酚水溶液裝填在透氧容器中。該透氧容器不特別限制,只要其由可對氧滲透但是無毒、不吸附乙醯胺苯酚及對耐用於濕熱滅菌的熱之液體(水)不滲透的任何材料製得。 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.

該透氧容器應該具有透氧性在23℃及90%RH下於常壓(1013hPa)下測量不低於200立方公分/平方公尺/天。該透氧性應該較佳為不低於500立方公分/平方公尺/天,更佳為不低於700立方公分/平方公尺/天,及最想要為700至10000立方公分/平方公尺/天。 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.

只要該透氧容器具有透氧性在23℃及90%RH下於常壓(1013hPa)下測量不低於200立方公分/平方公尺/天,其准許讓當裝填時帶入該透氧容器中及包含在該乙醯胺苯酚水溶液與該容器之頂端空間中且通過該透氧容器的氧充分地由該去氧劑吸收及移除。 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.

該透氧容器應該較佳具有儘可能高的透氧性,以便准許包含在裝填於其中的乙醯胺苯酚水溶液與在其中的頂端空間中之氧容易地由該去氧劑吸收及移除。 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.

該透氧容器可係可撓容器或固體容器。應該較佳的是,其係從對氧可滲透但是對液體(水)不滲透之有機聚合物形成。應該更佳的是,其係從對氧可滲透但是對液體(水)不滲 透之有機聚合物形成且呈膜或薄片形式。應該最佳的是,其係從對氧可滲透但是對液體(水)不滲透的有機聚合物形成且呈軟的(可撓的)膜或薄片形式。 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.

該形成透氧容器之對氧可滲透但是對液體(水)不滲透的有機聚合物可包括例如聚乙烯樹脂、聚丙烯樹脂、聚乙烯樹脂與聚丙烯樹脂之混合物、乙烯-醋酸乙烯酯共聚物、聚氯乙烯樹脂及多種熱塑性彈性體。該透氧的可撓容器可從有機聚合物組成物形成,其中一作為基底的固體有機聚合物係併入塑化劑或相容的軟有機聚合物(諸如熱塑性彈性體,包括以苯乙烯為基底的熱塑性彈性體及以烯烴為基底的熱塑性彈性體)。 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).

該透氧容器可係從前述有機聚合物形成的單層結構或具有二或更多層之多層結構。 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.

該從透氧的有機聚合物膜或薄片形成之透氧容器應該具有壁厚50至500微米,較佳為100至300微米,以便滿足對透氧性及容器性能之需求。對具有足夠強度及足夠耐濕熱滅菌法的容器來說,厚度等於或大於50微米係足夠。同樣地,對所需要的透氧性來說及亦對具有適當彈性之用於乙醯胺苯酚注射溶液製劑的袋型式容器來說,厚度等於或小於500微米係想要的。 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.

該透氧容器應該較佳具有一埠,裝填在該容器中之乙醯胺苯酚水溶液(或注射溶液)係透過其從該容器中排出而給藥至患者。在使用注射針來排出的情況中,該埠可提供一彈性塞子。該彈性塞子係由彈性體或橡膠製得,其較佳准 許注射針刺穿及該刺穿孔在該注射針已經移除後封閉(再密封)。該彈性塞子的材料包括丁基橡膠、異戊二烯橡膠、氯化的丁基橡膠(氯丁二烯)、其類似物。再者,該彈性塞子可具有其表面(至少與該乙醯胺苯酚水溶液接觸)塗佈一以氟為基底的樹脂、聚對二甲苯、DLC(類鑽碳)、聚丙烯、聚乙烯或其類似物層,其係附著於此或沈積在上面,以便包含在該彈性塞子中之任何組分不溶解在該乙醯胺苯酚水溶液中。 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.

該透氧容器之形狀不特別限制,其可呈袋子、瓶子、注射器、泡殼或其類似形式。 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.

該透氧容器可以任何方式形成而沒有特定限制。可根據所使用的材料型式及容器形狀而採用任何適當的製造方法。該製造方法的實施例包括擠壓吹模、射出吹模、充氣成型、射出成型、鑄造、平膜或薄片藉由折疊封閉周圍之熱密封、圓筒狀膜或薄片之熱密封以封閉該頂端及底部而提供具有底部及端帽的圓筒狀主體。 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.

該透氧容器的尺寸不特別限制。適當的尺寸係依該乙醯胺苯酚注射溶液製劑之形式及濃度而定,其係通常如此該內部體積係20至500立方公分,較佳為50至100立方公分。此尺寸對處理及患者的水控制係方便的。 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.

可於空氣中、於惰性氣體環境中、或於空氣與惰性氣體之混合物的環境中進行將該乙醯胺苯酚水溶液裝填在透氧容器中。該惰性氣體可例如係氮氣、氬氣、二氧化碳氣體等等。氮氣係較佳,因為其低價可利用性。再者,該裝填步驟可接著除氣。 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.

在空氣與惰性氣體之混合物的環境下進行將乙醯胺苯酚水溶液裝填於透氧容器中之情況中,該空氣對惰性氣體的混合比率應該較佳為1:99至99:1(以體積計),更佳為10:90至90:10(以體積計)。 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).

裝填該乙醯胺苯酚水溶液之透氧容器隨後進行濕熱滅菌。此程序可藉由使用蒸氣作為殺菌媒質及空氣作為加壓媒質、或使用蒸氣作為殺菌媒質及惰性氣體作為加壓媒質、或使用蒸氣作為殺菌媒質及空氣與惰性氣體之混合物作為加壓媒質達成。該用於此目的之惰性氣體可例如係氮氣、氬氣、二氧化碳氣體等等。氮氣係較佳,因為其低價可利用性。 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.

