JPH0959150A - Intravenous infusion liquid preparation - Google Patents
Intravenous infusion liquid preparationInfo
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- JPH0959150A JPH0959150A JP7227097A JP22709795A JPH0959150A JP H0959150 A JPH0959150 A JP H0959150A JP 7227097 A JP7227097 A JP 7227097A JP 22709795 A JP22709795 A JP 22709795A JP H0959150 A JPH0959150 A JP H0959150A
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- chamber
- vitamin
- infusion
- glucose
- preparation
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、グルコース、アミノ
酸、電解質およびビタミンＢ1を含有する経静脈用輸液
製剤に関する。TECHNICAL FIELD The present invention relates to an intravenous infusion preparation containing glucose, an amino acid, an electrolyte and vitamin B 1 .
【０００２】[0002]
【従来の技術】近年、経静脈栄養療法は著しい進歩を遂
げ、経口摂取の不足分を補うための栄養管理や、あまり
重篤でない上部消化管手術、さらには悪性腫瘍の根治手
術、重度の感染症例、肝機能障害等の重症例にも適用さ
れるようになった。このような重症例の患者に経静脈栄
養療法を施行し、大量の糖による負荷がかかると、糖代
謝に大きな異常をきたし、乳酸性アシドーシスを引き起
こすことがある（岡田正、Annual Report 1991：高カロ
リー輸液の投与とアシドーシス、中外医学社、東京、19
91、p83）。乳酸性アシドーシスは呼吸不全、血圧低下
等の循環不全の症状出現によりはじめて疑われ、血中乳
酸濃度の測定により診断される。しかし、臨床上迅速な
血中乳酸値の測定は、しばしば困難を伴うことが多い。
乳酸性アシドーシスの治療においては、循環動態および
低酸素血症の改善が必要とされ、症例に応じて昇圧剤、
重炭酸ナトリウム等のアルカリ化剤が使用されている。
ところが、これらの対処法では、重症の乳酸性アシドー
シス患者の場合、症状がさらに悪化する場合がある。そ
のため、経静脈栄養療法施行時、特に高カロリー輸液剤
を連続投与する際は、糖代謝異常による乳酸性アシドー
シスの発症に留意することが重要である。2. Description of the Related Art In recent years, parenteral nutrition therapy has made remarkable progress, such as nutritional management to make up for the lack of oral intake, less severe upper gastrointestinal surgery, radical surgery for malignant tumors, and severe infection. It has also been applied to severe cases such as cases and liver dysfunction. When parenteral nutrition therapy is applied to patients with such severe cases and a large amount of glucose is loaded, glucose metabolism may be significantly abnormal and lactic acidosis may be caused (Okada Tadashi, Annual Report 1991: High). Administration of calorie infusion and acidosis, Chugai Medical Co., Tokyo, 19
91, p83). Lactic acidosis is suspected only after the appearance of symptoms of circulatory insufficiency such as respiratory failure and decreased blood pressure, and is diagnosed by measuring blood lactate concentration. However, clinically rapid measurement of blood lactate is often difficult.
In the treatment of lactic acidosis, improvement of hemodynamics and hypoxemia is required.
Alkaliizing agents such as sodium bicarbonate are used.
However, these treatments may further aggravate the symptoms in patients with severe lactic acidosis. Therefore, it is important to pay attention to the onset of lactic acidosis due to abnormal glucose metabolism when performing parenteral nutrition therapy, especially when continuously administering a high-calorie infusion solution.
【０００３】一方、経静脈栄養療法施行時に発症した乳
酸性アシドーシスに対して、ビタミンＢ1が著しい効果
を示したとの臨床報告もなされている。ところが、ビタ
ミンＢ1が糖代謝と深い関係がありビタミンＢ1が欠乏す
ると脚気をおこすことは古くから知られてはいるもの
の、ビタミンＢ1欠乏症は、神経症状を主徴とするもの
から循環器障害を中心にもつもの、さらには急性型から
慢性型まで、様々な臨床像を呈する（J.Zak et al.、JP
EN：Dry beriberi:unusual complication of prolonged
parenteral nutrition、15、200 (1991)）ため、臨床
上的確な診断を下すには困難な場合が多い。さらに、ビ
タミンＢ1を添加するとしても、従来の輸液製剤にビタ
ミン注射液アンプルをあけ、注射器に移して輸液製剤中
に注入する必要があり、繁雑なばかりか誤投薬、微生物
汚染、ガラス微細片の混入等の危険性を伴う（高松英夫
ら、日本臨床、静脈経腸栄養：ビタミン製剤、629、199
1年特別号、p130）。そのため臨床においては、乳酸性
アシドーシスを惹起することなく経静脈栄養療法を施行
するためにビタミン類を簡便な操作で迅速に投与する輸
液製剤は、きわめて有用である。しかしながら、ビタミ
ン類は非常に不安定であり（斉藤和好ら、日本臨床、静
脈経腸栄養：静脈・経腸栄養と必須ビタミン、629、199
1年特別号、p27）、これらを予め添加し加熱滅菌した、
保存安定性に問題のない経静脈用輸液製剤を製造するこ
とは困難であるとされていた。[0003] On the other hand, clinical reports have been made that vitamin B 1 has a remarkable effect on lactic acidosis that develops during parenteral nutrition therapy. However, although vitamin B 1 is that is it is long been known to cause beriberi Vitamin B 1 has glucose metabolism closely related to deficiency, vitamin B 1 deficiency, cardiovascular and neurological symptoms from which the cardinal symptoms Those with a focus on disorders and various clinical features from acute type to chronic type (J.Zak et al., JP
EN: Dry beriberi: unusual complication of prolonged
Parenteral nutrition, 15, 200 (1991)), so it is often difficult to make a clinically accurate diagnosis. Furthermore, even if vitamin B 1 is added, it is necessary to open an ampoule of vitamin injection solution in a conventional infusion preparation, transfer it to a syringe and inject it into the infusion preparation. With risk of contamination (Hideo Takamatsu et al., Japanese clinical, parenteral nutrition: vitamin preparations, 629, 199
1 year special issue, p130). Therefore, in clinical practice, an infusion preparation in which vitamins are rapidly administered by a simple operation for performing parenteral nutrition therapy without inducing lactic acidosis is extremely useful. However, vitamins are extremely unstable (Kazuyoshi Saito et al., Japanese clinical, parenteral and parenteral nutrition: parenteral and parenteral nutrition and essential vitamins, 629, 199.
