JP4148632B2 - Peripheral parenteral nutrition infusion - Google Patents

Description

【００１８】
本発明における輸液容器は、少なくとも２つの室を有する容器であって、室と室の間の隔離壁が隔離開放可能なプラスチック製容器である。例えば、ポリエチレン、ポリプロピレン及びポリ塩化ビニルなどの軟質合成樹脂材料からなる輸液容器であって、室と室との隔離壁が外からの圧力によって、該隔離壁の全部または一部が開放され、該室と室が連通可能な容器がある。このような容器の一方の室に糖および脂肪乳剤を含有し、ｐＨが５．０〜６．５に調製された溶液（Ａ）を収容し、他の室に電解質およびアミノ酸を含有し、ｐＨ７．０〜７．５に調製された溶液（Ｂ）を収容してなる輸液容器である。
【００１９】
また、本発明の輸液容器は、ガスバリアー性が高い包装材料を使用することで、輸液容器に収容された輸液製剤の安定性を高めることができる。このような、輸液容器の外包装材料としては、エチレンビニルアルコール共重合体（ＥＶＯＨ）、ポリエチレンテレフタレート（ＰＥＴ）、ポリ塩化ビニリデン（ＰＶＤＣ）、ナイロンなどから構成包装材、またこれらの素材にシリカやアルミナなどのガスバリアー性物質を蒸着処理した包装材およびこれらの素材を組み合わせた多層フィルムから作成された包装材などが挙げられる。
【００２０】
本発明では、上記した方法によって調整した溶液（Ａ）および溶液（Ｂ）を混合した後の輸液製剤のｐＨは７．０〜７．５、滴定酸度は５mEq/L以下、浸透圧比は１〜２．７および油脂濃度は１５〜２５ g/Lであり、かつ乳化剤の添加量が油脂１重量部に対して、０．０５〜０．１０重量部に調整される。
【００２１】
【実施例】
以下に、実施例及び試験例に基づいて、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。
【００２２】
実施例１
溶液（Ａ）：精製ダイズ油２６．７gと精製卵黄レシチン１．６gとを均質に分散させた後に、濃グリセリン６．７gを適量の注射用水に溶解させた。該混合物を、ポリトロンホモジナイザー（ＫＩＮＥＭＡＴＩＣＡ社製）に加え、粗乳化液を得た。該粗乳化液に適量の注射用水を加え、全量を９６０ｍＬとした後、ゴーリンホモジナイザー（ＡＰＶ−Ｒａｎｉｅ社製）を用いて、平均粒子径が０．２８μm以下になるまで精乳化処理を行った。次に、得られた精乳化液にグルコース６６．７gおよびＬ−ヒスチジン０．２gを含む溶液を混合し、塩酸を加え溶液のｐＨを６．０に調整した。その後、注射用水を加え全量を１０００mLとした。このようにして得られた溶液を孔径１．２μmのフィルター（富士フィルム社製）に通過させ、溶液（Ａ）とした。
溶液（Ｂ）：下記表２の組成に従い、アミノ酸および一部電解質を含む溶液を調製した。次に、クエン酸を加え、溶液のｐＨを７．４に調整した。その後、注射用水を加え全量を１０００mLとした。このようにして得られた溶液を孔径０．２２μmのフィルター（富士フィルム社製）に通過させ、溶液（Ｂ）とした。
【００２３】
このようにして調製した溶液（Ａ）および溶液（Ｂ）を２つの室からなるポリプロピレン製輸液容器の各室に溶液（Ａ）：溶液（Ｂ）＝３：１の容量比で収容した。次に、各溶液を収容した輸液容器を高圧蒸気滅菌にて滅菌処理を行った。用時、２室からなる輸液容器の隔壁を外からの圧力により開封して、２つの溶液を混合した際の、輸液製剤の油脂濃度は２０．０g/Lであった。
【００２４】
実施例２
溶液（Ａ）：実施例１におけるレシチン量を１．３４gにした以外は実施例１と同一な組成および方法にて溶液を調製した。
溶液（Ｂ）：実施例１と同様な組成および方法にて溶液を調製した。
【００２５】
実施例１と同様にして、溶液（Ａ）および溶液（Ｂ）を２つの室からなるポリプロピレン製輸液容器の各室に溶液（Ａ）：溶液（Ｂ）＝３：１の容量比で収容した。次に、各溶液を収容した輸液容器を高圧蒸気滅菌にて滅菌処理を行った。用時、２室からなる輸液容器の隔壁を外からの圧力により開封して、２つの溶液を混合した際の、輸液製剤の油脂濃度は２０．０g/Lであった。
【００２６】
実施例３
溶液（Ａ）：実施例１におけるレシチン量を２．６７gにした以外は実施例１と同一な組成および方法にて溶液を調製した。
溶液（Ｂ）：実施例１と同様な組成および方法にて溶液を調製した。
【００２７】
実施例１と同様にして、溶液（Ａ）および溶液（Ｂ）を２つの室からなるポリプロピレン製輸液容器の各室に溶液（Ａ）：溶液（Ｂ）＝３：１の容量比で収容した。次に、各溶液を収容した輸液容器を高圧蒸気滅菌にて滅菌処理を行った。用時、２室からなる輸液容器の隔壁を外からの圧力により開封して、２つの溶液を混合した際の、輸液製剤の油脂濃度は２０．０g/Lであった。
【００２８】
比較例１
溶液（Ａ）：実施例１におけるレシチン量を０．８gにした以外は実施例１と同一な組成および方法にて溶液を調製した。
溶液（Ｂ）：実施例１と同様な組成および方法にて溶液を調製した。
【００２９】
実施例１と同様にして、溶液（Ａ）および溶液（Ｂ）を２つの室からなるポリプロピレン製輸液容器の各室に溶液（Ａ）：溶液（Ｂ）＝３：１の容量比で収容した。次に、各溶液を収容した輸液容器を高圧蒸気滅菌にて滅菌処理を行った。用時、２室からなる輸液容器の隔壁を外からの圧力により開封して、２つの溶液を混合した際の、輸液製剤の油脂濃度は２０．０g/Lであった。
【００３０】
比較例２
溶液（Ａ）：実施例１におけるレシチン量を４．０１gにした以外は実施例１と同一な組成および方法にて溶液を調製した。
溶液（Ｂ）：実施例１と同様な組成および方法にて溶液を調製した。
【００３１】
実施例１と同様にして、溶液（Ａ）および溶液（Ｂ）を２つの室からなるポリプロピレン製輸液容器の各室に溶液（Ａ）：溶液（Ｂ）＝３：１の容量比で収容した。次に、各溶液を収容した輸液容器を高圧蒸気滅菌にて滅菌処理を行った。用時、２室からなる輸液容器の隔壁を外からの圧力により開封して、２つの溶液を混合した際の、輸液製剤の油脂濃度は２０．０g/Lであった。
【００３２】
比較例３
溶液（Ａ）：精製ダイズ油１６６．７gと精製卵黄レシチン２４gを均質に分散させた後に、６０％グルコース水溶液６２５mLを加え、ポリトロンホモジナイザー（ＫＩＮＥＭＡＴＩＣＡ社製）を用い、攪拌粗乳化した。該粗乳化液に注射用水を加え、全量を８３３mLとした後、ゴーリンホモジナイザー（ＡＰＶ−Ｒａｎｉｅ社製）を用い、平均粒子径が０．１７μm以下になるまで精乳化処理を行った。次に、得られた粗乳化液２５２．４ｍＬに、２％Ｌ−ヒスチジン水溶液５mLおよび適量の注射用水を加えて混合し、塩酸でｐＨを６．０に調整した後、注射用水を加え全量を１０００mLとした。このようにして得られた溶液を孔径１．２μmのフィルター（富士フィルム社製）に通過させ、溶液（Ａ）とした
溶液（Ｂ）：下記表２の組成に従い、各成分を加温した適量の注射用水に溶解させ、アミノ酸および一部電解質を含む溶液を調製した。次に、クエン酸を加え、溶液のｐＨを７．０に調整した後、注射用水を加え全量を１０００mLとした。このようにして得られた溶液を孔径０．２２μmのフィルター（富士フィルム社製）に通過させ、溶液（Ｂ）とした。
【００３３】
このようにして調整した溶液（Ａ）および溶液（Ｂ）を２つの室からなるポリプロピレン製輸液容器の各室に溶液（Ａ）：溶液（Ｂ）＝３３：１７の容量比で収容した。次に、各溶液を収容した輸液容器を高圧蒸気滅菌にて滅菌処理を行った。用時、２室からなる輸液容器の隔壁を外からの圧力により開封して、２つの溶液を混合した際の、輸液製剤の油脂濃度は３３．３g/Lであった。
【００３４】
比較例４
７５g/Lグルコースおよび３０g/Lアミノ酸および電解質を含有し、脂肪を含有しない市販製剤を用意した。
【００３５】
比較例５
１００g/L精製大豆油、１２g/L精製卵黄レシチンおよび２２g/L濃グリセリンを含有する１０％脂肪乳剤（市販製剤）を用意した。
【００３６】
【表２】