在使用空氣與惰性氣體的混合物作為加壓媒質之情況中,該空氣對惰性氣體的混合比率應該較佳為1:99至99:1(以體積計),更佳為10:90至90:10(以體積計)。 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).

該濕熱滅菌法可在正常使用於殺菌注射溶液製劑之任何條件(溫度、壓力、時間等等)下達成。例如,該溫度應該係100至129℃,較佳為115至124℃。 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.

根據本發明,該在裝填於容器中之前用以製備乙醯胺苯酚水溶液的步驟、該用以將乙醯胺苯酚水溶液裝填在透氧容器中的步驟、及用於濕熱滅菌的步驟之至少一個或二個或全部皆可在引進惰性氣體的環境中或在惰性氣體環境中進行。再者,全部步驟可在空氣環境中進行。此等模式之組合係闡明在下列。 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)進行在惰性氣體環境中製備該乙醯胺苯酚水溶液(在惰性氣體棚中實現)及以惰性氣體吹氣該乙醯胺苯酚水溶液二者。該乙醯胺苯酚水溶液係於惰性氣體環境下裝填在透氧容器中,及容納該乙醯胺苯酚水溶液之透氧容器係使用惰性氣體作為加壓媒質進行濕熱滅菌。 (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)進行在惰性氣體環境中製備該乙醯胺苯酚水溶液(在惰性氣體棚中實現)及以惰性氣體吹氣該乙醯胺苯酚水溶液之任一種或二者。該乙醯胺苯酚水溶液係在惰性氣體環境下裝填於透氧容器中,及容納該乙醯胺苯酚水溶液之透氧容器係使用空氣作為加壓媒質進行濕熱滅菌。 (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)未進行在惰性氣體環境中製備該乙醯胺苯酚水溶液(在惰性氣體棚中實現)及以惰性氣體吹氣該乙醯胺苯酚水溶液之任一種或二者。另一方面,該乙醯胺苯酚水溶液係在惰性氣體環境下裝填於透氧容器中,及容納該乙醯胺苯酚水溶液之透氧容器係使用惰性氣體作為加壓媒質進行濕熱滅菌。 (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)未進行在惰性氣體環境中製備該乙醯胺苯酚水溶液(在惰性氣體棚中實現)及以惰性氣體吹氣該乙醯胺苯酚水溶液之任一種或二者。再者,該乙醯胺苯酚水溶液係在惰性氣體環境下裝填於透氧容器中,但是容納該乙醯胺苯酚水溶液的透氧容器係使用空氣作為加壓媒質進行濕熱滅菌。 (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)進行在惰性氣體環境中製備該乙醯胺苯酚水溶液(在惰性氣體棚中實現)及以惰性氣體吹氣該乙醯胺苯酚水溶液之任一種或二者。該乙醯胺苯酚水溶液係在空氣中裝填 於透氧容器中,及容納該乙醯胺苯酚水溶液之透氧容器係使用惰性氣體作為加壓媒質進行濕熱滅菌。 (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)該乙醯胺苯酚水溶液係在缺乏惰性氣體環境(在惰性氣體棚中實現)下製備及該乙醯胺苯酚水溶液不以惰性氣體進行吹氣。該乙醯胺苯酚水溶液係於空氣中裝填在透氧容器中,及容納該乙醯胺苯酚水溶液的透氧容器係使用空氣作為加壓媒質進行濕熱滅菌。 (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)在上述提及的模式(1)至(6)之任何一種中,該乙醯胺苯酚水溶液係在空氣與惰性氣體之混合物中裝填於透氧容器中,及/或容納該乙醯胺苯酚水溶液的透氧容器係使用空氣與惰性氣體之混合物作為加壓媒質進行濕熱滅菌。 (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.

在濕熱滅菌後,將容納該乙醯胺苯酚水溶液的透氧容器與去氧劑一起放置及密封在該不透氧的外容器中。 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.

該不透氧的外容器(包裝容器)在其性能上不特別限制,只要其能裝入容納該乙醯胺苯酚水溶液的透氧容器與去氧劑,及其對氧不滲透且無毒。 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.

該不透氧的外容器(包裝容器)應該具有透氧性在23℃及90%RH下於常壓(1013hPa)下測量不高於1.0立方公分/平方公尺/天。該透氧性應該較佳不高於0.3立方公分/平方公尺/天,及更佳為不高於0.1立方公分/平方公尺/天。 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.

只要該不透氧的外容器(包裝容器)具有透氧性在23℃及90%RH下於常壓(1013hPa)下測量不高於1.0立方公分/平方公尺/天,其准許在其中的去氧劑充分地吸收及移除從容納在該透氧容器中的乙醯胺苯酚水溶液與在該透氧容器中 的頂端空間所釋放出而通過該透氧容器之氧,同時障蔽在該不透氧的外容器外之空氣(氧)。 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.

該不透氧的外容器(包裝容器)應該較佳具有儘可能低的透氧性,以便准許該去氧劑容易地吸收及移除從容納在該透氧容器中的乙醯胺苯酚水溶液與在透氧容器中的頂端空間所釋放出之氧。 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.

該不透氧的外容器(包裝容器)可係可撓容器或固體容器。該不透氧的外容器較佳為從不滲透的有機聚合物膜或薄片形成。該不滲透的有機聚合物膜及薄片較佳具有彈性。 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.

