JP7215945B2 - fat emulsion - Google Patents

Description

The present invention relates to fat emulsions.

BACKGROUND ART Conventionally, in the life support of a patient, when oral nutrition, tube feeding, etc. are impossible or insufficient, nutritional support by intravenous infusion administration has been widely performed. Administration routes include central veins and peripheral veins. Regardless of the route of administration, it is said that the administration of fat is essential in addition to the supplementation of sugar, amino acids and electrolytes. In particular, when nutritional supplementation is performed from a peripheral vein, lipid emulsion is used as part of the energy source so that the required amount of energy can be administered without increasing the osmotic pressure as much as possible in order to avoid vascular pain and phlebitis. used. In addition, administration of fat is extremely important not only as an energy source but also from the viewpoint of essential fatty acid supplementation. Essential fatty acid deficiency is a rare occurrence in everyday life, but is common in patients on parenteral nutrition alone. In particular, it is said that if only carbohydrates are administered as an energy source without fat, deficiency will occur in 3 to 4 weeks. A lack of essential fatty acids causes a decrease in skin elasticity, eczema, hair loss, etc., and increases the cholesterol in the blood, increasing the risk of developing hyperlipidemia, hypercholesterolemia, arteriosclerosis, etc. It is said.

When administering fat intravenously, a lipid emulsion alone is generally used. When the lipid emulsion alone is mixed with other nutritional infusions, such as electrolyte infusions and amino acid infusions, the average particle size of the fat particles increases over time, and there is a risk of progression from aggregation to creaming and oil droplets. . This is because the surface of the fat particles is weakly negatively charged, so when cations with a valence of 2 or higher and basic amino acids are present, the electrical repulsive force between the fat particles weakens, making aggregation more likely to occur. is due to Oil droplets can adhere to the infusion set and cause blockage and bacterial growth. An increase in the average particle size of fat particles is known to change the pharmacokinetics of fat and cause pulmonary capillary embolism. In the United States, it is recommended that the volume of particles larger than 5 μm be less than 0.05% of the total fat as a standard for the particle size of fat emulsions (Non-Patent Document 1).

Some commercially available lipid emulsions are not intended to be mixed with other medications for their use and must be administered separately from other nutritional infusions. Therefore, a peripheral only route is required. It may also be administered through a side tube of a peripheral venous catheter or a side tube of a central venous catheter. At this time, if the contact time between the lipid emulsion and the nutrient infusion solution is shortened as much as possible, aggregation of the lipid particles can be prevented. However, since rapid administration of a lipid emulsion increases blood triglyceride concentration, administration at 0.1 g/kg/hour or less (in terms of fats and oils) is recommended (Non-Patent Document 2).

As a means of preventing aggregation and coarsening of fat particles, addition of specific organic acids (Patent Document 1) or addition of vitamins (Patent Document 2) to other nutritional infusions to be mixed instead of fat particles, fat emulsions have been disclosed to improve the stability of fat particles when mixed with other nutritional infusions.

JP-A-5-32541 Japanese Patent Application Laid-Open No. 2008-290968

USP (United States Pharmacopeia) 41, General Chapters <729> GLOBAL SIZE DISTRIBUTION IN LIPID INJECTABLE EMULSIONS Keiji Iriyama, "Nutrition - Evaluation and Treatment", 26(4), p. 324-327 (2009)

However, in the techniques disclosed in Patent Documents 1 and 2, a lipid emulsion or a nutrient infusion solution containing a lipid emulsion is passed through an infusion filter with a pore size of 0.2 μm, which prevents bacteria, foreign matter, air, etc. from entering the vein. There is a problem that it cannot be administered.

Accordingly, an object of the present invention is to provide a lipid emulsion that can be administered through an infusion filter with a pore size of 0.2 μm.

The present inventors have accumulated earnest research in order to solve the above problems. As a result, it contains oil, lysophosphatidylcholine, and an emulsifier (excluding lysophosphatidylcholine), and the content of the lysophosphatidylcholine is 0.40 to 2.10 parts by mass with respect to 10 parts by mass of the oil, and the emulsifier is contained. The inventors have found that a fat emulsion containing 0.40 to 3.00 parts by mass solves the above problems, and have completed the present invention.

