JP3615284B2 - Production method of fat emulsion - Google Patents

Description

Translated fromJapanese

【０００１】
【産業上の利用分野】
本発明は、糖、電解質、アミノ酸等の他の薬剤と混合しても、乳化状態の破壊が生じ難い、安定性に優れた脂肪乳剤の製造法に関する。
【０００２】
【従来の技術】
脂肪乳剤はカロリー補給及び必須脂肪酸補給を目的として開発され、現在臨床で広く用いられている。
【０００３】
脂肪乳剤の製造法は、脂肪乳剤中の粗大粒子が毒性を示すことから、脂肪粒子が微細でしかも粒度分布が狭い脂肪乳剤を調製することに主眼がおかれてきた。界面化学的な研究から、乳化剤の溶解順序によって、得られる脂肪乳剤の形態が異なり、乳化剤を油脂に溶解（Ａｇｅｎｔ ｉｎ Ｏｉｌ）する方が、水に溶解（Ａｇｅｎｔ ｉｎ Ｗａｔｅｒ）するよりも微細で安定な脂肪乳剤を調製できることが報告されている（Ｔ．Ｊ．Ｌｉｎ，ｅｔ ａｌ，Ｊ．Ｓｏｃ．Ｃｏｓｍｅｔ．Ｃｈｅｍ．，２６，１２１（１９７５））。一般に脂肪乳剤の製造には、乳化剤を油脂に溶解した後に水を添加する乳化剤の溶解方法が採られている（Ａ．Ｔａｋａｍｕｒａ，ｅｔ ａｌ，Ｊ．Ｐｈａｒｍ．Ｓｃｉ．７３．９１（１９８４）；Ｆ．Ｉｓｈｉｉ，ｅｔ ａｌ，Ｊ．Ｐｈａｍ．Ｐｈａｒｍａｃｏｌ．，４２，５１３（１９９０））。また、脂肪乳剤の製造には高圧条件下で粗乳化液を精乳化することが必須であり、精乳化する方法としては、高圧乳化機を用いる方法が開示されている。例えば、粗乳化液調製時に高速撹拌ホモジナイザーを用いて、Ａｇｅｎｔ ｉｎ Ｏｉｌ法により粗乳化液を調製し、この粗乳化液を高圧ホモジナイザーを用いて精乳化することにより、微細で均一性が高い脂肪乳剤が得られる（宮嶋孝志一郎ら，医薬品の開発，１５，３１４，廣川，東京，（１９９３）；特開昭５５−１４７２２８）。
【０００４】
最近、臨床現場において薬剤の投与方法が多様化され、脂肪乳剤と他の薬剤が混合される機会が増えている。例えば、ＴＰＮ（完全静脈栄養）管理されている患者には、脂肪乳剤を糖、電解質、アミノ酸等の栄養輸液剤と混合して投与される。脂肪乳剤が、ガラスバイアルまたはプラスチックバッグ等の容器中に単味で収容されている場合、その安定性に問題はないが、前述のように臨床現場で他の薬剤と混合された場合は乳化状態の破壊が起こりやすく粗大粒子が生成する。そこで、他の薬剤と混合されても安定性に問題のない脂肪乳剤の開発が望まれている。
【０００５】
これまでに、前記問題を改善する技術として、脂肪乳剤にクエン酸を添加する方法が開示されている（特開平５−３２５４１号公報）。しかし、この方法は、クエン酸が有する心機能低下等の副作用を考えると安全性の面で不安が残る。
【０００６】
【発明が解決しようとする課題】
従って、本発明の課題は、糖、電解質、アミノ酸等の他の薬剤と混合しても、乳化状態の破壊が生じ難い、安定性や安全性に優れた脂肪乳剤を提供することにある。
【０００７】
【課題を解決するための手段】