1 year special issue, p27), these were added in advance and heat sterilized,
It has been considered difficult to produce an intravenous infusion preparation having no problem in storage stability.
【０００４】ビタミンＢ1等を含む各種ビタミン剤が予
め配合された経静脈栄養輸液製剤は、既に特開平6−209
979公報に開示されている。しかし、前記公報に記載の
輸液製剤は脂肪をカロリー源として用いており、必須脂
肪酸の欠乏状態を防止できるものの、脂肪の投与により
臓器への蓄積や血中トリグリセリドの濃度上昇を招く危
険性がある（礒野可一ら、輸液ガイド：高カロリー輸液
製剤、文光堂、東京、1992、p106）。また、脂肪とビタ
ミンＢ1等が、同一の個室に収容されており、脂肪の分
解による遊離脂肪酸の生成を避けるためには輸液のｐＨ
を中性域に設定する必要がある（I.Hakansson、Acta.Ch
em.Scand.：Pysicochemical changes inartificial fat
emulsions during storage、20 2267 (1966)）。その
ために、前記公報において、輸液製剤のｐＨを好ましく
は5.5〜7.0に調整すると記載されているが、ビタミンＢ
1等の安定性にとって前記ｐＨは至適なものとは言い難
い。A parenteral nutrition transfusion preparation in which various vitamin preparations including vitamin B 1 and the like are premixed has already been disclosed in JP-A-6-209.
979 publication. However, although the infusion preparation described in the above publication uses fat as a calorie source and can prevent a deficiency state of essential fatty acids, there is a risk that administration of fat will lead to accumulation in organs and increase in blood triglyceride concentration. (Kiiso Isono et al., Infusion guide: High-calorie infusion preparation, Bunkodo, Tokyo, 1992, p106). In addition, fat and vitamin B 1 etc. are stored in the same private room, and in order to avoid the production of free fatty acids due to the decomposition of fat, the pH of the infusion solution should be
Must be set to the neutral range (I.Hakansson, Acta.Ch
em.Scand .: Pysicochemical changes inartificial fat
emulsions during storage, 20 2267 (1966)). Therefore, the above-mentioned publication describes that the pH of the infusion preparation is preferably adjusted to 5.5 to 7.0.
It is hard to say that the pH is optimal for the stability of 1 grade.
【０００５】[0005]
【発明が解決しようとする課題】本発明の課題は、加熱
滅菌時および保存時の安定性に優れ、臨床においては簡
便な操作で迅速に投与でき、乳酸性アシドーシスを惹起
することなく連続して投与可能な経静脈用輸液製剤を提
供することにある。The object of the present invention is excellent in stability during heat sterilization and storage, can be rapidly administered by a simple procedure in clinical practice, and can be continuously performed without causing lactic acidosis. It is to provide a transfusion preparation for intravenous administration that can be administered.
【０００６】[0006]
【課題を解決するための手段】本発明者らは、経静脈栄
養療法を施行する際、経静脈用輸液製剤の各栄養成分の
組成と乳酸性アシドーシスの発症との間に特有な関係が
あるものと考え、乳酸性アシドーシスを惹起することの
ない適切な組成を有し、しかも製剤学的安定性に問題の
ない経静脈用輸液製剤について鋭意検討した。その結
果、適切なカロリー源、窒素源、電解質成分とともにビ
タミンＢ1を予め輸液剤に添加しておくことで乳酸性ア
シドーシスを惹起することなく経静脈用輸液を連続して
投与できるとの知見を得た。本発明により、臨床上診断
に困難を伴う乳酸性アシドーシスの複雑な発症要因を少
なからず排除できるとの知見を得るに至った。また、乳
酸性アシドーシスの発症と輸液成分としての糖類の関係
を調べた結果、グルコースが最も乳酸性アシドーシスを
起し難いことが判った。さらに、保存安定性に問題のな
い輸液製剤を製造するため、複室に区画された可撓性容
器に各栄養成分を分離収容する際、各室に収容する成分
の適切な組合せと、各室に収容する輸液の適切な調製方
法について検討した。Means for Solving the Problems The present inventors have a peculiar relationship between the composition of each nutritional component of an intravenous infusion preparation and the onset of lactic acidosis when performing parenteral nutrition therapy. In consideration of the above, an infusion solution for intravenous administration, which has an appropriate composition that does not cause lactic acidosis and has no problem in pharmaceutical stability, was earnestly studied. As a result, it was found that by adding vitamin B 1 to an infusion solution together with an appropriate calorie source, nitrogen source, and electrolyte component in advance, intravenous infusion can be continuously administered without inducing lactic acidosis. Obtained. The present invention has led to the finding that a complicated onset factor of lactic acidosis, which is clinically difficult to diagnose, can be eliminated to some extent. In addition, as a result of examining the relationship between the onset of lactic acidosis and saccharides as an infusion component, it was found that glucose is the most difficult to cause lactic acidosis. Furthermore, in order to manufacture an infusion formulation with no problem in storage stability, when each nutrient component is separately stored in a flexible container divided into multiple chambers, an appropriate combination of components to be stored in each chamber and each chamber We examined an appropriate method for preparing the infusion solution stored in the hospital.