該不透氧的外容器(包裝容器)可從不透氧的金屬箔(諸如鋁箔)、沈積的膜或薄片、塗佈DLC(類鑽塗層)的有機聚合物膜或薄片、從不透氧的樹脂諸如聚乙烯醇或乙烯-乙烯醇形成之不透氧的膜或薄片、積層的膜或薄片、及多層膜或薄片形成。該沈積的膜或薄片可由一由有機聚合物製得的基材膜或薄片及一塗佈層構成。沈積在該基材膜或薄片上的塗佈層可係陶瓷(諸如氧化矽、氧化鋁及氧化鈦)或金屬。該沈積的膜或薄片包括沈積鋁的有機聚合物膜或薄片、沈積二氧化矽的有機聚合物膜或薄片、沈積氧化鈦的有機聚合物膜或薄片。該積層的膜或薄片可由不透氧的樹脂層諸如聚乙烯醇或乙烯-乙烯醇構成,其係將一層積層在另一層上。該多層膜或薄片可由一或二或更多層上述提及的不透氧膜或薄片及一層由非上述提到的其它有機聚合物製得之層構成,其係將一層積層在另一層上。 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. .

在該不透氧的外容器(包裝容器)係從不透氧的有 機聚合物膜或薄片形成之情況中,該不透氧膜或薄片的內層應該較佳從可熱密封的有機聚合物形成,因為該不透氧的外容器(包裝容器)通常藉由熱密封該經折疊的膜或薄片之周圍形成。 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.

該不透氧的外容器(包裝容器)可從例示在下列的任何材料形成而沒有特定限制。 The oxygen-impermeable outer container (packaging container) can be formed from any of the materials exemplified below without particular limitation.

該多層膜或薄片由聚丙烯(PP)、沈積二氧化矽的聚對酞酸乙二酯(PET)及聚丙烯(PP)構成,其係以所提及的順序將一層積層在另一層上。 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. .

該多層膜或薄片由雙軸定向的聚醯胺(OPA)、聚乙烯(PE)、沈積鋁的PET及聚乙烯構成,其係以所提及的順序將一層積層在另一層上。 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.

該多層膜或薄片由OPA、PE、沈積鋁的PET及PE構成,其係以所提及的順序將一層積層在另一層上。 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.

該多層膜或薄片由OPA、PE、鋁箔、PE及PE構成,其係以所提及的順序將一層積層在另一層上。 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.

該多層膜或薄片由OPA、PE、鋁箔、PE、PET及PE構成,其係以所提及的順序將一層積層在另一層上。 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.

該多層膜或薄片由PET、PE、沈積鋁的PET、PE、乙烯-醋酸乙烯酯共聚物(EVA)及PE構成,其係以所提及的順序將一層積層在另一層上。 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.

該多層膜或薄片由聚偏二氯乙烯、PE、沈積鋁的PET及PE構成,其係以所提及的順序將一層積層在另一層上。 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.

該多層膜或薄片由PET、沈積鋁的乙烯-乙烯醇共聚物 (EVOH)及PE構成,其係以所提及的順序將一層積層在另一層上。 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.

在該不透氧的外容器(包裝容器)係從不透氧的有機聚合物膜或薄片形成之情況中,該不透氧的膜或薄片應該具有厚度50至150微米,較佳為65至100微米,以便其滿足對氧不透性和容器性能的需求。該不透氧的膜或薄片之厚度不小於50微米對提供具有適當強度的外容器(包裝容器)係足夠。厚度不大於150微米係合適於該乙醯胺苯酚注射溶液製劑的可撓袋型式外容器,其具有適當的彈性及重量輕。 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.

該去氧劑係與容納該乙醯胺苯酚水溶液的透氧容器一起包裝在該不透氧的外容器(包裝容器)中,其無特別限制,只要其無毒及能有效地吸收氧以減低在環境中的氧濃度。 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.

該去氧劑的實施例包括金屬粉末(諸如鐵粉末)、無機物質(諸如亞硫酸鹽及金屬鹵化物)及有機物質(諸如抗壞血酸及多酚)作為主要材料。可使用其之任何一種,只要其無毒及在氧吸收度上優良。 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.

再者,亦可使用吸收氧及二氧化碳或吸收氧及釋放二氧化碳的物質。 Further, substances which absorb oxygen and carbon dioxide or absorb oxygen and release carbon dioxide can also be used.

該去氧劑可呈多種形式,諸如包括透氧袋與包含在其中的氧清除物質之包裝、藉由與氧吸收劑揉捏而形成的膜、以氧吸收劑模塑的容器、及包含不透氧的外層與氧吸收內層之層狀物件,如此其側邊吸收氧。可使用其之任何一種,只要其無毒及有好的氧吸收度。 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.

在已知的商業產物當中,Ageless(註冊商標名 稱)”(來自Mitsubishi Gas Chemical Company,Inc.)係合適於本發明。 Among the known commercial products, Ageless (registered trade name) Said) (from Mitsubishi Gas Chemical Company, Inc.) is suitable for the present invention.

該去氧劑應該係一種在正常溫度(25℃)及大氣壓下20小時,可從100毫升容納在透氧容器中的乙醯胺苯酚水溶液量吸收量係不少於100立方公分的氧之試劑,較佳為不少於200立方公分,及更佳為不少於400立方公分。 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.

該去氧劑的較佳實施例為Ageless(註冊商標名稱)ZH-200”(來自Mitsubishi Gas Chemical Company,Inc.),其在大氣壓下所吸收的氧量係等於或多於每20小時200立方公分。 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.