According to the present invention, it is possible to provide a lipid emulsion that can be administered through an infusion filter with a pore size of 0.2 μm.

FIG. 1 is a conceptual diagram showing a container having two chambers according to one embodiment of the present invention.

An embodiment according to one aspect of the present invention will be described below. The present invention is not limited only to the following embodiments.

In this specification, "X to Y" indicating a range means "X or more and Y or less".

<Fat emulsion>
One form of the present invention contains fat, lysophosphatidylcholine and an emulsifier (excluding lysophosphatidylcholine), and the content of the lysophosphatidylcholine is 0.40 to 2.10 parts by mass with respect to 10 parts by mass of the fat, The fat emulsion contains 0.40 to 3.00 parts by mass of the emulsifier.

In the fat emulsion according to the present embodiment, lysophosphatidylcholine is emulsified together with fats and oils and an emulsifier other than lysophosphatidylcholine. As a result, the average particle size of the fat particles contained in the fat emulsion can be reduced, and aggregation of the fat particles over time can be suppressed, so that the stability of the fat particles can be improved. Furthermore, the number of coarsened fat particles, such as fat particles having a particle size of 1.5 μm or more, which can clog an infusion filter with a pore size of 0.2 μm, can be reduced. Therefore, the lipid emulsion according to this embodiment can be administered through an infusion filter with a pore size of 0.2 μm.

An infusion filter with a pore size of 0.2 μm has the effect of trapping bacteria, foreign matter, and the like contaminating the infusion and the infusion line, removing air, and preventing these from entering the vein. Infusion solutions are often mixed with various concomitant drugs, and in many facilities, this work is performed by nurses in the wards rather than sterile preparations. Therefore, there is a possibility that bacteria, foreign matter, and the like may be mixed. In particular, when administering to a central vein via a catheter, contamination with bacteria may lead to catheter-related bloodstream infections, and in severe cases may cause hypotension, circulatory failure, organ damage, and the like.

Since the lipid emulsion according to this embodiment can be administered through an infusion filter with a pore size of 0.2 μm, it is very effective in preventing infectious diseases. In addition, the lipid emulsion according to the present embodiment can be conveniently administered because there is no need to secure an administration route separate from that for other infusion preparations.

Furthermore, even when mixed with other nutritional infusions containing amino acids, electrolytes, etc., or administered from the side tube of the infusion line, the lipid emulsion according to the present invention can suppress aggregation and coarsening of fat particles. It can be administered through a 0.2 μm pore size infusion filter.

(lysophosphatidylcholine)
The fat emulsion according to this embodiment contains lysophosphatidylcholine.

Lysophosphatidylcholine has a structure in which one fatty acid at position 2 is deviated from phosphatidylcholine (composed of four elements of phosphoric acid, choline, glycerin and fatty acid), which is the main component of lecithin.

Lecithin is contained in large amounts in major cell tissues such as the cerebral nervous system, blood, bone marrow, heart, lung, liver, and gastrointestinal tract, and is contained in all cell membranes in the body. Lecithin is known to have physiological functions and to act as a material for the neurotransmitter acetylcholine. Phosphoric acid and choline are hydrophilic and compatible with water, while glycerin and fatty acids are lipophilic and compatible with oil. Therefore, lecithin has an emulsifying effect. Since this emulsifying action activates lipid metabolism, lecithin is expected to be effective in improving hyperlipidemia and preventing arteriosclerosis. Lecithin also has a choline supplementation effect. A lack of choline causes many symptoms such as fatigue, weakened immune system, insomnia, arteriosclerosis, diabetes, and deposition of LDL cholesterol. Therefore, lysophosphatidylcholine, which has a similar structure to lecithin, is believed to have similar effects as lecithin.

Lysophosphatidylcholine is industrially produced from soybeans and egg yolks of chicken eggs, and is often used under the name of lysolecithin in the fields of foods and cosmetics. Lysophosphatidylcholine is widely distributed in nature, especially in animal cells, and is said to account for several percent of lipids in membrane systems.

(fat)
The fat emulsion according to this embodiment contains fats and oils.