本発明者らは、クエン酸等の添加剤を使用することなく、脂肪乳剤の製造法を改善することにより脂肪乳剤の安定性を向上させることができないか詳細に検討を行った。その結果、乳化剤の溶解方法がＡｇｅｎｔ ｉｎ ＯｉｌあるいはＡｇｅｎｔ ｉｎ Ｗａｔｅｒのどちらを採用しても微細で安定な脂肪乳剤を得られるが、意外にも、他の薬剤と混合した場合の安定性においては、乳化剤を水に分散させてから油脂と混合するＡｇｅｎｔ ｉｎ Ｗａｔｅｒの方法により脂肪乳剤を製造する方が優れているとの知見を得た。更に、脂肪乳剤を製造する際、乳化剤分散液および精乳化液の各調製時に加える水の添加量を適切な量に設定すること、あるいは各調整時の混合液を適切な温度条件に設定することにより、より優れた脂肪乳剤が得られることを見出した。
【０００８】
前述の知見を基に完成した本発明は、油脂を乳化剤を用いて乳化させる脂肪乳剤の製造法において、乳化剤と水を含む乳化剤分散液を調製した後、この乳化剤分散液に油脂を加えて混合し更に水を加えて混合して粗乳化液を調製し、次いで得られた粗乳化液を高圧乳化機で精乳化して精乳化液を調製し、この精乳化液に所定の油脂濃度とするに必要な水を加えて混合する脂肪乳剤の製造法である。また、乳化剤分散液および粗乳化液を調製する際加える水が、油脂に対する重量比としてそれぞれ０．３〜０．７であり、前記２回に分けて加える水の総量が、油脂に対する重量比として０．８〜１．４である脂肪乳剤の製造法である。また、乳化剤分散液に油脂を加えて混合する際、その混合液の温度を３５〜６５℃に調整して混合し、更に水を加えて混合する際には混合液の温度を５〜３５℃に調整して混合する脂肪乳剤の製造法である。また、粗乳化液中に含まれる乳化剤が、油脂に対する重量比として０．０４〜０．２である脂肪乳剤の製造法である。また、油脂が、エゴマ油、亜麻仁油および魚油の一種又はそれ以上の組み合わせによりなる脂肪乳剤の製造法である。
【０００９】
本発明により、糖、電解質、アミノ酸等の他の薬剤との混合において、乳化状態の破壊を生じ難い、安定性や安全性に優れた脂肪乳剤を提供することができるが、本発明により製造された脂肪乳剤は、その油脂濃度が精乳化後に得られた精乳化液に水を添加混合することにより好ましくは１０〜３０Ｗ／Ｖ％の濃度に調製されており、これを通常の脂肪乳剤と同様な条件で、ガラスバイアル、プラスチックバッグ等の製剤容器に充填、滅菌することができる。また、本発明の脂肪乳剤の製造法において、油脂以外に必要に応じて等張化剤、ｐＨ調整剤、ビタミン類、微量元素、安定化剤等を添加できる。
【００１０】
本発明に利用できる油脂としては、例えば精製した大豆油、エゴマ油、亜麻仁油、サフラワー油、ゴマ油、綿実油、ココナツ油等の植物油、魚油、鯨油等の動物油、中鎖脂肪酸トリグリセライド等の化学合成トリグリセライドを挙げることができる。特に、本発明は多価不飽和脂肪酸を高度に含有し酸化を受けやすいエゴマ油、亜麻仁油および魚油に適用した場合、他の薬剤と混合した場合の安定性の向上のみならず、これら油脂が保存中に酸化され難くなる効果を奏する。本発明において使用する乳化剤としては精製卵黄リン脂質、水添卵黄リン脂質、精製大豆リン脂質、水添大豆リン脂質等のレシチンが使用可能であるが、これに限定されるものではない。
【００１１】
【作用】
本発明は、脂肪乳剤の製造法において、乳化剤を水に分散させてから油脂と混合するＡｇｅｎｔ ｉｎ Ｗａｔｅｒの方法を採用し、且つ乳化剤分散液調製時と粗乳化液調製時２回に分けて水を添加して精乳化液を調製することにより、脂肪乳剤の安定性が向上し、糖、電解質、アミノ酸等の他の薬剤と混合しても乳化状態の破壊に起因する粗大粒子の生成が抑制され、安定性および安全性に問題のない脂肪乳剤を提供することが可能となる。