本發明之被包裝的乙醯胺苯酚注射溶液製劑之實施例係顯示在圖1中。 An example of a packaged acetaminophen phenol injection solution formulation of the present invention is shown in FIG.

此具體實例之被包裝的乙醯胺苯酚注射溶液製劑1包含一經密封的透氧容器3,其裝填pH 4至8包含乙醯胺苯酚作為有效成份之乙醯胺苯酚水溶液,及其藉由濕熱滅菌法殺菌;一去氧劑4;及一不透氧的包裝容器2,其包圍該裝填乙醯胺苯酚水溶液之經密封的透氧容器3與去氧劑4。該不透氧的包裝容器2係經密封及該去氧劑4係放置在該包裝容器2與裝填該乙醯胺苯酚水溶液之經密封的透氧容器3間之空間中。 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.

該經密封的透氧容器3包含一容器主體31,其具有一用以儲存該乙醯胺苯酚水溶液的內部空間、及一連通該空間的埠、及一用以封閉該容器主體31的埠之密封元件32。該容器主體31係一種由如上所述的透氧有機聚合物薄片或膜 製得之可撓的袋子。該密封元件32想要能夠係一排出刺穿針。 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.

該不透氧的包裝容器2係一袋狀。該不透氧的包裝容器2在儲存該氧吸收劑4與該容器主體3後,該不透氧的包裝容器2之開口部分係藉由熱密封來密封。該不透氧的外容器係由如上所述之不透氧的有機聚合物膜或薄片製得。如在圖1中所顯示,該去氧劑4可固定至該不透氧的包裝容器2之內部表面。 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.

該去氧劑可直接提供在該包裝容器的內部表面上。再者,該去氧劑可直接提供在該經密封的透氧容器之外表面上。 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.

該經密封的透氧容器之容器主體可係一瓶狀的堅硬或半硬質容器。 The container body of the sealed oxygen permeable container can be a rigid or semi-rigid container in the form of a bottle.

該經密封的透氧容器之容器主體可係一注射器。該注射器較佳包含一透氧的外圓筒、一在該外圓筒中的可滑動襯墊、及一用以密封該外圓筒的頂端之密封元件。 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.

(實施例) (Example)

本發明將伴隨著參照下列實施例更詳細地說明,此不想要限制其範圍。 The invention will be explained in more detail with reference to the following examples, which are not intended to limit the scope thereof.

在該等實施例中,使用下列程序來測量在該用於注射的水及該乙醯胺苯酚水溶液中之氧濃度。 In these examples, the following procedure was used to measure the oxygen concentration in the water for injection and the aqueous solution of acetaminophen.

在該用於注射的水及該乙醯胺苯酚水溶液中的氧濃度之測量 Measurement of oxygen concentration in the water for injection and the aqueous solution of acetaminophen

在水及溶液中之氧濃度係使用溶氧測量感應器Inlab 605(來自Mettler Toledo)測量。 The oxygen concentration in water and solution was measured using a dissolved oxygen measuring sensor Inlab 605 (from Mettler Toledo).

[實施例1] [Example 1]

(1)乙醯胺苯酚水溶液係如下製備。在氮氣環境中(或在氮氣棚中),對適當量已經升溫至35℃之用於注射的水進行氮氣吹氣,以便在其中的氧濃度保持不高於1毫克/升。該用於注射的水係提供1925克D-甘露醇、13克磷酸氫二鈉十二水合物及500克乙醯胺苯酚,伴隨著攪拌用以溶解。在冷卻至室溫後,加入12.5克的L-半胱胺酸鹽酸單水合物及溶解在其中。使用氫氧化鈉及鹽酸將所產生的溶液調整至pH 5.5,然後加入用於注射的水以便該溶液的總量變成50升。 (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)將100毫升在上述步驟(1)中所獲得之乙醯胺苯酚水溶液每種裝填在透氧性多層聚丙烯膜可撓袋子(100毫升標稱容量)中,接著以異戊二烯橡膠塞密封。該多層膜係由總厚度264微米的三層聚丙烯膜構成。該多層膜具有透氧性在23℃,90%RH下於常壓下809立方公分/平方公尺/天。該裝填步驟係在氮氣與空氣之混合物的環境中(以80:20的比率,以體積計)進行。 (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)在上述步驟(2)中之裝填該乙醯胺苯酚水溶液後,使用氮氣作為加壓媒質對該透氧的可撓袋(或透氧的多層聚丙烯可撓袋)進行濕熱滅菌(在121℃下15分鐘)。 (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)在上述步驟(3)中之濕熱滅菌後,將該裝填乙醯胺苯酚水溶液的透氧容器與一片Ageless(註冊商標名稱)ZH-200(來自Mitsubishi Gas Chemical Company,Inc.)一起放置在不透氧的袋子中,其中該Ageless在大氣壓下所吸收的 氧量等於或多於每20小時200立方公分。該不透氧的袋子係從PP、沈積二氧化矽的PET及PP之三層膜形成,且其三邊經密封及一邊打開,其具有厚度66微米及透氧性在23℃,90%RH下於常壓下係0.15立方公分/平方公尺/天。在該透氧容器及Ageless(註冊商標名稱)ZH-200已經放置於該不透氧的袋子中之後,該不透氧的袋子之打開邊係藉由熱密封來密封。以此方式獲得如想要的被包裝的乙醯胺苯酚注射溶液製劑。 (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.