【０００７】前述の知見に基づき完成した本発明は、連
通可能な隔離手段で区画された複数の室を有する可撓性
容器の各室に、グルコース、アミノ酸および電解質の各
成分から選ばれた１種もしくは２種以上を含有する輸液
剤を収容し、且つ加熱滅菌された輸液製剤において、前
記可撓性容器の少なくとも１室にビタミンＢ1を収容し
た経静脈用輸液製剤である。The present invention completed on the basis of the above-mentioned findings provides a flexible container having a plurality of chambers partitioned by communicating means, each chamber being selected from glucose, amino acid and electrolyte components. A transfusion preparation for intravenous administration, which contains an infusion solution containing one or more species and is heat-sterilized, wherein vitamin B 1 is contained in at least one chamber of the flexible container.
【０００８】また、前記経静脈輸液製剤は、グルコー
ス、アミノ酸、電解質およびビタミンＢ1が、下記の範
囲で配合されている。 ビタミンＢ1 ０．１〜３００ｍｇ／ｌ グルコース ２５〜５００ｇ／ｌ アミノ酸総量 １０〜４５ｇ／ｌ 各アミノ酸 Ｌ−イソロイシン ０．５〜５．６ｇ／ｌ Ｌ−ロイシン ０．９〜７．４ｇ／ｌ Ｌ−リジン ０．３〜７．１ｇ／ｌ Ｌ−メチオニン ０．０５〜６．９ｇ／ｌ Ｌ−フェニルアラニン ０．０４〜６．９ｇ／ｌ Ｌ−スレオニン ０．２〜３．３ｇ／ｌ Ｌ−トリプトファン ０．０８〜１．９ｇ／ｌ Ｌ−バリン ０．４〜６．２ｇ／ｌ Ｌ−アルギニン ０〜９．２ｇ／ｌ Ｌ−ヒスチジン ０〜３．５ｇ／ｌ グリシン ０〜７．２ｇ／ｌ Ｌ−アラニン ０〜５．０ｇ／ｌ Ｌ−システイン ０〜０．５ｇ／ｌ Ｌ−アスパラギン酸 ０〜２．４ｇ／ｌ Ｌ−グルタミン酸 ０〜２．９ｇ／ｌ Ｌ−プロリン ０〜４．６ｇ／ｌ Ｌ−セリン ０〜２．９ｇ／ｌ Ｌ−チロシン ０〜０．４ｇ／ｌ ナトリウム ２０〜１５０ｍＭ カリウム ０〜５０ｍＭ カルシウム ０〜２０ｍＭ マグネシウム ０〜２０ｍＭ リン ０〜２０ｍＭ 塩素 ２０〜１５０ｍＭ 亜鉛 ０〜１００μＭFurther, the intravenous infusion preparation contains glucose, amino acid, electrolyte and vitamin B 1 in the following range. Vitamin B 1 0.1 to 300 mg / l Glucose 25 to 500 g / l Amino acid total amount 10 to 45 g / l Each amino acid L-isoleucine 0.5 to 5.6 g / l L-leucine 0.9 to 7.4 g / l L -Lysine 0.3 to 7.1 g / l L-methionine 0.05 to 6.9 g / l L-phenylalanine 0.04 to 6.9 g / l L-threonine 0.2 to 3.3 g / l L-tryptophan 0.08-1.9 g / l L-valine 0.4-6.2 g / l L-arginine 0-9.2 g / l L-histidine 0-3.5 g / l glycine 0-7.2 g / l L -Alanine 0-5.0 g / l L-cysteine 0-0.5 g / l L-aspartic acid 0-2.4 g / l L-glutamic acid 0-2.9 g / l L-proline 0-4.6 g / l L-serine 0-2.9 g / L- tyrosine 0~0.4g / l sodium 20~150mM potassium 0~50mM calcium 0~20mM magnesium 0~20mM phosphorus 0~20mM chlorine 20~150mM zinc 0~100μM
【０００９】また、可撓性容器が２室に区画され、その
第１室にグルコースとビタミンＢ1を含有する輸液剤が
収容され、第２室にアミノ酸を含有する輸液剤がそれぞ
れ収容され、第１室および第２室に収容されている輸液
剤の一方または両方に電解質が配合されている。Further, the flexible container is divided into two chambers, the first chamber contains an infusion solution containing glucose and vitamin B 1 , and the second chamber contains an infusion solution containing an amino acid. An electrolyte is mixed with one or both of the infusion agents contained in the first chamber and the second chamber.
【００１０】また、前記経静脈用輸液製剤は、グルコー
スとビタミンＢ1を含有する輸液剤のｐＨが２．０〜
５．０に調整されている。Further, in the intravenous infusion preparation, the infusion solution containing glucose and vitamin B 1 has a pH of 2.0 to 2.0.
It has been adjusted to 5.0.
【００１１】本発明に用いられるビタミンＢ1として
は、従来使用されているものは何れも可能であり、例え
ば、チアミン、フルスルチアミン、チアミンジスルフィ
ド等、並びにこれらの塩が挙げられる。As the vitamin B 1 used in the present invention, any of those conventionally used can be used, and examples thereof include thiamine, fursultiamine, thiamine disulfide, and salts thereof.