【００３７】
試験例１
上記実施例１〜３及び比較例１〜５で得られた各混合溶液について、ｐＨ、浸透圧比、滴定酸度および平均粒子径を下記に記載する方法で測定した。この結果を表３に記載する。
（１）ｐＨ
各混合溶液のｐＨをｐＨメーター（Ｆ−２４、堀場製作所社製）を用いて測定した。
（２）浸透圧比
生理食塩水（０．９g/dL塩化ナトリウム溶液）の浸透圧に対する各混合溶液の浸透圧比を測定した。なお、浸透圧の測定は浸透圧測定装置（オスモスタットＯＭ−６０２０、京都第一科学社製）を用いた。
（３）滴定酸度
０．０５mol/L水酸化ナトリウム溶液を各混合溶液に滴下していき、ｐＨ７．４になった時点における水酸化ナトリウム溶液の滴下量から滴定酸度を算出した。なお、滴定量の測定は自動滴定装置（ＣＯＭＴＩＴＥ９００、平沼産業社製）を用いた。
（４）平均粒子径
粒子径および粒度分布測定装置（ＮＩＣＯＭＰ３８０ＺＬＳ、Particle Sizing System社製）を用いて、動的光散乱法により、各混合溶液中の脂肪粒子の平均粒子径を測定した。
【００３８】
【表３】

【００３９】
試験例２
さらに、上記実施例１〜３及び比較例１〜３で得られた各混合溶液の製品評価を行うため、２５℃、６０％ＲＨ条件下で各混合溶液を一定期間保存した。そして溶液混合直後から４８時間経過後の各混合溶液の性状を観察し、ｐＨおよび平均粒子径を試験例１と同様な方法で測定した。
【００４０】
上記実施例１〜３および比較例２〜３で得られた各混合溶液は、４８時間経過後にも油滴は形成されず、ｐＨが一定で、平均粒子径も変化がなく、安定な輸液製剤であった。一方、比較例１の製剤はレシチン添加量が少ないため乳化が不十分であり、混合前製剤より脂肪粒子は大きかった。また、混合溶液においても脂肪粒子の粒子径は不安定なものであった。
【００４１】
試験例３
各種の輸液製剤を用いて組織障害に及ぼす影響の検討を行った。
被験液として、実施例１、比較例３、比較例４、ならびに５０g/Lグルコース溶液および１２０g/Lグルコース溶液を用意した。これらの５種の被験液各５０ml/kgをＳＤ系雄性ラット（体重１５０〜２００g）に１日１回、４日間腹腔内投与した。以後は絶食とした。第５日目に、さらに被験液各１００ml/kgを腹腔内投与した。最終投与５分後に、生理食塩水に溶解した５％ポタミンスカイブルー液２ml/kgをラットの尾静脈より投与した。そして２時間５５分経過後にラットを放血致死させた後、ラットの腹水を採取した。この腹水を遠心分離処理（150×g、5分間、4℃）し、上清を採取して、分光光度計（Ｕ−３２００、日立製作所社製）を用いて吸光度を測定した。この吸光度の値からポンタミンスカイブルー色素量（漏出色素量）を算出した。この結果を下記表４に記載する。
【００４２】
【表４】
各種輸液製剤による組織障害に及ぼす影響