[實施例2] [Embodiment 2]

(1)該乙醯胺苯酚水溶液係使用與在上述實施例1之步驟(1)中相同的方法製備,除了不進行氮氣吹氣及全體步驟係在空氣中進行而沒有使用氮棚外。 (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)在空氣中,將100毫升在上述步驟(1)中所獲得的乙醯胺苯酚水溶液每種裝填在與於實施例1的步驟(2)中所使用者相同之透氧容器(其係一透氧的多層聚丙烯可撓袋子,標稱容量100毫升)中。在裝填後,該可撓的袋子係以異戊二烯橡膠塞密封。 (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)在上述步驟(2)中之裝填乙醯胺苯酚水溶液後,該透氧的可撓袋子(或透氧的多層聚丙烯可撓袋子)係使用與在實施例1的步驟(3)中相同的方法進行濕熱滅菌。 (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)在上述步驟(3)之濕熱滅菌後,將容納該乙醯胺苯酚水溶液的透氧容器與一片與在實施例1的步驟(4)中所使用者相同的去氧劑一起,放置在與於實施例1的步驟(4)中所使用者 相同的不透氧袋子(其三邊經密封)中。在該透氧容器及去氧劑已經放置於該不透氧的袋子中之後,藉由熱密封來密封該不透氧袋子的打開邊。以此方式獲得如想要的被包裝的乙醯胺苯酚注射溶液製劑。 (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.

[實施例3] [Example 3]

(1)該乙醯胺苯酚水溶液係使用與在上述實施例1的步驟(1)中相同的方法製備,除了不進行氮氣吹氣及全體步驟係在空氣中進行而沒有使用氮棚外。 (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)將100毫升在上述步驟(1)中所獲得的乙醯胺苯酚水溶液每種於空氣中裝填在與於實施例1的步驟(2)中所使用者相同的透氧容器(其係一透氧的多層聚丙烯可撓袋子,標稱容量100毫升)中。在裝填後,該可撓的袋子係以異戊二烯橡膠塞密封。 (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)在上述步驟(2)中之裝填該乙醯胺苯酚水溶液後,該透氧的可撓袋子(或透氧的多層聚丙烯可撓的袋子)係使用與在實施例1的步驟(3)中相同的方法進行濕熱滅菌,除了使用空氣作為加壓媒質外。 (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)在上述步驟(3)之濕熱滅菌後,將容納該乙醯胺苯酚水溶液的透氧容器與一片與在實施例1的步驟(4)中所使用者相同的去氧劑一起,放置在與於實施例1的步驟(4)中所使用者相同的不透氧袋子(其三邊經密封)中。在該透氧容器與該去氧劑已經放置於不透氧的袋子中之後,藉由熱密封來密封該不透氧的袋子之打開邊。以此方式獲得如想要的被包裝的乙醯 胺苯酚注射溶液製劑。 (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.

[實施例4] [Example 4]

(1)該乙醯胺苯酚水溶液係使用與在上述實施例1的步驟(1)中相同的方法製備及進行氮氣吹氣,除了全體步驟係在空氣中進行而沒有使用氮棚外。 (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)在空氣中,將100毫升在上述步驟(1)中所獲得的乙醯胺苯酚水溶液每種裝填在與於實施例1的步驟(2)中所使用者相同的透氧容器(其係一透氧的多層聚丙烯可撓袋子,標稱容量100毫升)中。在裝填後,該可撓袋子係以異戊二烯橡膠塞密封。 (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)在上述步驟(2)中之裝填該乙醯胺苯酚水溶液後,該透氧的可撓袋子(或透氧的多層聚丙烯可撓袋子)係使用與在實施例1的步驟(3)中相同的方法進行濕熱滅菌。 (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)在上述步驟(3)中之濕熱滅菌後,將容納該乙醯胺苯酚水溶液的透氧容器與一片與在實施例1的步驟(4)中所使用者相同的去氧劑一起,放置在與於實施例1的步驟(4)中所使用者相同的不透氧袋子(其三邊經密封)中。在該透氧容器及去氧劑已經放置於不透氧的袋子中之後,藉由熱密封來密封該不透氧的袋子之打開邊。以此方式獲得如想要的被包裝的乙醯胺苯酚注射溶液製劑。 (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.

[比較例1] [Comparative Example 1]

(1)重覆在實施例1中的步驟(1)至(3)以獲得經高 壓蒸氣殺菌之容納該乙醯胺苯酚水溶液的透氧容器(或透氧的多層聚丙烯可撓袋子)。 (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)在上述步驟(1)中之濕熱滅菌後,將容納該乙醯胺苯酚水溶液的透氧容器(或透氧的多層聚丙烯可撓袋子)放置在與於實施例1的步驟(4)中所使用者相同的不透氧袋子(其三邊經密封)中,沒有去氧劑。在該透氧容器已經放置於不透氧袋子中之後,藉由熱密封來密封該不透氧袋子的打開邊。以此方式獲得如想要的被包裝的乙醯胺苯酚注射溶液製劑。 (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.

[比較例2] [Comparative Example 2]

(1)重覆在實施例1中的步驟(1)以獲得該乙醯胺苯酚水溶液,除了該方法係在空氣中進行沒有使用氮棚及不進行氮氣吹氣外。 (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)在空氣中,將100毫升於上述步驟(1)中所獲得的乙醯胺苯酚水溶液每種裝填在與於實施例1的步驟(2)中所使用者相同的透氧容器(其係一透氧的多層聚丙烯可撓袋子,標稱容量100毫升)中。在裝填後,該可撓的袋子係以異戊二烯橡膠塞密封。 (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)重覆在實施例1中的步驟(3)以對在上述步驟(2)中所獲得之容納乙醯胺苯酚水溶液的透氧容器(或透氧的多層聚丙烯可撓袋子)進行濕熱滅菌,除了使用空氣作為加壓媒質外。 (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)在上述步驟(3)之濕熱滅菌後,將容納該乙醯胺苯酚水溶液的透氧容器放置在與於實施例1的步驟(4)中所使用者相 同的不透氧袋子(其三邊經密封),沒有去氧劑。在該透氧容器已經放置於不透氧的袋子中之後,藉由熱密封來密封該不透氧的袋子之打開邊。以此方式獲得如想要的被包裝的乙醯胺苯酚注射溶液製劑。 (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.