【００１２】本発明に用いられるアミノ酸は、遊離アミ
ノ酸のみならずナトリウム塩、酢酸塩、塩酸塩等の塩を
使用しても良く、さらには一部のアミノ酸をペプチドに
しても良い。As the amino acids used in the present invention, not only free amino acids but also salts such as sodium salts, acetates, hydrochlorides and the like may be used, and further some amino acids may be used as peptides.
【００１３】本発明に用いられる電解質としては、従来
使用されているものは何れも可能であり、例えば、炭酸
水素ナトリウム、炭酸ナトリウム、リン酸二水素ナトリ
ウム、リン酸水素二ナトリウム、酢酸ナトリウム、乳酸
ナトリウム、クエン酸ナトリウム、塩化ナトリウム、塩
化カリウム、ヨウ化カリウム、リン酸二水素カリウム、
リン酸水素二カリウム、乳酸カリウム、クエン酸カリウ
ム、酢酸カリウム、乳酸カルシウム、グリセロリン酸カ
ルシウム、グルコン酸カルシウム、塩化マグネシウム、
硫酸マグネシウム、塩化亜鉛、硫酸亜鉛、硫酸鉄、塩化
第一鉄、塩化第二鉄、グルコン酸鉄、硫酸銅、硫酸マン
ガン等を挙げることができる。As the electrolyte used in the present invention, any of those conventionally used can be used, and examples thereof include sodium hydrogen carbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate and lactic acid. Sodium, sodium citrate, sodium chloride, potassium chloride, potassium iodide, potassium dihydrogen phosphate,
Dipotassium hydrogen phosphate, potassium lactate, potassium citrate, potassium acetate, calcium lactate, calcium glycerophosphate, calcium gluconate, magnesium chloride,
Examples thereof include magnesium sulfate, zinc chloride, zinc sulfate, iron sulfate, ferrous chloride, ferric chloride, iron gluconate, copper sulfate and manganese sulfate.
【００１４】なお、本発明の経静脈用輸液製剤において
は、微量元素、ビタミン類等必要な栄養素を、一日必要
摂取量を考慮して配合することができる。In the intravenous infusion preparation of the present invention, necessary nutrients such as trace elements and vitamins can be added in consideration of the daily required intake.
【００１５】本発明に用いられる輸液容器としては、例
えばプラスチック製の柔軟な可撓性容器であって、その
中央部が帯状に剥離可能に熱疑似溶着法により溶着さ
れ、厳密に隔離された個室のそれぞれに輸液注入口又は
排出口が設けられたものが使用できる。前記輸液容器を
用いた本発明は、輸液投与直前に隔離された個室間を連
通することによって、臨床においても簡便な操作で迅速
に輸液を投与できる。The infusion container used in the present invention is, for example, a flexible plastic container made of plastic, and its central portion is welded by a thermal pseudo-welding method so that it can be peeled into a strip shape, and is a strictly separated private chamber. Each of which is provided with an infusion inlet or an outlet can be used. In the present invention using the infusion solution, by communicating between the isolated individual chambers immediately before administration of the infusion solution, the infusion solution can be rapidly administered by a simple operation even in clinical practice.
【００１６】本発明の経静脈用輸液製剤は、通常用いら
れている製剤学的添加剤、すなわち安定化剤やｐＨ調節
剤などを使用し、公知の方法に準拠して製造できる。The intravenous infusion preparation of the present invention can be produced in accordance with a known method by using a conventionally used pharmaceutical additive, that is, a stabilizer, a pH adjusting agent and the like.
【００１７】以下、実施例に基づいて本発明をより詳細
に説明するが、本発明はこれらの実施例に限定されるも
のではない。Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.
【００１８】[0018]
実施例１ 下記表１に示した第１室に収容する各栄養成分を、蒸留
水に加温溶解して７００ｍｌとし、クエン酸でｐＨを
２．０に調整した後、全量を８００ｍｌとした。この溶
液をメンブランフィルターで濾過し、２室バッグの第１
室に充填した。次に、下記表２に示した第２室組成物
を、蒸留水に加温溶解して２５０ｍｌとし、酢酸でｐＨ
を７．４に調整した後全量を３００ｍｌとした。この溶
液をメンブランフィルターで濾過し、２室バッグの第２
室に充填し、空間部を窒素ガスで置換後密栓し、常法に
したがって高圧蒸気滅菌を行った。Example 1 The respective nutrient components contained in the first chamber shown in Table 1 below were dissolved in distilled water by heating to 700 ml, and after adjusting the pH to 2.0 with citric acid, the total amount was 800 ml. The solution is filtered through a membrane filter and placed in a first two-chamber bag.
The chamber was filled. Next, the second chamber composition shown in Table 2 below was dissolved in distilled water with heating to 250 ml, and the pH was adjusted with acetic acid.
Was adjusted to 7.4 and the total amount was adjusted to 300 ml. The solution is filtered through a membrane filter and placed in a two-chamber bag
The chamber was filled, the space was replaced with nitrogen gas, and the container was sealed, and high-pressure steam sterilization was performed according to a conventional method.
【００１９】[0019]
【表１】 [Table 1]
【００２０】[0020]
【表２】 [Table 2]
【００２１】実施例２〜４ 実施例２、３および４は、それぞれ第１室に収容するビ
タミンＢ1を含む輸液のｐＨを３．０、４．０、５．０
に調整したほかは、実施例１と同様に製造した。Examples 2 to 4 In Examples 2, 3 and 4, the pH of the infusion solution containing vitamin B 1 contained in the first chamber was 3.0, 4.0 and 5.0, respectively.
The same procedure as in Example 1 was carried out except that the above was adjusted.