【００１２】
【実施例】
以下に実施例を挙げて本発明を説明する。
【００１３】
実施例１
精製卵黄レシチン１８ｇ、濃グリセリン３３．７５ｇに注射用蒸留水１５０ｍｌを添加し、６０℃に加温後、ポリトロンホモジナイザー（キネマティック製ＰＴ３０００型）で１０，０００ｒｐｍ、１分間撹拌混合し乳化剤分散液を得る。この乳化剤分散液に、６０℃に調整した精製エゴマ油３００ｇを添加し、混合液を６０℃に保ちながらポリトロンホモジナイザーで２０，０００ｒｐｍ、１分間撹拌する。次いで、前記混合液を２０℃に急速冷却後、２０℃に調製した注射用蒸留水１５０ｍｌを添加し、混合液を２０℃に保ちながらポリトロンホモジナイザーで２０，０００ｒｐｍ、５分間撹拌混合して粗乳化液を得る。この粗乳化液をマイクロフルイダイザー（マイクロフルイデックス製Ｍ−１１０Ｙ型）で１０，０００ｐｓｉ、パス回数８回の高圧乳化条件で精乳化を行う。得られた精乳化液を５％重曹水溶液を用いてｐＨを６．５〜７．５に調整後、注射用蒸留水を加えて全量を１５００ｍｌとし、孔径３μｍのメンブランフィルターでろ過を行い、油脂濃度が２０Ｗ／Ｖ％の脂肪乳剤を得た。得られた脂肪乳剤１００ｍｌをガラスバイアルに充填し、窒素置換後密栓した。これを高圧蒸気滅菌することにより、２μｍ以上の粗大粒子を含まない、精製エゴマ油含有脂肪乳剤を得た。
【００１４】
実施例２
精製卵黄レシチン６ｇ、濃グリセリン１１．２５ｇに注射用蒸留水５０ｍｌを添加し、６０℃に加温後ポリトロンホモジナイザーで１０，０００ｒｐｍ、１分間撹拌混合して乳化剤分散液を得る。この乳化剤分散液を４０℃に冷却し、４０℃に調整したダイズ油１００ｇを添加し、混合液を４０℃に保ちながらポリトロンホモジナイザーで２０，０００ｒｐｍ、１分間撹拌混合する。次いで、前記混合液を２０℃に急速冷却後、２０℃に調整した注射用蒸留水５０ｍｌを添加し、以下実施例１と同様の操作を行い、全量を５００ｍｌとして、２μｍ以上の粗大粒子を含まない、油脂濃度が２０Ｗ／Ｖ％のダイズ油含有脂肪乳剤を得た。
【００１５】
実施例３
注射用蒸留水の添加量を乳化剤分散液調整時に６０ｍｌ、粗乳化液調整時に４０ｍｌとし、注射用蒸留水を添加してから撹拌混合する際の粗乳化液調製温度を５℃とした以外は実施例２と同様の操作を行い、２μｍ以上の粗大粒子を含まないダイズ油脂肪乳剤を得た。
【００１６】
比較例１
注射用蒸留水の添加量を乳化剤分散液調製時に１００ｍｌ、粗乳化液調整時には全く添加しない条件とした他は実施例２と同様の操作を行い、２μｍ以上の粗大粒子を含まないダイズ油脂肪乳剤を得た。
【００１７】
比較例２
注射用蒸留水の添加量を乳化剤分散液調整時に２５ｍｌ、粗乳化液調整時に７５ｍｌとした他は実施例２と同様の操作を行い、２μｍ以上の粗大粒子を含まないダイズ油脂肪乳剤を得た。
【００１８】
比較例３および４
乳化剤分散液にダイズ油を加えて混合する際、その混合液の調製温度を２０℃（比較例３）および９０℃、（比較例４）にそれぞれ保ちながらポリトロンホモジナイザーで撹拌混合し粗乳化液を調製する条件以外は実施例２と同様の操作を行い、２μｍ以上の粗大粒子を含まないダイズ油脂肪乳剤を得た。
【００１９】
比較例５