Fats and oils are not particularly limited, and fats and oils commonly used in fat emulsions can be used. Examples of fats and oils include vegetable oils, fish oils, medium-chain fatty acid triglycerides, chemically synthesized triglycerides, and the like. Therefore, in one embodiment, the fat is at least one selected from the group consisting of vegetable oil, fish oil, medium chain fatty acid triglycerides and chemically synthesized triglycerides, preferably vegetable oil.

Examples of vegetable oils include soybean oil, cottonseed oil, safflower oil, corn oil, coconut oil, perilla oil, perilla oil, olive oil, and the like.

Examples of fish oils include sardine oil, mackerel oil, saury oil, tuna oil, liver oil, and the like. Also, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), etc., which are components of fish oil, may be used.

Examples of medium-chain fatty acid triglycerides include coconut oil, palm oil, “Panathate (registered trademark)” (NOF Corporation), and the like.

Examples of chemically synthesized triglycerides include 2-linoleoyl-1,3-dioctanoylglycerol (8L8) and 2-linoleoyl-1,3-didecanoylglycerol (10L10).

(Emulsifiers (except lysophosphatidylcholine))
The fat emulsion according to this embodiment contains an emulsifier other than lysophosphatidylcholine. As used herein, emulsifiers are meant to exclude lysophosphatidylcholine. In the fat emulsion according to the present embodiment, lysophosphatidylcholine is emulsified together with fats and oils and an emulsifier other than lysophosphatidylcholine. Thereby, in addition to the above effects, the hemolytic property of lysophosphatidylcholine can be significantly reduced.

As described above, lysophosphatidylcholine is reported to have many beneficial effects on the human body and is used in the food and cosmetic fields. However, due to its hemolytic properties (destruction of erythrocytes), it is extremely difficult to use it for nutritional infusions administered intravascularly. When significant hemolysis occurs in vivo, red blood cell deficiency can lead to anemia. However, emulsification of lysophosphatidylcholine with fats and emulsifiers other than lysophosphatidylcholine eliminates its hemolytic properties, and fat emulsions containing lysophosphatidylcholine can be administered safely.

The lipid emulsion according to this form is based on the "Basic Concept of Biological Safety Evaluation Required for Manufacturing and Marketing Approval Applications for Medical Devices" It can satisfy the attached "Biological Safety Test Method Guidance for Medical Devices" and its hemolysis rate is 2% or less. In a preferred embodiment, the fat emulsion has a hemolysis rate of 2% or less. As the hemolysis rate, a value calculated by the method described in Examples is used.

The emulsifier is not particularly limited as long as it is an emulsifier that can be used in fat emulsions. The emulsifier is preferably lecithin, more preferably egg yolk phospholipid, hydrogenated egg yolk phospholipid, soybean phospholipid, hydrogenated soybean phospholipid, phosphatidylcholine, phosphatidylethanolamine and It is at least one selected from phosphatidylglycerol.

Lecithin is a general term for lipids containing several types of phospholipids, and generally contains phosphatidylcholine as a main component. Lecithins include egg yolk lecithin, hydrogenated egg yolk lecithin, soybean lecithin, hydrogenated soybean lecithin and the like.

Lecithin may contain lysophosphatidylcholine in addition to phosphatidylethanolamine, sphingomyelin, triglyceride, cholesterol, etc., as components other than phosphatidylcholine.

Therefore, when the emulsifier is only lecithin containing lysophosphatidylcholine, the content of lysophosphatidylcholine and emulsifier in the fat emulsion is defined as follows:
When the content of lysophosphatidylcholine is Xg, the content of lecithin is Yg, and the content of lysophosphatidylcholine in lecithin is Zg,
Content of lysophosphatidylcholine in fat emulsion: (X + Z) g
Content of emulsifier in fat emulsion: (YZ) g.

(Content of oil, lysophosphatidylcholine and emulsifier)
The fat emulsion according to the present embodiment has a lysophosphatidylcholine content of 0.40 to 2.10 parts by mass and an emulsifier (excluding lysophosphatidylcholine) content of 0.40 to 2.10 parts by mass with respect to 10 parts by mass of fats and oils. 3.00 parts by mass.