【００２２】実施例５ 下記表３に示した第１室組成物を、蒸留水に加温溶解し
て７００ｍｌとし、クエン酸でｐＨを３．５に調整した
後、全量を８００ｍｌとした。この溶液をメンブランフ
ィルターで濾過し、２室バッグの第１室に充填した。次
に、下記表４に示した第２室組成物を、蒸留水に加温溶
解して全量を４００ｍｌとした。この溶液をメンブラン
フィルターで濾過し、２室バッグの第２室に充填し、空
間部を窒素ガスで置換後密栓し、常法にしたがって高圧
蒸気滅菌を行った。冷後、脱酸素剤を封入してエバール
フィルムにて外包装を行った。Example 5 The first chamber composition shown in Table 3 below was dissolved in distilled water under heating to 700 ml, and the pH was adjusted to 3.5 with citric acid, and then the total amount was 800 ml. This solution was filtered with a membrane filter and filled in the first chamber of a two-chamber bag. Next, the second chamber composition shown in Table 4 below was dissolved by heating in distilled water to a total amount of 400 ml. This solution was filtered with a membrane filter and filled in the second chamber of a two-chamber bag, the space was replaced with nitrogen gas, and the container was sealed and subjected to high-pressure steam sterilization according to a conventional method. After cooling, an oxygen scavenger was enclosed, and outer packaging was performed with an EVAL film.
【００２３】[0023]
【表３】 [Table 3]
【００２４】[0024]
【表４】 [Table 4]
【００２５】実施例６ 下記表５に示した第１室組成物を、蒸留水に加温溶解し
て７００ｍｌとし、クエン酸でｐＨを３．０に調整した
後、全量を８００ｍｌとした。この溶液をメンブランフ
ィルターで濾過し、２室バッグの第１室に充填した。次
に、下記表６に示した第２室組成物を、蒸留水に加温溶
解して全量を４００ｍｌとした。この溶液をメンブラン
フィルターで濾過し、２室バッグの第２室に充填し、空
間部を窒素ガスで置換後密栓し、常法にしたがって高圧
蒸気滅菌を行った。冷後、脱酸素剤を封入してエバール
フィルムにて外包装を行った。Example 6 The first chamber composition shown in Table 5 below was dissolved in distilled water by heating to 700 ml, and after adjusting the pH to 3.0 with citric acid, the total amount was 800 ml. This solution was filtered with a membrane filter and filled in the first chamber of a two-chamber bag. Next, the second chamber composition shown in Table 6 below was dissolved by heating in distilled water to a total amount of 400 ml. This solution was filtered with a membrane filter and filled in the second chamber of a two-chamber bag, the space was replaced with nitrogen gas, and the container was sealed and subjected to high-pressure steam sterilization according to a conventional method. After cooling, an oxygen scavenger was enclosed, and outer packaging was performed with an EVAL film.
【００２６】[0026]
【表５】 [Table 5]
【００２７】[0027]
【表６】 [Table 6]
【００２８】実施例７ 下記表７に示した第１室組成物を、蒸留水に加温溶解し
て７００ｍｌとし、クエン酸でｐＨを３．０に調整した
後、全量を８００ｍｌとした。この溶液をメンブランフ
ィルターで濾過し、２室バッグの第１室に充填した。次
に、下記表８に示した第２室組成物を、蒸留水に加温溶
解して全量を４００ｍｌとした。この溶液をメンブラン
フィルターで濾過し、２室バッグの第２室に充填し、空
間部を窒素ガスで置換後密栓し、常法にしたがって高圧
蒸気滅菌を行った。冷後、脱酸素剤を封入してエバール
フィルムにて外包装を行った。Example 7 The first chamber composition shown in Table 7 below was dissolved in distilled water by heating to 700 ml, and the pH was adjusted to 3.0 with citric acid, and then the total amount was 800 ml. This solution was filtered with a membrane filter and filled in the first chamber of a two-chamber bag. Next, the second chamber composition shown in Table 8 below was dissolved by heating in distilled water to a total amount of 400 ml. This solution was filtered with a membrane filter and filled in the second chamber of a two-chamber bag, the space was replaced with nitrogen gas, and the container was sealed and subjected to high-pressure steam sterilization according to a conventional method. After cooling, an oxygen scavenger was enclosed, and outer packaging was performed with an EVAL film.
【００２９】[0029]
【表７】 [Table 7]
【００３０】[0030]
【表８】 [Table 8]
【００３１】以下に記載する各試験例で実施例以外に使
用した対照例等の輸液剤は、実施例１と同様に製造し
た。Infusion solutions such as control examples used in the following test examples other than the examples were prepared in the same manner as in Example 1.
【００３２】試験例１ １０５℃ ２５分間の高圧蒸気滅菌を行った実施例１〜
４および第１室に収容するビタミンＢ1を含む輸液のｐ
Ｈを１．５、６．０、７．０とそれぞれ調整した対照例
１〜３を被検液として、各被検液中のビタミンＢ1の含
有量を液体クロマトグラフ法により測定しその結果を表
９に示した。各実施例共に極端な含量低下は認められな
いが、特に、実施例１〜４、すなわちビタミンＢ1とグ
ルコースを含む輸液のｐＨが２．０〜５．０に調整され
た輸液製剤では９０％以上の含有量を維持し、加熱滅菌
等の製造工程を経ても安定であることが明らかとなっ
た。Test Example 1 Examples 1 to 5 which were subjected to high-pressure steam sterilization at 105 ° C. for 25 minutes
4 and p of the infusion solution containing vitamin B 1 stored in the first chamber
Using Control Examples 1 to 3 in which H was adjusted to 1.5, 6.0, and 7.0, respectively, as test liquids, the content of vitamin B 1 in each test liquid was measured by liquid chromatography, and the result was obtained. Is shown in Table 9. No drastic decrease in the content was observed in each of the Examples, but especially 90% in Examples 1 to 4, that is, in the infusion preparation in which the pH of the infusion solution containing vitamin B 1 and glucose was adjusted to 2.0 to 5.0. It has been clarified that the above content is maintained and that it is stable even after undergoing manufacturing processes such as heat sterilization.