已發現在實施例1至4及比較例1及2中所獲得的被包裝的乙醯胺苯酚注射溶液製劑具有如顯示在表1中的組成物及pH值。 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.

測試1用以在濕熱滅菌後及在裝填於外容器(包裝容器)中之前測量在該乙醯胺苯酚水溶液中的氧濃度: 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):

此測試係進行,以測量在實施例1的步驟(3)中、在實施例2的步驟(3)中、在實施例3的步驟(3)中、在實施例4的步驟(3)中、在比較例1的步驟(1)中及在比較例2的步驟(3)中所獲得之乙醯胺苯酚水溶液每種的氧濃度。收集在濕熱滅菌後及在裝填於外容器(包裝容器)中之前的全部樣品。測量結果係顯示在表2至4中。 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.

測試2用以測量在該乙醯胺苯酚注射溶液製劑中的氧濃度: Test 2 was used to measure the oxygen concentration in the acetaminophen injection solution formulation:

此測試係進行,以測量在實施例1的步驟(4)中、在實施例2的步驟(4)中、在實施例3的步驟(4)中、在實施例4的步驟(4)中、在比較例1的步驟(2)中及在比較例2的步驟(4)中所獲得之乙醯胺苯酚注射溶液製劑每種的氧濃度。全部樣品皆係成品。在室溫下儲存於空氣中24小時及四天後,對該乙醯胺苯酚水溶液進行測量。測量結果係顯示在表2至4中。 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.

測試3用於穩定性: Test 3 is used for stability:

測試在實施例1至4及比較例1及2中所獲得的乙醯胺苯酚注射溶液製劑每種之樣品的外觀、pH、L-半胱胺酸鹽酸水合物含量、分解產物的總量、及乙醯胺苯酚殘餘比率。此測試在製造後及在儲存於60℃下七天及21天後立即進行。剩餘方法及結果係顯示在下列表2至4中。 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.

測試4用於穩定性: Test 4 is used for stability:

測試在實施例1中所獲得的乙醯胺苯酚注射溶液製劑每種之樣品的外觀、pH、L-半胱胺酸鹽酸水合物含量、分解產物的總量、及乙醯胺苯酚的殘餘比率。此測試係在儲存於40 ℃下三個月及六個月後進行。結果係顯示在下列表2至4中。 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)評估乙醯胺苯酚水溶液在乙醯胺苯酚注射溶液製劑中的外觀: (1) Evaluation of the appearance of an aqueous solution of acetaminophen in an acetamide phenol injection solution preparation:

檢驗每個樣品的透明度及顏色。 Verify the transparency and color of each sample.

(2)在乙醯胺苯酚注射溶液製劑中的乙醯胺苯酚水溶液之pH: (2) pH of an aqueous solution of acetaminophen in an acetamide phenol injection solution preparation:

使用pH計量器測試每個樣品的pH。 The pH of each sample was tested using a pH meter.

(3)在乙醯胺苯酚注射溶液製劑的乙醯胺苯酚水溶液中之L-半胱胺酸鹽酸水合物含量: (3) L-cysteine acid hydrate content in an aqueous solution of acetaminophen in the preparation of acetaminophen injection solution:

每個樣品係以水稀釋以提供規定濃度的稀釋溶液。藉由液相層析法檢驗該稀釋溶液之L-半胱胺酸鹽酸水合物含量(就毫克/100毫升而論)。 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)在乙醯胺苯酚注射溶液製劑的乙醯胺苯酚水溶液中之分解產物的總量: (4) The total amount of decomposition products in an aqueous solution of acetaminophen in the preparation of acetaminophen injection solution:

藉由液相層析法獲得各別分解產物的總量(%)(就色譜圖的波峰面積之面積百分比而論)。 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)在乙醯胺苯酚注射溶液製劑的乙醯胺苯酚水溶液中之乙醯胺苯酚的殘餘比率: (5) Residual ratio of acetaminophen in an aqueous solution of acetaminophen in the preparation of acetaminophen injection solution:

每個樣品係以水稀釋以提供規定濃度的稀釋溶液。藉由液相層析法檢驗該稀釋溶液的乙醯胺苯酚含量。殘餘比率係就在測試前之起始含量(100%)的百分比(%)表示。 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.

可從表2至4注意到,根據實施例1至4的乙醯胺苯酚注射溶液製劑在長時間儲存穩定性上極優異。 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.

相較之下,根據比較例1及2的乙醯胺苯酚注射溶液製劑在長時間儲存穩定性上係較差。 In contrast, the acetaminophen phenol injection solution preparations according to Comparative Examples 1 and 2 were inferior in long-term storage stability.

根據本發明的乙醯胺苯酚注射溶液製劑雖然採用液體形式,但其在室溫下之長時間儲存穩定性上傑出。其保持乙醯胺苯酚具有非常些微的變質及分解,或及其甚至在儲存一段長時間後保留高乙醯胺苯酚殘餘比率。因此,其可有效地使用於醫學治療,諸如治療手術後疼痛。 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.