ダイズ油を添加した後、注射用蒸留水を添加して攪拌混合する際の調製温度を４０℃とした以外は実施例２と同様の操作を行い、２μｍ以上の粗大粒子を含まないダイズ油含有脂肪乳剤を得た。
【００２０】
比較例６
精製エゴマ油３００ｇに、精製卵黄レシチン１８ｇ、濃グリセリン３３．７５ｇを添加し、９０℃に加温後、ポリトロンホモジナイザーで２０，０００ｒｐｍ、７分間撹拌混合し乳化剤を精製エゴマ油に分散した溶液を得る。この溶液を２０℃に急速冷却後、注射用蒸留水３００ｍｌを添加し、混合液を２０℃に保ちながらポリトロンホモジナイザーで２０，０００ｒｐｍ、１４分間撹拌混合して粗乳化液を得た。この粗乳化液を、実施例１と同様の操作を行い、全量を１５００ｍｌとして、２μｍ以上の粗大粒子を含まないＡｇｅｎｔ ｉｎ Ｏｉｌ法により調製した精製エゴマ油脂肪乳剤を得た。
【００２１】
試験例
脂肪乳剤を他の薬剤と混合した場合の安定性を調べるために、実施例１〜３並びに比較例１〜６をそれぞれ被験液として、表１に示す組成の電解質液１００ｍｌに各被験液１０ｍｌを混合し２００ｍｌガラスバイアルに充填後、ガラスバイアルを開封した状態で２５℃、７５％ＲＨの条件下に２４時間保存した。保存後、各保存液１５ｍｌをそれぞれ蒸留水で洗浄した内径約９ｃｍのシャーレに注ぎ、蛍光灯下で粗大粒子の凝集により生成した油滴を肉眼で数え安定性の良否を評価した。各被験液の油滴数に基づく安定性の評価結果を表２に示した。
【００２２】
【表１】

【００２３】
【表２】

【００２４】
試験の結果、実施例１、２および３の各被験液は、電解質と混合しても油滴は生成せず、エマルションの破壊が起こり易い電解質と混合した場合でも安定性に問題のないことが明らかとなった。なお、本発明の製造法と異なる条件で製造した比較例１〜６の各被験液は、いずれも電解質と混合後２４時間で油滴の生成が認められた。
【００２５】
【発明の効果】
本発明により脂肪乳剤を製造すれば、他の薬剤と混合した場合でも粗大粒子が生成し難い安定性の優れた脂肪乳剤を提供することができる。
従って、本発明により、粗大粒子による副作用を懸念することなく安全にしかも長期間脂肪乳剤を投与することができる。更に、本発明の製造法は、従来のＡｇｅｎｔ ｉｎ Ｏｉｌ法に比べ、各製造工程の調製温度を低く設定することが可能で、調製時間も短縮でき製造コストの削減及び作業効率の向上が期待できる。[0001]
[Industrial application fields]
The present invention relates to a method for producing a fat emulsion that is less likely to break up in an emulsified state even when mixed with other drugs such as sugars, electrolytes, and amino acids and has excellent stability.
[0002]
[Prior art]
Fat emulsions have been developed for the purpose of supplementing calories and essential fatty acids, and are now widely used in clinical practice.