【００３３】[0033]
【表９】 [Table 9]
【００３４】試験例２ 本発明の経静脈用輸液製剤の保存安定性を調べるため
に、実施例５の輸液製剤を４０℃における苛酷条件下で
１カ月保存した後に、第１室および第２室組成物の性
状、４３０ｎｍにおける透過率（着色の指標）および各
成分の含量を測定した。表１０に示すように本発明の輸
液製剤は各室収容の輸液に着色は認められなかった。ま
た、含量低下が懸念されるビタミンＢ1とグルコースに
ついては、両成分ともに保存後の残存率が９０％以上で
あることから、安定性に問題のないことが明らかとなっ
た。なお、アミノ酸、電解質の各成分についても、同様
な含量測定を行ったが、著しい含量低下は認められず、
その安定性に問題はなかった。Test Example 2 In order to examine the storage stability of the intravenous infusion preparation of the present invention, the infusion preparation of Example 5 was stored under severe conditions at 40 ° C. for 1 month, and then stored in the first and second chambers. The properties of the composition, the transmittance at 430 nm (index of coloring) and the content of each component were measured. As shown in Table 10, the infusion solution of the present invention showed no coloring in the infusion solution contained in each chamber. Regarding vitamin B 1 and glucose, which may cause a decrease in content, the residual ratio after storage of both components was 90% or more, which revealed that there was no problem in stability. A similar content measurement was performed for each of the amino acid and electrolyte components, but no significant decrease in content was observed.
There was no problem in its stability.
【００３５】[0035]
【表１０】 [Table 10]
【００３６】試験例３ ７週齢のCrj:CD系雄性ラットを用い（１群６匹）、5%エ
タノール水飲水下、四塩化炭素（0.4ml/kg/day）を週２
回、７週間にわたって経口投与し、四塩化炭素誘発慢性
肝障害（ＣＨＦ）モデルを作製した。一夜絶食したＣＨ
Ｆラット（１４週齢）をエーテル麻酔下にて、右外頸静
脈よりカテーテル留置術を施行した。次いで、表１１に
示した組成の被験液１〜４を１日目は1.0ml/hr、２日目
は2.0ml/hr、３日目以降は2.5ml/hrの投与速度で持続注
入した。なお、被験液１は実施例５の輸液、被験液２は
実施例５の輸液に総合ビタミン剤を混注した輸液、被験
液３は実施例５からビタミンＢ1を除いた輸液、被験液
４は被験液３からビタミンＢ1を除いた総合ビタミン剤
を添加した輸液である。輸液投与中２０日目において被
験液３および４の投与群で状態の悪化した動物が認めら
れたため、投与を中止し全動物を解剖した。輸液投与終
了後の血液pH、血中乳酸濃度の測定結果を、表１２にま
とめた。血液pHの正常値として、同週齢の自由摂餌群の
値を測定したところ7.333〜7.411であり、被験液１およ
び２の投与群では正常値から逸脱した例はなかった。し
かし、被験液３の投与群では３例、被験液４の投与群で
は２例、正常値より低値を示し、アシドーシスの発症が
認められた。また、血中乳酸濃度の正常値として、同週
齢の自由摂餌群の値を測定したところ16.8〜25.0mg/dl
であり、被験液１および２の投与群では正常値から逸脱
した例はなかった。しかし、被験液３の投与群では３
例、被験液４の投与群では２例、正常値より高値を示
し、乳酸性アシドーシスの発症が明らかとなった。血中
および肝中のチアミン濃度について表１３にまとめた
が、被験液３および４の投与群では被験液１および２の
投与群と比べて明らかな低値を示し、体内チアミンレベ
ルが顕著に低下していることが判明した。以上、本発明
の経静脈用輸液製剤を用いれば、慢性肝障害時において
も、経静脈栄養療法施行時の乳酸性アシドーシスを発症
することなく、連続して投与可能であり、また、使用に
際して誤投薬、微生物汚染、ガラス微細片混入等の危険
性のある混注操作もなく、簡便な操作で迅速に投与でき
ることが明らかとなった。Test Example 3 Seven-week-old Crj: CD male rats (6 rats per group) were used, and carbon tetrachloride (0.4 ml / kg / day) was given 2 times a week under 5% ethanol water drinking.
Oral administration was performed once and for 7 weeks to prepare a carbon tetrachloride-induced chronic liver injury (CHF) model. CH fasted overnight
An F rat (14 weeks old) was anesthetized with ether, and a catheter was placed through the right external jugular vein. Then, test liquids 1 to 4 having the compositions shown in Table 11 were continuously infused at a dose rate of 1.0 ml / hr on the first day, 2.0 ml / hr on the second day, and 2.5 ml / hr on the third day and thereafter. In addition, the test liquid 1 is the infusion liquid of Example 5, the test liquid 2 is the infusion liquid of the multivitamin preparation mixed with the infusion liquid of Example 5, the test liquid 3 is the infusion liquid excluding vitamin B 1 from Example 5, and the test liquid 4 is This is an infusion solution in which a multivitamin preparation excluding vitamin B 1 was added to Test Solution 3. On day 20 during the administration of the infusion solution, animals in which the condition was deteriorated were observed in the test solution 3 and 4 administration groups, so the administration was stopped and all animals were dissected. Table 12 shows the measurement results of blood pH and blood lactate concentration after the end of infusion administration. As a normal value of blood pH, the value in the free feeding group of the same week was measured and was 7.333 to 7.411, and there was no case where the test liquids 1 and 2 administration groups deviated from the normal value. However, 3 cases in the test solution 3 administration group and 2 cases in the test solution 4 administration group showed lower than normal values, and the onset of acidosis was observed. As a normal value for blood lactate concentration, the value in the free-fed group at the same age was measured to be 16.8 to 25.0 mg / dl.