数値は、平均値±標準誤差
*、**：50g/Lグルコース投与群と比較して、Ｐ＜0.05およびＰ＜0.01で有意差あり（多重比較検定）
【００４３】
表４の結果から、浸透圧がヒト血漿より高張である１２０g/Lグルコースは浸透圧が等張である５０g/Lグルコースと比較して漏出色素量の有意な増加を認めた。実施例１は５０g/Lグルコースと比較して漏出色素量も少なく、また、レシチン量、ｐＨ、浸透圧比、滴定酸度および平均粒子径が本発明の範囲から外れる比較例３と比較して、漏出色素量が低値であった。また、脂肪を含有しない比較例４と比較しても低値であった。以上のことから、本発明は組織に対する刺激作用がなく、また血管炎および血管痛を生じないことが示唆された。
【００４４】
試験例４
各種の輸液製剤を用いてウサギ耳介静脈での血管障害性について評価した。白色種ウサギ、雄性、１３週齢を用い、実施例１、比較例３および比較例４の３種の被験液を、毎日１回、５日間、１０ml／kg／hrの容量で、耳介後静脈内に６時間持続投与した。５日目投与後に、全例について耳介静脈血管の水腫の程度および耳介静脈血管周囲の発赤の程度を表５の評価基準に従い、肉眼的に評価し、この数値の平均値および標準誤差を求めた。この結果を表６に記載する。
【００４５】
【表５】
肉眼的検査評価基準

【００４６】
【表６】
各種輸液製剤による投与部位の血管障害度

数値は、平均値±標準誤差
*比較例４と比較して、Ｐ＜0.05で有意差あり（多重比較検定）
【００４７】
表６の結果から、比較例３および比較例４では、投与血管周囲にはっきりとした水腫や発赤の変化が認められたのに対し、実施例１では、ごく軽度の変化にとどまり、明らかに血管障害度の少ないことが判明した。
【００４８】
試験例５
精製ダイズ油１８０gと精製卵黄レシチン１０．８gを均質に分散させた後に、適量の蒸留水を加え、ポリトロンホモジナイザー（ＫＩＮＥＭＡＴＩＣＡ社製）を用い、攪拌粗乳化した。該粗乳化液に適量の注射水を加え、全量を１０００mLとした後、ゴーリンホモジナイザーを用い、平均粒子径が０．２８μm以下になるまで精乳化処理を行い、脂肪濃度１８０g/Lの脂肪乳剤を得た。次に、得られた脂肪乳剤に対し、下記表７に示す容量比で脂肪乳剤、注射用水および１００g/Lグルコース溶液を混合し、脂肪濃度が１０g/L、２０g/L、５０g/L、９０g/Lのグルコース含有脂肪乳剤を調製して、合計４種の被験液を作成した。
【００４９】
【表７】
（単位：容量部）

【００５０】
上記で得た４種の被験液を用いて試験例２と同様な方法で漏出色素量を求め、脂肪濃度の違いによる組織障害に及ぼす影響の検討を行った。参考のために５０g/Lグルコース溶液を調整して同様に検討した。この結果を下記表８に記載する。
【００５１】
【表８】
脂肪濃度の違いによる組織障害に及ぼす影響

**50/Lグルコース単独投与群と比較して、Ｐ＜0.01で有意差あり（多重比較検定）
【００５２】
表８の結果から、漏出色素量は１０g/L及び２０g/L脂肪含有輸液群では対照群と同程度であったが、５０g/L及び９０g/L脂肪含有輸液群では有意に増加した。このことから、５０及び９０g/L脂肪含有輸液群は組織刺激作用を有することが示唆される。従って、５０g/L以下の脂肪配合量が適切であると考えられた。
【００５３】
試験例６
乳化剤であるレシチン含有量の違いによる栄養学的効果について検討した。
被験液として、レシチン含有量が０．０５、０．１０および０．１５重量部／油脂１重量部である実施例２、実施例３および比較例２を用い、対照液としてレシチン含有量が０．１２重量部／油脂１重量部である比較例５を用いた。
【００５４】
ＳＤ系雄性ラット（体重２００〜２４０g）を投与前に１６時間絶食した。その後、輸液ポンプを用いて前記３種の被験液各４０ml/kg体重を１．０ml／分の速度で、ラットの尾静脈より持続投与した。また、対照液は４ml/kg体重を投与した。投与終了後４５分後にラットの尾静脈から血液を採血した。この血液を遠心分離処理（150×g、5分間、4℃）を行い、上清を採取して、リン脂質測定用試薬（リン脂質Ｃ−テストワコー、和光純薬社製）を用いて、血中のリン脂質濃度を測定した。この結果を下記表９に記載する。
【００５５】
【表９】