[0003]
The method for producing a fat emulsion has been focused on preparing a fat emulsion having fine fat particles and a narrow particle size distribution because coarse particles in the fat emulsion are toxic. From the surface chemical study, the form of the resulting fat emulsion differs depending on the dissolution order of the emulsifier, and it is finer and more stable to dissolve the emulsifier in oil (Agent in Oil) than in water (Agent in Water). It has been reported that fat emulsions can be prepared (TJ Lin, et al, J. Soc. Cosmet. Chem., 26, 121 (1975)). In general, a fat emulsion is prepared by dissolving an emulsifier in an oil and fat and then adding water (A. Takamura, et al, J. Pharm. Sci. 73.91 (1984); F). Ishii, et al, J. Pharm. Pharmacol., 42, 513 (1990)). In addition, it is indispensable to finely emulsify a crude emulsion under high-pressure conditions for the production of fat emulsions, and a method using a high-pressure emulsifier is disclosed as a method for finely emulsifying. For example, when preparing a crude emulsion, a high-speed stirring homogenizer is used to prepare a crude emulsion by the Agent in Oil method, and the crude emulsion is finely emulsified using a high-pressure homogenizer to obtain a fine and highly uniform fat emulsion. (Kyoichiro Miyajima et al., Development of Pharmaceuticals, 15, 314, Yodogawa, Tokyo, (1993); JP 55-147228).
[0004]
Recently, the administration method of drugs has been diversified in the clinical field, and the opportunity to mix fat emulsions with other drugs has increased. For example, fat emulsions are mixed with nutrient infusions such as sugars, electrolytes and amino acids and administered to patients under TPN (total parenteral nutrition) management. When the fat emulsion is contained in a simple container such as a glass vial or plastic bag, there is no problem with its stability, but when mixed with other drugs at the clinical site as described above, it is in an emulsified state. It is easy to break down and coarse particles are generated. Therefore, it is desired to develop a fat emulsion that does not have a problem in stability even when mixed with other drugs.
[0005]
So far, as a technique for improving the above problem, a method of adding citric acid to a fat emulsion has been disclosed (Japanese Patent Laid-Open No. 5-32541). However, this method remains uneasy in terms of safety in view of side effects such as reduced cardiac function of citric acid.
[0006]
[Problems to be solved by the invention]
Accordingly, an object of the present invention is to provide a fat emulsion that is not easily destroyed in an emulsified state even when mixed with other drugs such as sugars, electrolytes, and amino acids, and has excellent stability and safety.
[0007]
[Means for Solving the Problems]
The present inventors have examined in detail whether the stability of a fat emulsion can be improved by improving the production method of a fat emulsion without using an additive such as citric acid. As a result, a fine and stable fat emulsion can be obtained regardless of whether the emulsifier dissolution method is Agent in Oil or Agent in Water, but surprisingly, in the case of mixing with other drugs, It was found that it is better to produce a fat emulsion by the Agent in Water method in which an emulsifier is dispersed in water and then mixed with fats and oils. Furthermore, when manufacturing a fat emulsion, set the amount of water added at the time of each preparation of the emulsifier dispersion and the fine emulsion to an appropriate amount, or set the mixture at the time of each adjustment to an appropriate temperature condition. Thus, it was found that a more excellent fat emulsion can be obtained.