If the content of lysophosphatidylcholine is less than 0.40 parts by mass or the content of the emulsifier is less than 0.40 parts by mass with respect to 10 parts by mass of fats and oils, the fat particles are stabilized when mixed with other nutritional infusions. It is not preferable because it lowers the performance. Moreover, when the content of lysophosphatidylcholine exceeds 2.10 parts by mass, the hemolysis rate of the fat emulsion may exceed 2% due to the presence of non-emulsified lysophosphatidylcholine. If the content of the emulsifier exceeds 3.00 parts by mass, the content of free fatty acids increases, which may cause fever, headache, hypercholesterolemia, etc., which is not preferable.

In one embodiment, the fat emulsion preferably has a lysophosphatidylcholine content of 0.40 to 2.10 parts by mass with respect to 10 parts by mass of oil, and The content of the emulsifier (excluding lysophosphatidylcholine) is 0.55 to 2.40 parts by mass, more preferably the content of lysophosphatidylcholine is 0.40 to 2.05 parts by mass, and the emulsifier (excluding lysophosphatidylcholine) is ) is 0.55 to 2.40 parts by mass.

In one embodiment, the fat emulsion preferably has a lysophosphatidylcholine content of 0.40 to 1.25 parts by mass with respect to 10 parts by mass of oil, and The content of the emulsifier (excluding lysophosphatidylcholine) is 0.40 to 3.00 parts by mass, more preferably the content of lysophosphatidylcholine is 0.40 to 1.25 parts by mass, and the emulsifier (excluding lysophosphatidylcholine) ) is 0.55 to 2.40 parts by mass.

The concentration of fats and oils contained in the fat emulsion according to the present embodiment is, for example, 2.0 to 20.0 w/v%, preferably 5.0 to 10.0 w/v%. In the lipid emulsion according to the present embodiment, since the average particle size of the fat particles contained therein can be reduced, it is possible to prevent pulmonary capillary embolism and the like.

(Average particle size of fat particles)
In the fat emulsion according to the present embodiment, the average particle size of fat particles is preferably 0.120 μm or less, more preferably 0.115 μm or less, in order to pass through an infusion filter with a pore size of 0.2 μm. It is preferably 0.100 μm or less. For the average particle size of fat particles, a value measured using a dynamic light scattering method is adopted.

(other ingredients)
The fat emulsion according to this embodiment can contain other ingredients, if necessary. Other ingredients are not particularly limited as long as they are ingredients that can be added to the fat emulsion, and include solvents, sugars, pH adjusters, and the like.

Examples of solvents include water (eg, distilled water for injection).

Examples of sugars include glucose (grape sugar), monosaccharides such as fructose, and disaccharides such as maltose.

The sugar concentration is 50 w/v % or less, preferably 5 to 30 w/v %.

Examples of pH modifiers include sodium hydroxide, hydrochloric acid, phosphoric acid, phosphates, citric acid, citrates, acetic acid, acetates, succinic acid, and the like.

In one embodiment, the fat emulsion further comprises solvent and sugar, preferably water and glucose.

(pH)
The pH of the fat emulsion according to this embodiment may be from 4.5 to 8.5. The pH of the fat emulsion can be adjusted using the above-mentioned pH adjuster, if necessary. The pH of the fat emulsion can be confirmed with a pH meter.

(Dose)
From the viewpoint of preventing essential fatty acid deficiency, the dose of the fat emulsion according to the present embodiment is preferably 2 g to 20 g/day in terms of fats and oils.

(Production method)
The fat emulsion according to the present embodiment can be produced, for example, by subjecting lysophosphatidylcholine to a mechanical dispersion treatment (emulsification) together with fats and oils and emulsifiers (excluding lysophosphatidylcholine). Machines used for mechanical dispersion include propeller stirrers, paddle mixers, homomixers with high-speed shearing force, high-pressure homogenizers, filmics, and the like.

Specifically, a dispersion of lysophosphatidylcholine, oil and emulsifier is prepared. After roughly emulsifying the prepared dispersion, the crude emulsion is emulsified by a high-pressure emulsification method to prepare a fat emulsion according to the present embodiment. If necessary, water (eg, distilled water for injection), other ingredients (eg, glucose), and the like may be added to the dispersion and crude emulsion.