**比較例５群と比較して、Ｐ＜0.05で有意差あり（多重比較検定）
【００５６】
表９の結果から、血中のリン脂質濃度はレシチンの含有量に依存して増加する傾向にあった。０．０５および０．１０重量部／脂肪１重量部のレシチン含有輸液製剤群では、血中のリン脂質濃度は比較例２および５と比較して、有意に低値であった。このことから、血中からリン脂質が速やかに代謝されるレシチンの添加量は０．１０重量部／脂肪１重量部以下であることが示唆される。
【００５７】
【発明の効果】
本発明の末梢栄養輸液剤は、脂肪、還元糖、アミノ酸及び電解質を配合した輸液製剤であって、油脂濃度を低く抑え、乳化剤を少なく配合し、かつ前記成分混合時のｐＨを中性付近とし、滴定酸度および浸透圧比を適切に調整することにより、静脈炎および血管痛の発生を著しく少なくさせることができ、しかも従来の末梢栄養輸液剤より安全性及び安定性の面で優れた効果を有するものである。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a peripheral parenteral nutritional infusion preparation comprising fat, sugar, amino acid and electrolyte. More specifically, the present invention relates to a peripheral parenteral nutritional infusion preparation with less occurrence of phlebitis and vascular pain.
[0002]
[Prior art]
Patients after digestive surgery often cannot be taken orally, and the nutritional management of the patient is performed by injecting all the nutrients necessary for the human body directly into the vein. Intravenous nutrition includes central and peripheral parenteral nutrition. Central parenteral nutrition has the advantage that all the nutrients necessary for the human body can be administered parenterally over a long period of time. However, surgery for inserting a catheter into the central vein is required, which may involve medical accidents such as pneumothorax, arterial puncture, and vein wall perforation, and complications such as sepsis associated with catheter placement. On the other hand, peripheral venous nutrition performs nutrient infusions that can be administered from the peripheral vein in substantially the same way as general infusions, so the procedure is simple and there is little risk of medical accidents. However, since conventional peripheral parenteral nutrition infusions depend on sugar for supplemental calories, the osmotic pressure of the infusion becomes hypertonic, which is a major cause of vascular pain and phlebitis. For this reason, peripheral parenteral nutrition infusion containing fat instead of carbohydrate as a caloric supplement source has been studied and already proposed (JP-A-6-312923 and JP-A-9-20650).
However, the peripheral parenteral nutrition infusion formulation disclosed in JP-A-6-312923 has a high fat content, a high titratable acidity, and a large amount of lecithin added as an emulsifier, so that vascular pain and phlebitis occur. The frequency of is high. Further, the peripheral parenteral nutrition infusion formulation disclosed in JP-A-9-20650 discloses that pH, osmotic pressure ratio and the like are in a certain range, but it is sufficient from the viewpoint of the incidence of vascular pain and phlebitis. is not.
[0003]
[Problems to be solved by the invention]
The present invention has been made in view of the above situation, and provides a peripheral parenteral nutritional infusion preparation containing fat, sugar, amino acid and electrolyte, in which the occurrence of vascular pain and phlebitis does not occur as much as possible. Objective.
[0004]
[Means for Solving the Problems]
As a result of various earnest studies to achieve the above-mentioned problems, the inventor of the present invention, in a peripheral nutritional infusion preparation containing sugar, fat, amino acid and electrolyte, suppresses the oil and fat concentration low, contains less emulsifier, and By adjusting the pH at the time of mixing components to near neutral and adjusting the titratable acidity and osmotic pressure ratio appropriately, the stability of the mixed solution can be secured, and the occurrence of phlebitis and vascular pain can be suppressed more reliably than before. It has been found that a peripheral parenteral nutrition infusion preparation capable of being provided can be provided. In addition, a solution containing sugar and fat (A) in one chamber of the two-chamber container and a solution containing electrolyte and amino acid (B) in another chamber are housed, and the pH of the solution in each chamber is adjusted to a specific range. Thus, the inventors have found that the peripheral vein infusion preparation can be stably supplied, and have reached the present invention.
[0005]
That is, the present invention is a peripheral nutritional infusion preparation containing a fat emulsion obtained by emulsifying fats and oils using an emulsifier, a sugar, an amino acid and an electrolyte, and the pH of the peripheral nutritional infusion preparation is 7.0 to 7.5, The titratable acidity is 5 mEq / L or less, the osmotic pressure ratio is 1 to 2.7, the fat and oil concentration is 15 to 25 g / L, and the addition amount of the emulsifier is 0.05 to 0.10 with respect to 1 part by weight of the fat and oil. It is a peripheral parenteral nutrition infusion solution characterized by being part by weight.
[0006]
In addition, the present invention contains a fat emulsion and sugar obtained by emulsifying fats and oils using an emulsifier, a solution (A) having a pH adjusted to 5.0 to 6.5, an electrolyte and an amino acid, and a pH of 7.0. A nutritional infusion preparation comprising the solution (B) adjusted to ˜7.5, the pH at the time of mixing is 7.0 to 7.5, the titration acidity is 5 mEq / L or less, and the osmotic pressure ratio is 1 to 2.7. And the fat concentration is 15 to 25 g / L, and the fat emulsion is emulsified with 0.05 to 0.10 parts by weight of an emulsifier with respect to 1 part by weight of the fats and oils. Infusion formulation.
[0007]
Furthermore, the present invention is a container having a plurality of chambers, and a fat emulsion and a sugar obtained by emulsifying fats and oils with an emulsifier in one chamber of an infusion container in which a separation wall between the chamber and the other chamber can be separated and opened. A solution (A) containing and having a pH adjusted to 5.0 to 6.5, containing an electrolyte and an amino acid in another chamber, and adjusted to pH 7.0 to 7.5 (B Is a transfusion container containing a peripheral parenteral nutritional transfusion preparation.