[0008]
The present invention, which has been completed based on the aforementioned findings, is a method for producing a fat emulsion in which fats and oils are emulsified using an emulsifier, and after preparing an emulsifier dispersion containing an emulsifier and water, the fats and oils are added to the emulsifier dispersion and mixed. Further, water is added and mixed to prepare a crude emulsion, and then the resulting crude emulsion is finely emulsified with a high-pressure emulsifier to prepare a fine emulsion, and this fat emulsion has a predetermined fat concentration. Is a method for producing a fat emulsion in which necessary water is added and mixed. Moreover, the water added when preparing the emulsifier dispersion and the crude emulsion is 0.3 to 0.7 as the weight ratio to the oil and fat, respectively, and the total amount of water added in two batches is the weight ratio to the fat and oil. This is a method for producing a fat emulsion of 0.8 to 1.4. Moreover, when adding fats and oils to an emulsifier dispersion and mixing, the temperature of the liquid mixture is adjusted to 35-65 degreeC, it mixes, and when adding water and mixing further, the temperature of a liquid mixture is 5-35 degreeC. This is a method for producing a fat emulsion that is adjusted and mixed. Moreover, it is a manufacturing method of the fat emulsion whose emulsifier contained in a rough | crude emulsion is 0.04-0.2 as a weight ratio with respect to fats and oils. Further, the present invention is a method for producing a fat emulsion in which the fat / oil is a combination of one or more of sesame oil, linseed oil and fish oil.
[0009]
According to the present invention, it is possible to provide a fat emulsion that is less likely to break the emulsified state and excellent in stability and safety when mixed with other drugs such as sugars, electrolytes, and amino acids. The fat emulsion is prepared to a concentration of preferably 10 to 30 W / V% by adding water to the fine emulsion obtained after the fine emulsification and mixing, and this is the same as a normal fat emulsion. It is possible to fill and sterilize pharmaceutical containers such as glass vials and plastic bags under appropriate conditions. Further, in the method for producing a fat emulsion of the present invention, an isotonic agent, a pH adjuster, vitamins, trace elements, a stabilizer and the like can be added as necessary in addition to fats and oils.
[0010]
Examples of oils and fats that can be used in the present invention include chemical oils such as refined soybean oil, sesame oil, linseed oil, safflower oil, sesame oil, cottonseed oil, coconut oil and other animal oils, fish oil, whale oil and other animal oils, and medium chain fatty acid triglycerides. Triglycerides can be mentioned. In particular, when the present invention is applied to sesame oil, linseed oil and fish oil that are highly polyvalent unsaturated fatty acid and susceptible to oxidation, not only the stability when mixed with other drugs, but also these fats and oils It has the effect of being hardly oxidized during storage. As the emulsifier used in the present invention, lecithin such as purified egg yolk phospholipid, hydrogenated egg yolk phospholipid, purified soybean phospholipid, hydrogenated soybean phospholipid can be used, but is not limited thereto.
[0011]
[Action]
The present invention employs the Agent in Water method in which an emulsifier is dispersed in water and then mixed with fats and oils in a method for producing a fat emulsion, and water is divided into two when preparing an emulsifier dispersion and when preparing a crude emulsion. To improve the stability of fat emulsions and suppress the formation of coarse particles due to the destruction of the emulsified state even when mixed with other drugs such as sugar, electrolytes, and amino acids. Thus, it becomes possible to provide a fat emulsion having no problem in stability and safety.
[0012]
【Example】
Hereinafter, the present invention will be described with reference to examples.
[0013]
Example 1
After adding 150 ml of distilled water for injection to 18 g of purified egg yolk lecithin and 33.75 g of concentrated glycerin and heating to 60 ° C., the mixture is stirred and mixed at 10,000 rpm for 1 minute with a Polytron homogenizer (PT3000 type manufactured by Kinematic). obtain. 300 g of purified sesame oil adjusted to 60 ° C. is added to this emulsifier dispersion, and the mixture is stirred at 20,000 rpm for 1 minute with a Polytron homogenizer while maintaining the mixture at 60 ° C. Next, after rapidly cooling the mixture to 20 ° C., 150 ml of distilled water for injection prepared at 20 ° C. was added, and the mixture was stirred and mixed with a Polytron homogenizer at 20,000 rpm for 5 minutes while being roughly emulsified. Obtain a liquid. This crude emulsified solution is finely emulsified with a microfluidizer (M-110Y type manufactured by Microfluidics) under high pressure emulsification conditions of 10,000 psi and 8 passes. After adjusting the pH of the resulting emulsified liquid to 6.5-7.5 using 5% aqueous sodium bicarbonate, distilled water for injection was added to a total volume of 1500 ml, and filtered through a membrane filter with a pore size of 3 μm. A fat emulsion having a concentration of 20 W / V% was obtained. 100 ml of the obtained fat emulsion was filled in a glass vial, sealed with nitrogen, and sealed. This was autoclaved to obtain a purified sesame oil-containing fat emulsion free of coarse particles of 2 μm or more.