Since the fat emulsion according to the present embodiment contains lysophosphatidylcholine, the average particle size of fat particles can be reduced with a small number of emulsifications.

The prepared fat emulsion is appropriately sterilized. Sterilization methods include, for example, filtration sterilization and autoclave sterilization.

<Nutritional infusion solution>
Another form of the present invention is a nutritional infusion containing the fat emulsion.

The nutritional infusion solution according to the present embodiment can contain an infusion solution containing at least one of amino acids, electrolytes, vitamins, and trace elements in addition to the fat emulsion. In the present specification, "infusion solution containing at least one of amino acids, electrolytes, vitamins and trace elements" is also simply referred to as "infusion solution according to this embodiment".

As described above, the fat emulsion according to the present invention can improve the stability of fat particles. Therefore, even if it is mixed with other nutritional infusions, aggregation of fat particles can be suppressed. Thereby, the nutritional infusion solution according to the present embodiment can be administered through an infusion filter with a pore size of 0.2 μm.

In the nutritional infusion solution according to this embodiment, the container for containing the lipid emulsion and the infusion solution according to this embodiment is not particularly limited, and may be a container having one chamber or a container having two or more chambers.

In a preferred embodiment, the nutritional infusion solution according to the present embodiment has two chambers separated by a partition wall that can be opened when used, one containing the lipid emulsion, and the other containing an amino acid, Contains an infusion solution containing at least one of electrolytes, vitamins and trace elements.

Gas-permeable plastics used in medical containers, such as polyethylene, polypropylene, polyvinyl chloride, cross-linked ethylene/vinyl acetate copolymer, ethylene/α-olefin copolymer, ethylene/vinyl alcohol Examples include flexible plastics such as copolymers, cyclic olefin resins, blends and laminates of these polymers.

In the case of a container having two or more chambers, the isolation walls between the chambers are opened in whole or in part by external pressure to allow communication between the chambers. Examples of the partition walls include those formed by easily peelable seals and those formed by sandwiching between chambers with clips.

FIG. 1 is a conceptual diagram showing a container having two chambers. A grid portion in FIG. 1 indicates a partition wall. Such a container can contain the lipid emulsion as the solution (A) and an infusion containing at least one of amino acids, electrolytes, vitamins and trace elements as the solution (B).

Filling and accommodation of lipid emulsions, infusions, etc. into containers can be carried out according to conventional methods. For example, a method of filling each liquid to be accommodated in an inert gas atmosphere, plugging, and heat sterilizing can be used.

The heat sterilization method can be performed by a known method, and examples thereof include high-pressure steam sterilization, hot water sterilization, and hot water shower sterilization. The operating conditions of the sterilization method, such as sterilization time, sterilization temperature, etc., can be the same as those of ordinary sterilization operating conditions of this kind. Furthermore, the heat sterilization can be performed in an inert gas atmosphere such as nitrogen, if necessary.

In addition, in order to reliably prevent deterioration of the nutrient infusion solution such as oxidation, the container can be packaged in an outer container that is substantially impermeable to oxygen together with the oxygen scavenger.

As the material of the outer container, films and sheets of various materials generally used can be used. For example, alumina deposition film, aluminum deposition film, laminated film having an aluminum foil layer, silica deposition film, polyethylene terephthalate, ethylene. - Vinyl alcohol polymer, polyvinyl alcohol, polyvinylidene chloride, polyethylene naphthalate, polyamide, polyacrylonitrile, polyester, or a multilayer film composed of a laminate having these resins as layer components. Furthermore, a film having a layer component having a light blocking effect such as an aluminum foil or a light shielding ink layer may be used.

The oxygen scavenger is not particularly limited, and for example, one containing an iron compound such as iron hydroxide, iron oxide or iron carbide as an active ingredient can be used. Commercially available products include Ageless (manufactured by Mitsubishi Gas Chemical Co., Ltd.), Modulan (manufactured by Nippon Kayaku Co., Ltd.), Secur (manufactured by Nippon Soda Co., Ltd.), and the like.