[0008]
Further, the present invention is a method for producing a solution (A) containing a sugar and a fat emulsion, characterized in that after fats and oils are emulsified with an emulsifier, a solution (A) is prepared by adding sugar.
[0009]
BEST MODE FOR CARRYING OUT THE INVENTION
The solution (A) used in the present invention contains a fat emulsion and a sugar. The fat emulsion of the present invention emulsifies fats and oils using an emulsifier, and generally contains fat particles having an average particle size of 200 to 300 nm, more preferably 230 to 270 nm.
Examples of fats and oils include vegetable oil, fish oil, medium chain fatty acid triglyceride, or chemically synthesized triglyceride. Specific examples include vegetable oils such as soybean oil, safflower oil, olive oil, cottonseed oil, corn oil, coconut oil, perilla oil, and sesame oil, whale oil, and synthetic triglycerides of medium chain and long chain fatty acids.
In addition, these fats and oils may mix 2 or more types. The density | concentration of the fats and oils in a solution (A) is 20-33 g / L.
[0010]
Examples of the emulsifier used in the present invention include egg yolk phospholipid, hydrogenated egg yolk phospholipid, soybean phospholipid, hydrogenated soybean phospholipid, and nonionic surfactant. Specific examples include purified egg yolk lecithin, purified soybean lecithin and hydrogenated products thereof, nonionic surfactants such as polysorbate 80 and HCO-60 (both are trade names). In addition, these emulsifiers may mix 2 or more types. The added concentration of the emulsifier is 0.05 to 0.10 parts by weight, preferably 0.05 to 0.07 parts by weight, with respect to 1 part by weight of the fats and oils.
[0011]
The sugar used in the present invention may be conventionally used in various infusions, and examples thereof include monosaccharides such as glucose and fructose, and disaccharides such as maltose. Of these, reducing sugars such as glucose, fructose and maltose are particularly preferred. The solution (A) prepared in the present invention may contain a polyhydric alcohol such as glycerol or sugar alcohol. Examples of the sugar alcohol include sorbitol, xylitol, mannitol and the like. Two or more of these sugars and polyhydric alcohols may be blended. The concentration of sugar and / or polyhydric alcohol in the solution (A) is 25 to 80 g / L, preferably 45 to 65 g / L.
[0012]
The solution (A) used in the present invention includes hydrochloric acid, acetic acid, lactic acid, citric acid, malic acid and the like as a pH adjuster. These pH adjusters are added as appropriate to adjust the pH in the solution (A) to 5.0 to 6.5, preferably to pH 5.0 to 6.0. When the pH is lower than 5.0, fats and oils are likely to be decomposed. When the pH is higher than 6.5, reducing sugars are likely to be decomposed.
[0013]
As a preparation method of the solution (A) of the present invention, fats and oils are emulsified using an emulsifier, and the average particle diameter of fat particles is adjusted to 200 to 300 nm, and then a sugar is added to obtain the solution (A). Good. As a specific example, a solution obtained by adding an emulsifier to fats and oils is roughly emulsified using a Polytron homogenizer (manufactured by KINEMATICA). Then, the obtained coarse emulsion is subjected to fine emulsification treatment using a gorin homogenizer (manufactured by APV-Ranie) until the average particle size becomes 200 to 300 nm. Next, a solution containing sugar is mixed into the obtained fine emulsion, and a pH adjusting solution is added to adjust the pH of the solution to 5.0 to 6.5. The solution thus obtained is filtered through a filter (manufactured by Fuji Film Co., Ltd.) having a pore size of 1.2 μm to prepare a solution (A).
[0014]
The solution (B) used in the present invention contains an amino acid and an electrolyte. Amino acids include essential amino acids, non-essential amino acids and / or salts, esters or N-acyl forms of these amino acids. Specifically, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, L-valine, L-alanine, L-arginine, L-aspartic acid, Examples include amino acids such as L-cysteine, L-glutamic acid, L-histidine, L-proline, L-serine, L-tyrosine, aminoacetic acid. These amino acids include inorganic acid salts such as L-arginine hydrochloride, L-cysteine hydrochloride, L-glutamine hydrochloride, L-histidine hydrochloride, L-lysine hydrochloride, L-lysine acetate, L-lysine. Organic acid salts such as malate, ester forms such as L-tyrosine methyl ester and L-methionone methyl ester, N-acetyl-L-cysteine, N-acetyl-L-tryptophan, N-acetyl-L-proline and the like N-substituted products, L-tyrosyl-L-tyrosine, L-alanyl-L-tyrosine, L-argyl-L-tyrosine, L-tyrosyl-L-arginine and other peptides may be used.
[0015]
Examples of the electrolyte used in the present invention include water-soluble salts of inorganic components such as sodium, potassium, calcium, magnesium, zinc, iron, copper, manganese, iodine, and phosphorus, such as sodium chloride, sodium acetate, and sodium citrate. Potassium chloride, potassium iodide, potassium citrate, potassium glycerophosphate, potassium acetate, calcium citrate, calcium glycerophosphate, calcium gluconate, magnesium sulfate, magnesium chloride and the like.
[0016]
The solution (B) used in the present invention is preferably added with citric acid, malic acid, lactic acid, gluconic acid and the like as a pH adjuster. Appropriate amounts of these pH adjusters are added to adjust the pH in the solution (B) to 7.0 to 7.5, preferably 7.1 to 7.3. When the pH is lower than 7.0, the pH of the mixed preparation is not adjusted to an appropriate range. On the other hand, when the pH is higher than 7.5, the solution (B) is likely to be colored.
[0017]
In the present invention, the peripheral vein infusion preparation contains, for example, the components shown in Table 1 below. These preparation methods follow conventional methods.
[Table 1]