[0014]
Example 2
50 g of distilled water for injection is added to 6 g of purified egg yolk lecithin and 11.25 g of concentrated glycerin, heated to 60 ° C., and stirred and mixed with a Polytron homogenizer at 10,000 rpm for 1 minute to obtain an emulsifier dispersion. The emulsifier dispersion is cooled to 40 ° C., 100 g of soybean oil adjusted to 40 ° C. is added, and the mixture is stirred and mixed with a Polytron homogenizer at 20,000 rpm for 1 minute. Next, after rapidly cooling the mixed solution to 20 ° C., 50 ml of distilled water for injection adjusted to 20 ° C. is added, and then the same operation as in Example 1 is performed to make the total amount 500 ml and contain coarse particles of 2 μm or more. A soybean oil-containing fat emulsion having an oil / fat concentration of 20 W / V% was obtained.
[0015]
Example 3
Implemented except that the amount of distilled water for injection was 60 ml when adjusting the emulsifier dispersion, 40 ml when adjusting the coarse emulsion, and the temperature for preparing the crude emulsion when stirring and mixing after adding distilled water for injection was 5 ° C. The same operation as in Example 2 was performed to obtain a soybean oil fat emulsion containing no coarse particles of 2 μm or more.
[0016]
Comparative Example 1
The same procedure as in Example 2 was performed except that the amount of distilled water for injection was 100 ml at the time of preparation of the emulsifier dispersion and no addition at the time of preparation of the crude emulsion, and the soybean oil fat emulsion containing no coarse particles of 2 μm or more Got.
[0017]
Comparative Example 2
A soybean oil fat emulsion containing no coarse particles of 2 μm or more was obtained by performing the same operation as in Example 2 except that the amount of distilled water for injection was 25 ml when adjusting the emulsifier dispersion and 75 ml when adjusting the coarse emulsion. .
[0018]
Comparative Examples 3 and 4
When adding soybean oil to the emulsifier dispersion and mixing, the mixture is stirred and mixed with a Polytron homogenizer while maintaining the preparation temperature of the mixture at 20 ° C. (Comparative Example 3), 90 ° C. and (Comparative Example 4). Except for the conditions for preparation, the same operation as in Example 2 was performed to obtain a soybean oil fat emulsion containing no coarse particles of 2 μm or more.
[0019]
Comparative Example 5
After the soybean oil was added, the same operation as in Example 2 was performed except that the preparation temperature for adding and stirring and mixing by stirring was 40 ° C. The soybean oil containing no coarse particles of 2 μm or more was contained. A fat emulsion was obtained.
[0020]
Comparative Example 6
18 g of purified egg yolk lecithin and 33.75 g of concentrated glycerin are added to 300 g of purified sesame oil, heated to 90 ° C., and stirred and mixed with a Polytron homogenizer at 20,000 rpm for 7 minutes to obtain a solution in which the emulsifier is dispersed in the purified sesame oil. . After rapidly cooling this solution to 20 ° C., 300 ml of distilled water for injection was added, and the mixture was stirred and mixed with a Polytron homogenizer at 20,000 rpm for 14 minutes to obtain a crude emulsion. The crude emulsion was treated in the same manner as in Example 1 to obtain a purified egoma oil fat emulsion prepared by the Agent in Oil method containing no coarse particles of 2 μm or more with a total amount of 1500 ml.