(infusion containing at least one of amino acids, electrolytes, vitamins and trace elements)
Examples of amino acids include various amino acids (essential amino acids and non-essential amino acids) conventionally contained in amino acid infusions for the purpose of providing nutrients to living bodies. Examples of amino acids include L-isoleucine, L-leucine, L-valine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, L-arginine, L-histidine, glycine, L- Alanine, L-proline, L-aspartic acid, L-serine, L-tyrosine, L-glutamic acid, L-cysteine, L-cystine and the like. These amino acids do not necessarily have to be used in the form of free amino acids, and inorganic acid salts (for example, L-lysine hydrochloride, L-lysine sulfite, L-cysteine hydrochloride (monohydrate), etc.), organic acid salts (e.g., L-lysine acetate, L-lysine malate, L-cysteine malate, etc.), in vivo hydrolyzable esters (e.g., L-tyrosine methyl ester, L-methionine methyl ester , L-methionine ethyl ester, etc.), N-substituted forms (eg, N-acetyl-L-tryptophan, N-acetyl-L-cysteine, N-acetyl-L-proline, etc.). Dipeptides in which homologous or heterologous amino acids are peptide-bonded (for example, L-tyrosyl-L-tyrosine, L-alanyl-L-tyrosine, L-arginyl-L-tyrosine, L-tyrosyl-L-arginine, etc.) It may be used in the form of

Examples of electrolytes include various aqueous salts conventionally used for infusions.

For example, electrolytes include inorganic components (sources of metal ions such as sodium, potassium, calcium, and magnesium; sources of anions such as phosphorus) that are required to maintain the functions of the body and the electrolyte balance of body fluids. are selected as appropriate from among these.

Among the electrolytes, phosphoric acid, its ester, or salts thereof are preferably used as the water-soluble salt of phosphorus, which is a phosphorus source.

Preferable examples of phosphate esters include phosphate esters of polyhydric alcohols and sugars. Phosphate esters of polyhydric alcohols include glycerophosphate, mannitol-1-phosphate and sorbitol-1-phosphate. Sugar phosphates include glucose-6-phosphate, fructose-6-phosphate and mannose-6-phosphate. As salts of these phosphates, alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as magnesium and calcium salts can be used, and alkali metal salts can be preferably used.

The salts of phosphoric acid include alkali metal dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate, and alkali metal hydrogen phosphates such as sodium hydrogen phosphate and potassium hydrogen phosphate.

Preferred specific examples of the metal ion supply source include the following.

Sodium Sources: Sodium Chloride, Sodium Lactate, Sodium Acetate, Sodium Sulfate, Sodium Glycerophosphate, Sodium Bicarbonate, Sodium Carbonate, Sodium Dihydrogen Phosphate, Disodium Hydrogen Phosphate, Sodium Citrate, Amino Acid Sodium Salts, Sodium Hydroxide ;
Potassium sources: potassium chloride, potassium glycerophosphate, potassium sulfate, potassium acetate, potassium lactate, potassium iodide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium citrate, amino acid potassium salts, potassium hydroxide;
Calcium Sources: Calcium Gluconate, Calcium Chloride, Calcium Glycerophosphate, Calcium Lactate, Calcium Pantothenate, Calcium Acetate;
Magnesium Sources: Magnesium Sulfate, Magnesium Chloride, Magnesium Glycerophosphate, Magnesium Acetate, Magnesium Lactate, Amino Acid Magnesium Salts.

The anion source can be supplied in the form of counter ions of metal ions in the metal ion source, or in the form contained in salts of amino acids, vitamins, and the like. It can also be supplied in the form of hydrochloric acid, phosphoric acid, etc., without being combined with a metal ion source, amino acid, or vitamin.

Vitamins include vitamin A, vitamin B1, vitamin B2, nicotinic acids, pantothenic acids, vitamin B6, biotin, folic acid, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, and the like. Moreover, these derivatives can be used.

Vitamin A and its derivatives include vitamin A1 (retinol), vitamin A2 (3-dehydroretinol), vitamin A3 (subvitamin A), retinene (vitamin A aldehyde), vitamin A acid, retinol palmitate, retinol acetate, and the like. mentioned.