應該要由熟習該項技術者了解,可依設計需求及其它因素而發生多種修改、組合、次組合及改變,只要它們係在所附加的申請專利範圍或其同等物之範圍內。 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.

[工業可行性] [industrial feasibility]

本發明之乙醯胺苯酚注射溶液製劑係如在下列描述般建構。 The acetaminophen phenol injection solution formulation of the present invention is constructed as described below.

(1)一被包裝的乙醯胺苯酚注射溶液製劑包含一不透氧的包裝容器,及一包括pH 4至8包含乙醯胺苯酚作為有效成份之乙醯胺苯酚水溶液的乙醯胺苯酚注射溶液製劑,及一裝填該乙醯胺苯酚水溶液之經密封的透氧容器,其中該乙醯胺苯酚注射溶液製劑係藉由濕熱滅菌法殺菌,該不透氧的包裝容器包圍該乙醯胺苯酚注射溶液製劑及經密封,及該被包裝的乙醯胺苯酚注射溶液製劑具有一去氧劑以吸收在該經密封的不透氧包裝容器中的氧。 (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.

根據本發明之被包裝的乙醯胺苯酚注射溶液製劑由一乙醯胺苯酚水溶液、一裝填其的透氧內容器、及一起儲存該內容器與去氧劑的不透氧外容器(包裝容器)構成。該經裝填的內容器進行濕熱滅菌,然後將其與去氧劑放置在外容器(包裝容器)中,然後密封該外容器(包裝容器)。不像現存之使用小玻瓶的乙醯胺苯酚注射溶液製劑般,本發明不需要在乙醯胺苯酚水溶液之製備那時、在將乙醯胺苯酚水溶液裝填進容器中那時及在隨後的濕熱滅菌時間處,藉由惰性氣體來置換的嚴格氧控制。因此,本發明准許該乙醯胺苯酚水溶液在裝填於容器前之製備、將該乙醯胺苯酚水溶液裝填在容器中及濕熱滅菌的步驟之至少一個或全部在空氣中進行。再者,甚至當使用惰性氣體用於去氧時,其不需要如在過去所實行般的此嚴格控制。雖然該氧控制方法經簡化,該乙醯胺苯酚注射溶液製劑在長時間儲存穩定性上傑出,其允許甚至在儲存於室溫下三年或較長之情況中,在其中的乙醯胺苯酚完整保持在極高比率下。 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.

若該透氧容器係由透氧的有機聚合物膜或薄片製得及該不透氧的包裝容器係由不透氧的有機聚合物膜或薄片製得時,其容易運輸及處理而不會因掉下或傾卸而受損傷。 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.

根據本發明之被包裝的乙醯胺苯酚注射溶液製劑在長時間儲存穩定性上傑出,不像現存者,其雖然在用於乙醯胺苯酚水溶液之製備、將其裝填在不透氧的外容器(包裝容器)中、及在惰性氣體環境中進行濕熱滅菌的各別步驟中有嚴格的氧控制,但其不可避免地將遭受氧污染。 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.

本發明之具體實例可如下列描述般進行。 Specific examples of the invention can be carried out as described below.

(2)根據上述(1)之被包裝的乙醯胺苯酚注射溶液製劑,其中該乙醯胺苯酚水溶液在製備那時有或沒有進行氧控制。 (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)根據上述(1)或(2)之被包裝的乙醯胺苯酚注射溶液製劑,其係藉由在惰性氣體、惰性氣體與空氣的混合物、或空氣環境中將該乙醯胺苯酚水溶液裝填於該透氧容器中而製造。 (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)根據上述(1)至(3)之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中用於該裝填乙醯胺苯酚水溶液的透氧容器之藉由濕熱滅菌法殺菌係藉由使用惰性氣體、惰性氣體與空氣之混合物、或空氣作為加壓媒質達成。 (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)根據上述(1)至(4)之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該乙醯胺苯酚水溶液包括量係2至50毫克/毫升的乙醯胺苯酚。 (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)根據上述(1)至(5)之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該透氧容器具有透氧性在23℃及90%RH下於常壓(1013hPa)下測量係不低於200立方公分/平方公尺/天。 (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)根據上述(1)至(6)之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該不透氧的包裝容器具有透氧性在23℃及90%RH下於常壓(1013hPa)下測量係不高於1.0立方公分/平方公尺/天。 (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)根據上述(1)至(7)之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該透氧容器係由透氧的有機聚合物膜或 薄片製得及該不透氧的包裝容器係由不透氧的有機聚合物膜或薄片製得。 (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)根據上述(1)至(8)之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該乙醯胺苯酚水溶液包括至少一種pH調整劑、張力劑、抗氧化劑及緩衝劑物種。 (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)根據上述(9)之被包裝的乙醯胺苯酚注射溶液製劑,其中該pH調整劑係氫氧化鈉及/或鹽酸。 (10) A packaged acetaminophen injection solution preparation according to the above (9), wherein the pH adjuster is sodium hydroxide and/or hydrochloric acid.

(11)根據上述(9)或(10)之被包裝的乙醯胺苯酚注射溶液製劑,其中該張力劑係甘露醇。 (11) A packaged acetaminophen injection solution preparation according to the above (9) or (10), wherein the tonicity agent is mannitol.