[0018]
The infusion container in the present invention is a container having at least two chambers, and a plastic container in which an isolation wall between the chambers can be separated and opened. For example, in an infusion container made of a soft synthetic resin material such as polyethylene, polypropylene and polyvinyl chloride, the isolation wall between the chambers is opened by the pressure from the outside, or all or a part of the isolation wall is opened. There is a container that can communicate between rooms. One chamber of such a container contains a solution (A) containing a sugar and a fat emulsion and having a pH adjusted to 5.0 to 6.5, and the other chamber contains an electrolyte and an amino acid. An infusion container containing the solution (B) prepared in a range of 0.0 to 7.5.
[0019]
Moreover, the infusion container of this invention can improve stability of the infusion formulation accommodated in the infusion container by using a packaging material with high gas barrier property. Such outer packaging materials for infusion containers include packaging materials composed of ethylene vinyl alcohol copolymer (EVOH), polyethylene terephthalate (PET), polyvinylidene chloride (PVDC), nylon, etc., and these materials include silica and Examples thereof include a packaging material obtained by vapor-depositing a gas barrier material such as alumina, and a packaging material prepared from a multilayer film obtained by combining these materials.
[0020]
In the present invention, the pH of the infusion preparation after mixing the solution (A) and the solution (B) prepared by the above method is 7.0 to 7.5, the titratable acidity is 5 mEq / L or less, and the osmotic pressure ratio is 1 to 2.7 and fat and oil concentration are 15-25 g / L, and the addition amount of an emulsifier is adjusted to 0.05-0.10 weight part with respect to 1 weight part of fat.
[0021]
【Example】
Below, based on an Example and a test example, this invention is demonstrated in detail, This invention is not limited to these Examples.
[0022]
Example 1
Solution (A):After 26.7 g of purified soybean oil and 1.6 g of purified egg yolk lecithin were uniformly dispersed, 6.7 g of concentrated glycerin was dissolved in an appropriate amount of water for injection. The mixture was added to a polytron homogenizer (manufactured by KINEMATICA) to obtain a crude emulsion. An appropriate amount of water for injection was added to the crude emulsion to make the total volume 960 mL, and then fine emulsification was performed using a gorin homogenizer (manufactured by APV-Ranie) until the average particle size became 0.28 μm or less. Next, a solution containing 66.7 g of glucose and 0.2 g of L-histidine was mixed with the resulting fine emulsion, and hydrochloric acid was added to adjust the pH of the solution to 6.0. Thereafter, water for injection was added to make a total volume of 1000 mL. The solution thus obtained was passed through a filter (manufactured by Fuji Film Co., Ltd.) having a pore size of 1.2 μm to obtain a solution (A).
Solution (B):A solution containing an amino acid and a partial electrolyte was prepared according to the composition shown in Table 2 below. Next, citric acid was added to adjust the pH of the solution to 7.4. Thereafter, water for injection was added to make a total volume of 1000 mL. The solution thus obtained was passed through a filter (manufactured by Fuji Film Co., Ltd.) having a pore size of 0.22 μm to obtain a solution (B).
[0023]
The solution (A) and the solution (B) thus prepared were accommodated in each chamber of a polypropylene infusion container having two chambers at a volume ratio of solution (A): solution (B) = 3: 1. Next, the infusion container containing each solution was sterilized by high-pressure steam sterilization. At the time of use, the fat concentration of the infusion preparation was 20.0 g / L when the partition of the infusion container consisting of two chambers was opened by external pressure and the two solutions were mixed.
[0024]
Example 2
Solution (A):A solution was prepared by the same composition and method as in Example 1 except that the amount of lecithin in Example 1 was 1.34 g.
Solution (B):A solution was prepared by the same composition and method as in Example 1.
[0025]
In the same manner as in Example 1, the solution (A) and the solution (B) were accommodated in each chamber of a polypropylene infusion container having two chambers at a volume ratio of solution (A): solution (B) = 3: 1. . Next, the infusion container containing each solution was sterilized by high-pressure steam sterilization. At the time of use, the fat concentration of the infusion preparation was 20.0 g / L when the partition of the infusion container consisting of two chambers was opened by external pressure and the two solutions were mixed.
[0026]
Example 3
Solution (A):A solution was prepared by the same composition and method as in Example 1 except that the amount of lecithin in Example 1 was 2.67 g.
Solution (B):A solution was prepared by the same composition and method as in Example 1.
[0027]
In the same manner as in Example 1, the solution (A) and the solution (B) were accommodated in each chamber of a polypropylene infusion container having two chambers at a volume ratio of solution (A): solution (B) = 3: 1. . Next, the infusion container containing each solution was sterilized by high-pressure steam sterilization. At the time of use, the fat concentration of the infusion preparation was 20.0 g / L when the partition of the infusion container consisting of two chambers was opened by external pressure and the two solutions were mixed.
[0028]
Comparative Example 1
Solution (A):A solution was prepared by the same composition and method as in Example 1 except that the amount of lecithin in Example 1 was changed to 0.8 g.
Solution (B):A solution was prepared by the same composition and method as in Example 1.
[0029]
In the same manner as in Example 1, the solution (A) and the solution (B) were accommodated in each chamber of a polypropylene infusion container having two chambers at a volume ratio of solution (A): solution (B) = 3: 1. . Next, the infusion container containing each solution was sterilized by high-pressure steam sterilization. At the time of use, the fat concentration of the infusion preparation was 20.0 g / L when the partition of the infusion container consisting of two chambers was opened by external pressure and the two solutions were mixed.
[0030]
Comparative Example 2
Solution (A):A solution was prepared by the same composition and method as in Example 1 except that the amount of lecithin in Example 1 was 4.01 g.
Solution (B):A solution was prepared by the same composition and method as in Example 1.
[0031]
In the same manner as in Example 1, the solution (A) and the solution (B) were accommodated in each chamber of a polypropylene infusion container having two chambers at a volume ratio of solution (A): solution (B) = 3: 1. . Next, the infusion container containing each solution was sterilized by high-pressure steam sterilization. At the time of use, the fat concentration of the infusion preparation was 20.0 g / L when the partition of the infusion container consisting of two chambers was opened by external pressure and the two solutions were mixed.
[0032]
Comparative Example 3
Solution (A):After 166.7 g of purified soybean oil and 24 g of purified egg yolk lecithin were uniformly dispersed, 625 mL of a 60% aqueous glucose solution was added, and the mixture was coarsely emulsified with stirring using a Polytron homogenizer (manufactured by KINEMATICA). Water for injection was added to the crude emulsion to make the total volume 833 mL, and then fine emulsification was performed using a gorin homogenizer (manufactured by APV-Ranie) until the average particle size was 0.17 μm or less. Next, to 252.4 mL of the obtained crude emulsion, 5 mL of 2% L-histidine aqueous solution and an appropriate amount of water for injection were added and mixed. After adjusting the pH to 6.0 with hydrochloric acid, water for injection was added to make the total amount. 1000 mL. The solution thus obtained was passed through a filter having a pore diameter of 1.2 μm (manufactured by Fuji Film Co., Ltd.) to obtain a solution (A).
Solution (B):In accordance with the composition shown in Table 2 below, each component was dissolved in an appropriate amount of water for injection to prepare a solution containing an amino acid and a partial electrolyte. Next, citric acid was added to adjust the pH of the solution to 7.0, and water for injection was added to make a total volume of 1000 mL. The solution thus obtained was passed through a filter (manufactured by Fuji Film Co., Ltd.) having a pore size of 0.22 μm to obtain a solution (B).
[0033]
The solution (A) and the solution (B) thus prepared were accommodated in each chamber of a polypropylene infusion container having two chambers at a volume ratio of solution (A): solution (B) = 33: 17. Next, the infusion container containing each solution was sterilized by high-pressure steam sterilization. At the time of use, the fat concentration of the infusion preparation was 33.3 g / L when the septum of the infusion container consisting of two chambers was opened by external pressure and the two solutions were mixed.
[0034]
Comparative Example 4
A commercial formulation containing 75 g / L glucose and 30 g / L amino acid and electrolyte and no fat was prepared.
[0035]
Comparative Example 5
A 10% fat emulsion (commercial preparation) containing 100 g / L purified soybean oil, 12 g / L purified egg yolk lecithin and 22 g / L concentrated glycerin was prepared.
[0036]
[Table 2]