Therefore, there was no case where the test liquids 1 and 2 were deviated from the normal values in the administration groups. However, in the test liquid 3 administration group, 3
For example, in the test liquid 4 administration group, 2 cases showed higher than normal values, and the onset of lactic acidosis was revealed. The blood and liver thiamin concentrations are summarized in Table 13. The test liquids 3 and 4 administration groups show clearly lower levels than the test liquids 1 and 2 administration groups, and the body thiamin levels are significantly reduced. It turned out that As described above, with the intravenous infusion preparation of the present invention, even during chronic liver injury, it is possible to administer continuously without developing lactic acidosis during parenteral nutrition therapy, and it is also possible to use It was clarified that quick administration can be performed by a simple operation, without any mixed injection operation that may cause medication, contamination of microorganisms, contamination of fine glass particles, and the like.
【００３７】[0037]
【表１１】 [Table 11]
【００３８】[0038]
【表１２】 [Table 12]
【００３９】[0039]
【表１３】 [Table 13]
【００４０】[0040]
【発明の効果】本発明によれば、悪性腫瘍の根治手術を
受けた患者、重度の感染症患者、肝機能障害患者等に経
静脈用輸液製剤を投与するにあたり、乳酸性アシドーシ
スを惹起することなく連続して投与可能で、且つ滅菌時
および保存時の安定性に優れ、臨床において、簡便な操
作で迅速に投与できる経静脈用輸液製剤を提供すること
ができる。INDUSTRIAL APPLICABILITY According to the present invention, when administering an intravenous infusion formulation to a patient who has undergone radical surgery for a malignant tumor, a patient with severe infection, a patient with impaired liver function, etc., it is possible to induce lactic acidosis. It is possible to provide an intravenous infusion preparation that can be continuously administered without administration, has excellent stability during sterilization and storage, and can be rapidly administered in a clinical manner by a simple operation.
フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 33/14 Ａ６１Ｋ 33/30 33/30 33/42 33/42 Ａ６１Ｊ 1/00 ３５１Ａ //(Ａ６１Ｋ 31/51 31:70 31:195 33:14 33:30 33:42） Continuation of the front page (51) Int.Cl. 6 Identification number Reference number within the agency FI Technical display location A61K 33/14 A61K 33/30 33/30 33/42 33/42 A61J 1/00 351A // (A61K 31 / 51 31:70 31: 195 33:14 33:30 33:42)
Claims (4)
室を有する可撓性容器の各室に、グルコース、アミノ酸
および電解質の各成分から選ばれた１種もしくは２種以
上を含有する輸液剤を収容し、且つ加熱滅菌された輸液
製剤において、前記可撓性容器の少なくとも１室にビタ
ミンＢ1を収容することを特徴とする経静脈用輸液製
剤。1. An infusion solution containing one or more selected from glucose, amino acid, and electrolyte components in each chamber of a flexible container having a plurality of chambers partitioned by a communicating isolation means. A transfusion preparation for intravenous administration, which contains an agent and is heat-sterilized, wherein vitamin B 1 is contained in at least one chamber of the flexible container.
ミノ酸、電解質およびビタミンＢ1が、下記の範囲で配
合された輸液剤となるよう可撓性容器の各室に収容され
ている請求項１記載の経静脈用輸液製剤。 ビタミンＢ1 ０．１〜３００ｍｇ／ｌ グルコース ２５〜５００ｇ／ｌ アミノ酸総量 １０〜４５ｇ／ｌ 各アミノ酸 Ｌ−イソロイシン ０．５〜５．６ｇ／ｌ Ｌ−ロイシン ０．９〜７．４ｇ／ｌ Ｌ−リジン ０．３〜７．１ｇ／ｌ Ｌ−メチオニン ０．０５〜６．９ｇ／ｌ Ｌ−フェニルアラニン ０．０４〜６．９ｇ／ｌ Ｌ−スレオニン ０．２〜３．３ｇ／ｌ Ｌ−トリプトファン ０．０８〜１．９ｇ／ｌ Ｌ−バリン ０．４〜６．２ｇ／ｌ Ｌ−アルギニン ０〜９．２ｇ／ｌ Ｌ−ヒスチジン ０〜３．５ｇ／ｌ グリシン ０〜７．２ｇ／ｌ Ｌ−アラニン ０〜５．０ｇ／ｌ Ｌ−システイン ０〜０．５ｇ／ｌ Ｌ−アスパラギン酸 ０〜２．４ｇ／ｌ Ｌ−グルタミン酸 ０〜２．９ｇ／ｌ Ｌ−プロリン ０〜４．６ｇ／ｌ Ｌ−セリン ０〜２．９ｇ／ｌ Ｌ−チロシン ０〜０．４ｇ／ｌ ナトリウム ２０〜１５０ｍＭ カリウム ０〜５０ｍＭ カルシウム ０〜２０ｍＭ マグネシウム ０〜２０ｍＭ リン ０〜２０ｍＭ 塩素 ２０〜１５０ｍＭ 亜鉛 ０〜１００μＭ2. Glucose, amino acid, electrolyte and vitamin B 1 are contained in each chamber of the flexible container so as to be an infusion agent mixed in the following range when the isolation means is connected. The intravenous infusion preparation described. Vitamin B 1 0.1 to 300 mg / l Glucose 25 to 500 g / l Amino acid total amount 10 to 45 g / l Each amino acid L-isoleucine 0.5 to 5.6 g / l L-leucine 0.9 to 7.4 g / l L -Lysine 0.3 to 7.1 g / l L-methionine 0.05 to 6.9 g / l L-phenylalanine 0.04 to 6.9 g / l L-threonine 0.2 to 3.3 g / l L-tryptophan 0.08-1.9 g / l L-valine 0.4-6.2 g / l L-arginine 0-9.2 g / l L-histidine 0-3.5 g / l glycine 0-7.2 g / l L -Alanine 0-5.0 g / l L-cysteine 0-0.5 g / l L-aspartic acid 0-2.4 g / l L-glutamic acid 0-2.9 g / l L-proline 0-4.6 g / l L-serine 0-2.9 g / L- tyrosine 0~0.4g / l sodium 20~150mM potassium 0~50mM calcium 0~20mM magnesium 0~20mM phosphorus 0~20mM chlorine 20~150mM zinc 0~100μM
室にグルコースとビタミンＢ1を含有する輸液剤が収容
され、第２室にアミノ酸を含有する輸液剤がそれぞれ収
容され、第１室および第２室に収容されている輸液剤の
一方または両方に電解質が配合されている請求項１又は
２記載の経静脈用輸液製剤。3. A flexible container is divided into two chambers, the first of which is divided into two chambers.