(12)根據上述(9)至(11)之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該抗氧化劑係半胱胺酸鹽酸水合物。 (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)根據上述(9)至(12)之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該緩衝劑係磷酸氫鈉水合物。 (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)根據上述(1)至(13)之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該不透氧的包裝容器包圍該乙醯胺苯酚注射溶液製劑與該去氧劑。 (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)根據上述(14)之被包裝的乙醯胺苯酚注射溶液製劑,其中該去氧劑係放置在該包裝容器與裝填該乙醯胺苯酚水溶液之經密封的透氧容器間之空間中。 (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)根據上述(1)至(13)之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該不透氧的包裝容器或該經密封的透氧容器具有該去氧劑。 (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‧‧‧被包裝的乙醯胺苯酚注射溶液製劑 1‧‧‧Packed acetaminophen injection solution preparation

2‧‧‧不透氧的包裝容器 2‧‧‧Oxygen-impermeable packaging containers

3‧‧‧經密封的透氧容器 3‧‧‧ Sealed oxygen permeable container

4‧‧‧去氧劑 4‧‧‧Deoxidizer

31‧‧‧容器主體 31‧‧‧ container body

32‧‧‧密封元件 32‧‧‧Sealing components

Claims (16)

一種被包裝的乙醯胺苯酚注射溶液製劑,其包含:一不透氧的包裝容器;及一乙醯胺苯酚注射溶液製劑,其包括pH 4至8包含乙醯胺苯酚作為有效成份的乙醯胺苯酚水溶液;及一裝填該乙醯胺苯酚水溶液之經密封的透氧容器;其中該乙醯胺苯酚注射溶液製劑係藉由濕熱滅菌法殺菌,該不透氧的包裝容器包圍該乙醯胺苯酚注射溶液製劑且經密封,及該被包裝的乙醯胺苯酚注射溶液製劑具有一去氧劑以吸收在該經密封的不透氧包裝容器中的氧。 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. 如請求項1之被包裝的乙醯胺苯酚注射溶液製劑,其中該乙醯胺苯酚水溶液在製備那時有或沒有進行氧控制。 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. 如請求項1或2之被包裝的乙醯胺苯酚注射溶液製劑,其係藉由在惰性氣體、惰性氣體與空氣的混合物或空氣環境中將該乙醯胺苯酚水溶液裝填在該透氧容器中而製造。 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. 如請求項1至3之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中用於該裝填乙醯胺苯酚水溶液的透氧容器之藉由濕熱滅菌法殺菌係藉由使用惰性氣體、惰性氣體與空氣之混合物、或空氣作為加壓媒質達成。 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. 如請求項1至4之任何一項之被包裝的乙醯胺苯酚注射溶液 製劑,其中該乙醯胺苯酚水溶液包括量係2至50毫克/毫升的乙醯胺苯酚。 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. 如請求項1至5之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該透氧容器具有透氧性在23℃及90%RH下於常壓(1013hPa)下測量係不低於200立方公分/平方公尺/天。 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. 如請求項1至6之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該不透氧的包裝容器具有透氧性在23℃及90%RH下於常壓(1013hPa)下測量係不高於1.0立方公分/平方公尺/天。 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. 如請求項1至7之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該透氧容器係由透氧的有機聚合物膜或薄片製得及該不透氧的包裝容器係由不透氧的有機聚合物膜或薄片製得。 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. 如請求項1至8之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該乙醯胺苯酚水溶液包括至少一種pH調整劑、張力劑、抗氧化劑及緩衝劑物種。 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. 如請求項9之被包裝的乙醯胺苯酚注射溶液製劑,其中該pH調整劑係氫氧化鈉及/或鹽酸。 The packaged acetaminophen injection solution preparation of claim 9, wherein the pH adjuster is sodium hydroxide and/or hydrochloric acid. 如請求項9或10之被包裝的乙醯胺苯酚注射溶液製劑,其中該張力劑係甘露醇。 A packaged acetaminophen injection solution formulation according to claim 9 or 10, wherein the tonicity agent is mannitol. 如請求項9至11之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該抗氧化劑係半胱胺酸鹽酸水合物。 A packaged acetaminophen phenol injection solution formulation according to any one of claims 9 to 11, wherein the antioxidant is cysteine acid hydrate. 如請求項9至12之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該緩衝劑係磷酸氫鈉水合物。 A packaged acetaminophen phenol injection solution formulation according to any one of claims 9 to 12, wherein the buffer is sodium hydrogen phosphate hydrate. 如請求項1至13之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該不透氧的包裝容器包圍該乙醯胺苯酚注射溶液製劑與該去氧劑。 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. 如請求項14之被包裝的乙醯胺苯酚注射溶液製劑,其中該去氧劑係放置在該包裝容器與裝填該乙醯胺苯酚水溶液之經密封的透氧容器間之空間中。 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. 如請求項1至13之任何一項之被包裝的乙醯胺苯酚注射溶液製劑,其中該不透氧的包裝容器或該經密封的透氧容器具有該去氧劑。 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.
TW103126100A 2014-07-30 2014-07-30 Packaged acetaminophen injection solution preparation TWI623310B (en)

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Publication number Priority date Publication date Assignee Title
TWI800878B (en) * 2020-07-29 2023-05-01 日商耐貝醫藥股份有限公司 Drug set

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EP3725286A1 (en) * 2019-04-18 2020-10-21 B. Braun Melsungen AG Medicinal product comprising a container and an aqueous liquid containing bicarbonate

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EP2377516B1 (en) * 2010-04-14 2012-06-20 B. Braun Melsungen AG Acetaminophen composition
IN2014MN00844A (en) * 2011-10-07 2015-05-01 Mitsubishi Gas Chemical Co

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI800878B (en) * 2020-07-29 2023-05-01 日商耐貝醫藥股份有限公司 Drug set

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