[0037]
Test example 1
About each mixed solution obtained in the said Examples 1-3 and Comparative Examples 1-5, pH, an osmotic pressure ratio, titration acidity, and an average particle diameter were measured by the method described below. The results are listed in Table 3.
(1) pH
The pH of each mixed solution was measured using a pH meter (F-24, manufactured by Horiba, Ltd.).
(2) Osmotic pressure ratio
The osmotic pressure ratio of each mixed solution to the osmotic pressure of physiological saline (0.9 g / dL sodium chloride solution) was measured. The osmotic pressure was measured using an osmotic pressure measuring device (Osmostat OM-6020, manufactured by Kyoto Daiichi Kagaku).
(3) Titration acidity
A 0.05 mol / L sodium hydroxide solution was added dropwise to each mixed solution, and the titrated acidity was calculated from the amount of sodium hydroxide solution added when the pH reached 7.4. The titration measurement was performed using an automatic titrator (COMMITE 900, manufactured by Hiranuma Sangyo Co., Ltd.).
(4) Average particle size
The average particle size of the fat particles in each mixed solution was measured by a dynamic light scattering method using a particle size and particle size distribution measuring device (NICOMP 380ZLS, manufactured by Particle Sizing System).
[0038]
[Table 3]

[0039]
Test example 2
Furthermore, in order to perform product evaluation of each mixed solution obtained in Examples 1 to 3 and Comparative Examples 1 to 3, each mixed solution was stored for a certain period under conditions of 25 ° C. and 60% RH. Then, the properties of each mixed solution after lapse of 48 hours from immediately after mixing the solution were observed, and the pH and average particle size were measured in the same manner as in Test Example 1.
[0040]
Each of the mixed solutions obtained in Examples 1 to 3 and Comparative Examples 2 to 3 does not form oil droplets after 48 hours, has a constant pH, does not change the average particle size, and is a stable infusion preparation Met. On the other hand, the preparation of Comparative Example 1 was insufficiently emulsified because the amount of lecithin added was small, and the fat particles were larger than the preparation before mixing. Moreover, the particle diameter of the fat particles was also unstable in the mixed solution.
[0041]
Test example 3
The effect on tissue damage was examined using various infusion preparations.
As test solutions, Example 1, Comparative Example 3, Comparative Example 4, and 50 g / L glucose solution and 120 g / L glucose solution were prepared. Each of these five test solutions (50 ml / kg) was intraperitoneally administered once daily to SD male rats (body weight 150-200 g) for 4 days. After that, it was fasted. On the fifth day, 100 ml / kg of each test solution was further administered intraperitoneally. Five minutes after the final administration, 2 ml / kg of 5% potamine sky blue solution dissolved in physiological saline was administered from the tail vein of the rat. After 2 hours and 55 minutes, the rats were exsanguinated to death, and the ascites of the rats were collected. The ascites was centrifuged (150 × g, 5 minutes, 4 ° C.), the supernatant was collected, and the absorbance was measured using a spectrophotometer (U-3200, manufactured by Hitachi, Ltd.). From this absorbance value, the amount of pontamsky sky blue dye (leakage dye amount) was calculated. The results are listed in Table 4 below.
[0042]
[Table 4]
Effects of various infusion preparations on tissue damage

Numerical values are mean ± standard error
*, **: Significantly different at P <0.05 and P <0.01 compared to the 50 g / L glucose administration group (multiple comparison test)
[0043]
From the results in Table 4, 120 g / L glucose having an osmotic pressure higher than that of human plasma showed a significant increase in the amount of leaked pigment as compared to 50 g / L glucose having an isotonic pressure. In Example 1, the amount of leaking dye was small compared to 50 g / L glucose, and the amount of lecithin, pH, osmotic pressure ratio, titratable acidity, and average particle size were out of the scope of the present invention. The amount of dye was low. Moreover, even if it compared with the comparative example 4 which does not contain fat, it was a low value. From the above, it was suggested that the present invention has no stimulating action on tissues and does not cause vasculitis and vascular pain.
[0044]
Test example 4
Various infusion preparations were used to evaluate vascular damage in rabbit ear veins. Using white rabbits, male, 13 weeks old, the test fluids of Example 1, Comparative Example 3 and Comparative Example 4 were administered once a day for 5 days at a volume of 10 ml / kg / hr after the auricle. Intravenous administration was continued for 6 hours. After administration on the fifth day, the degree of edema of the auricular veins and the degree of redness around the auricular veins were evaluated macroscopically according to the evaluation criteria shown in Table 5 for all cases. Asked. The results are listed in Table 6.
[0045]
[Table 5]
Macroscopic evaluation criteria