[0021]
Test Example In order to examine the stability when the fat emulsion was mixed with other drugs, Examples 1 to 3 and Comparative Examples 1 to 6 were used as test solutions, respectively, and each test solution was added to 100 ml of an electrolyte solution having the composition shown in Table 1. After mixing 10 ml and filling into a 200 ml glass vial, the glass vial was opened and stored for 24 hours under conditions of 25 ° C. and 75% RH. After storage, 15 ml of each stock solution was poured into a petri dish having an inner diameter of about 9 cm washed with distilled water, and oil droplets produced by aggregation of coarse particles were counted with a naked eye under a fluorescent lamp to evaluate the stability. Table 2 shows the stability evaluation results based on the number of oil droplets in each test solution.
[0022]
[Table 1]

[0023]
[Table 2]

[0024]
As a result of the test, each test solution of Examples 1, 2, and 3 does not generate oil droplets even when mixed with an electrolyte, and there is no problem in stability even when mixed with an electrolyte that easily breaks an emulsion. It became clear. In addition, as for each test liquid of Comparative Examples 1-6 manufactured on the conditions different from the manufacturing method of this invention, the production | generation of the oil droplet was recognized by all for 24 hours after mixing with electrolyte.
[0025]
【The invention's effect】
When a fat emulsion is produced according to the present invention, a fat emulsion having excellent stability in which coarse particles are hardly formed even when mixed with other drugs can be provided.
Therefore, according to the present invention, it is possible to administer a fat emulsion safely and for a long time without worrying about side effects due to coarse particles. Furthermore, in the production method of the present invention, the preparation temperature of each production process can be set lower than the conventional Agent in Oil method, the preparation time can be shortened, and the production cost can be reduced and the working efficiency can be expected. .

Claims (3)

Translated fromJapanese

乳化剤と水とを含む乳化剤分散液を調製する工程、
前記乳化剤分散液に３５〜６５℃において油脂と水の重量比が１：０.３〜０.７となるように油脂を混合する工程、
得られた混合液に、５〜３５℃において前記油脂１に対して０.３〜０.７の重量比の水を、油脂と水の総量の重量比が１：０.８〜１.４となるように加えて混合して粗乳化液を調製する工程、
次いで得られた粗乳化液を５〜３５℃において高圧乳化機で精乳化して精乳化液を調製する工程、および
前記精乳化液に油脂濃度を１０〜２０Ｗ／Ｖ％とするに必要な水を加えて混合する工程を含む脂肪輸液の製造法。A step of preparing an emulsifier dispersion containing an emulsifier and water,
Whereinthe weight ratio of oil and water at 35 to 65 ° C. in the emulsifierdispersion1:.. 03-07 and stepof fats and oils mixed-so,
To the resultingmixture, 0 to the fat or oil 1 at 5 to 35 ° C.3 to 07 water weight ratio, the weight ratio of the total amount of fat and water1:.... 08-14 preparing amixed combined crude emulsionwas added so that,
Subsequently, the crude emulsion thus obtainedis finely emulsified with a high-pressure emulsifier at 5 to 35 ° C. to prepare a fine emulsion, andwater necessary for the oil concentration in the fine emulsionto be 10 to 20 W / V%. preparation offat肪輸solutioncomprising a step of adding and mixing a.粗乳化液中に含まれる乳化剤が、油脂に対する重量比として０.０４〜０.２であることを特徴とする請求項１に記載の脂肪輸液の製造法。The method for producing a fat infusion according to claim 1, wherein the emulsifier contained in the crude emulsion is 0.04 to 0.2 as a weight ratio to fats and oils.油脂が、エゴマ油、亜麻仁油および魚油の一種又はそれ以上の組み合わせよりなることを特徴とする請求項１又は２に記載の脂肪輸液の製造法。The method for producing a fat infusion according to claim 1 or 2, wherein the fats and oils are composed of one or more combinations of sesame oil, linseed oil and fish oil.