An infusion solution containing glucose and vitamin B 1 is contained in the chamber, an infusion solution containing an amino acid is contained in the second chamber, and one or both of the infusion solutions contained in the first chamber and the second chamber are contained. The intravenous infusion preparation according to claim 1 or 2, which contains an electrolyte.
液剤のｐＨが２．０〜５．０に調整されている請求項３
記載の経静脈用輸液製剤。4. The pH of the infusion solution containing glucose and vitamin B 1 is adjusted to 2.0 to 5.0.
The intravenous infusion preparation described.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7227097A JPH0959150A (en) | 1995-08-11 | 1995-08-11 | Intravenous infusion liquid preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7227097A JPH0959150A (en) | 1995-08-11 | 1995-08-11 | Intravenous infusion liquid preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0959150A true JPH0959150A (en) | 1997-03-04 |
Family
ID=16855450
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7227097A Pending JPH0959150A (en) | 1995-08-11 | 1995-08-11 | Intravenous infusion liquid preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0959150A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11322609A (en) * | 1998-05-14 | 1999-11-24 | Taisho Pharmaceut Co Ltd | Formulated liquid preparation of vitamin b1 |
| WO2004103375A1 (en) * | 2003-05-22 | 2004-12-02 | Otsuka Pharmaceutical Factory, Inc. | Transfusion preparation for peripheral intravenous administration and method of stabilizing vitamin b1 |
| JP2005330244A (en) * | 2004-05-21 | 2005-12-02 | Ajinomoto Co Inc | Transfusion for peripheral intravenous administration |
| JP2006083164A (en) * | 2004-08-17 | 2006-03-30 | Nipro Corp | Transfusion product |
| JP2007137836A (en) * | 2005-11-21 | 2007-06-07 | Ajinomoto Co Inc | Nutrition transfusion for peripheral vein |
| WO2019113543A1 (en) * | 2017-12-07 | 2019-06-13 | Reven, Llc | Compositions and methods for the treatment of metabolic conditions |
| US11110053B2 (en) | 2008-07-25 | 2021-09-07 | Reven Pharmaceuticals Inc. | Compositions and methods for the prevention and treatment of cardiovascular diseases |
| US11202798B2 (en) | 2010-07-22 | 2021-12-21 | Reven Pharmaceuticals, Inc. | Method of treating or ameliorating skin conditions with a magnetic dipole stabilized solution |
-
1995
- 1995-08-11 JP JP7227097A patent/JPH0959150A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11322609A (en) * | 1998-05-14 | 1999-11-24 | Taisho Pharmaceut Co Ltd | Formulated liquid preparation of vitamin b1 |
| WO2004103375A1 (en) * | 2003-05-22 | 2004-12-02 | Otsuka Pharmaceutical Factory, Inc. | Transfusion preparation for peripheral intravenous administration and method of stabilizing vitamin b1 |
| JP2005330244A (en) * | 2004-05-21 | 2005-12-02 | Ajinomoto Co Inc | Transfusion for peripheral intravenous administration |
| JP2006083164A (en) * | 2004-08-17 | 2006-03-30 | Nipro Corp | Transfusion product |
| JP2007137836A (en) * | 2005-11-21 | 2007-06-07 | Ajinomoto Co Inc | Nutrition transfusion for peripheral vein |
| US11110053B2 (en) | 2008-07-25 | 2021-09-07 | Reven Pharmaceuticals Inc. | Compositions and methods for the prevention and treatment of cardiovascular diseases |
| US11202798B2 (en) | 2010-07-22 | 2021-12-21 | Reven Pharmaceuticals, Inc. | Method of treating or ameliorating skin conditions with a magnetic dipole stabilized solution |
| WO2019113543A1 (en) * | 2017-12-07 | 2019-06-13 | Reven, Llc | Compositions and methods for the treatment of metabolic conditions |
| US11344529B2 (en) | 2017-12-07 | 2022-05-31 | Reven Ip Holdco Llc | Compositions and methods for the treatment of metabolic conditions |
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