[0046]
[Table 6]
Degree of vascular injury at the administration site by various infusion preparations

Numerical values are mean ± standard error
* Compared with Comparative Example 4, there is a significant difference at P <0.05 (multiple comparison test)
[0047]
From the results in Table 6, in Comparative Example 3 and Comparative Example 4, clear edema and redness change were recognized around the administration blood vessel, whereas in Example 1, only a slight change was observed, and clearly the blood vessel It turned out that there was little obstacle degree.
[0048]
Test Example 5
After 180 g of purified soybean oil and 10.8 g of purified egg yolk lecithin were uniformly dispersed, an appropriate amount of distilled water was added, and the mixture was coarsely emulsified with a polytron homogenizer (manufactured by KINEMATICA). An appropriate amount of water for injection is added to the crude emulsion to make a total volume of 1000 mL, and then fine emulsification treatment is performed using a gorin homogenizer until the average particle size is 0.28 μm or less. Obtained. Next, a fat emulsion, water for injection, and a 100 g / L glucose solution were mixed with the obtained fat emulsion at a volume ratio shown in Table 7 below, so that fat concentrations were 10 g / L, 20 g / L, 50 g / L, 90 g. / L glucose-containing fat emulsion was prepared to prepare a total of 4 test solutions.
[0049]
[Table 7]
(Unit: Capacity)

[0050]
Using the four types of test solutions obtained above, the amount of the leaked pigment was determined in the same manner as in Test Example 2, and the effect on tissue damage due to the difference in fat concentration was examined. For reference, a 50 g / L glucose solution was prepared and examined in the same manner. The results are shown in Table 8 below.
[0051]
[Table 8]
Effects on tissue damage due to differences in fat concentration

** Significantly different at P <0.01 compared to 50 / L glucose alone administration group (multiple comparison test)
[0052]
From the results of Table 8, the amount of leaking pigment was similar to the control group in the 10 g / L and 20 g / L fat-containing infusion groups, but significantly increased in the 50 g / L and 90 g / L fat-containing infusion groups. This suggests that the 50 and 90 g / L fat-containing infusion group has a tissue stimulating action. Therefore, it was considered that a fat content of 50 g / L or less was appropriate.
[0053]
Test Example 6
The nutritional effect by the difference in lecithin content as an emulsifier was examined.
Example 2, Example 3 and Comparative Example 2 having lecithin content of 0.05, 0.10 and 0.15 parts by weight / fat oil 1 part by weight as test liquids, and lecithin content of 0 as control liquid Comparative Example 5 having 12 parts by weight / 1 part by weight of fats and oils was used.
[0054]
SD male rats (body weight 200-240 g) were fasted for 16 hours before administration. Thereafter, 40 ml / kg body weight of each of the three test solutions was continuously administered from the tail vein of the rat using an infusion pump at a rate of 1.0 ml / min. The control solution was 4 ml / kg body weight. Blood was collected from the tail vein of the rat 45 minutes after the completion of administration. The blood is centrifuged (150 × g, 5 minutes, 4 ° C.), the supernatant is collected, and a phospholipid measurement reagent (Phospholipid C-Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.) is used. The blood phospholipid concentration was measured. The results are listed in Table 9 below.
[0055]
[Table 9]

** Significantly different at P <0.05 compared with Comparative Example 5 group (multiple comparison test)
[0056]
From the results of Table 9, the blood phospholipid concentration tended to increase depending on the lecithin content. In the lecithin-containing infusion preparation groups of 0.05 and 0.10 parts by weight / fat 1 part by weight, the phospholipid concentration in the blood was significantly lower than those in Comparative Examples 2 and 5. This suggests that the addition amount of lecithin, in which phospholipids are rapidly metabolized from blood, is 0.10 parts by weight / fat part by weight or less.
[0057]
【The invention's effect】
The peripheral nutritional infusion of the present invention is an infusion preparation containing fat, reducing sugar, amino acid and electrolyte, containing a low concentration of fats and oils, containing less emulsifier, and the pH at the time of mixing the ingredients is near neutral. In addition, by appropriately adjusting the titratable acidity and osmotic pressure ratio, the occurrence of phlebitis and vascular pain can be remarkably reduced, and the safety and stability are superior to those of conventional peripheral nutritional fluids. Is.

Claims (2)

A nutritional infusion preparation for peripheral intravenous administration comprising a fat emulsion obtained by emulsifying fats and oils with an emulsifier and a solution containing sugar (A) and a solution containing electrolyte and amino acid (B), wherein the solution (A) has a pH of 5. 0 to 6.0, solution (B) is adjusted to pH 7.0 to 7.5, pH at mixing is 7.0 to 7.5 , titration acidity is 5 mEq / L or less, and osmotic pressure ratio is 1 to 2. 7 and oils content of about 15-25 g / L, and relative to the addition amount of oil 1 part by weight of an emulsifier, for peripheral intravenous administration nutrition infusion preparation which is a 0.05 to 0.10 parts by weight . A solution (A) containing a fat emulsion obtained by emulsifying fats and oils using an emulsifier and a sugar in one chamber of an infusion container, which is a container having two chambers and in which a separation wall between the chambers can be separated and opened The infusion container containing the nutritional infusion preparation for peripheral vein administration according to claim 1, wherein the solution (B) containing electrolyte and amino acid is contained in another chamber.