Vitamin B1 and its derivatives include thiamine, prosultiamine, actothiamine, thiamine disulfide and fursultiamine and their salts (eg thiamine hydrochloride, thiamine nitrate) and the like.

Vitamin B2 and its derivatives include riboflavin, riboflavin phosphate, flavin mononucleotide and flavin adenine dinucleotide and hydrochloride salts thereof.

Nicotinic acids and derivatives thereof include niacin, nicotinic acid amide and salts thereof.

Pantothenic acids and derivatives thereof include pantothenic acid, panthenol and salts thereof (eg, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium), and the like.

Vitamin B6 and its derivatives include pyridoxine, pyridoxine phosphate, pyridoxal and pyridoxacine and their hydrochloride salts.

Biotin and derivatives thereof include salts thereof (eg, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium), and the like.

Examples of folic acid and derivatives thereof include salts thereof (eg, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium) and the like.

Vitamin B12 and its derivatives include cyanocobalamin, hydroxycobalamin, methylcobalamin, and the like.

Vitamin C and its derivatives include ascorbic acid, sodium ascorbate, ascorbyl palmitate, ascorbyl dipalmitate, ascorbyl phosphate magnesium salt, and the like.

Vitamin D and its derivatives include vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol), vitamin D4, provitamin D2 (ergosterin), provitamin D3 (dehydrocholesterin), and the like.

Vitamin E and its derivatives include α-tocopherol, tocopherol acetate, β-tocopherol, γ-tocopherol, δ-tocopherol and the like.

Vitamin K and its derivatives include vitamin K1 (phylloquinone, phytonadione), vitamin K2 (farnoquinone), vitamin K3 (menadione), vitamin K4, vitamin K5, vitamin K6, vitamin K7, and the like.

Trace elements are elements such as iron, zinc, copper, iodine, manganese, selenium, chlorine, molybdenum, etc., which are essential for living organisms, although they are present in trace amounts.

Iron sources include iron sulfate, ferrous chloride, ferric chloride, iron gluconate, and the like.

Zinc sources include zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, zinc acetate, and the like.

Copper sources include copper sulfate and the like.

Sources of manganese include manganese sulfate and the like.

Iodine and chlorine can be supplied in the form of counter ions of metal ions in the metal ion supply source described above, or in the form contained in salts of amino acids, vitamins, and the like. Alternatively, it can be supplied in the form of hydrochloric acid or the like without being combined with a metal ion source, amino acid, or vitamin.

The infusion solution according to this embodiment can further contain sugar.

Sugars include glucose (glucose), fructose, maltose, xylitol, sorbitol, glycerin and the like.

In one embodiment, the infusion solution according to this aspect contains amino acids, electrolytes, vitamins, trace elements and sugars. Specifically, the infusion solution according to this embodiment can contain the following components in 1000 mL of the infusion solution:
Amino acid 10-55g, vitamin C 25-130mg, vitamin A 1000-5000IU, vitamin D 2.5-15μg, vitamin E 5-20mg, vitamin K 0.5-3mg, sugar 50-500g, vitamin B1 1-50mg, calcium 3-15 mEq, phosphorus 1-20 mmol, zinc 0-30 μmol, magnesium 2-15 mEq, potassium 10-35 mEq, sodium 15-70 mEq, chlorine 0-80 mEq, iron 4-100 μmol, copper 0.5-40 μmol, manganese 1.0 ˜60 μmol and 0.3-1 μmol iodine.

An infusion solution containing at least one of amino acids, electrolytes, vitamins and trace elements preferably contains the following components in 1000 mL of infusion solution. The daily dosage of the infusion solution is 500-2500 mL, preferably 900-1500 mL.

The infusion solution according to this embodiment may contain solvents, pH adjusters, stabilizers, and the like, if necessary.

Examples of solvents include water (eg, distilled water for injection).

Examples of pH adjusters include sodium hydroxide, hydrochloric acid, phosphoric acid, phosphates, citric acid, citrates, and the like.

Examples of stabilizing agents include sulfites such as sodium bisulfite.

The pH of the infusion solution according to this embodiment may be 4.0 to 7.5. The pH of the infusion solution can be adjusted using the above-mentioned pH adjusters, if necessary. The pH of the infusion solution can be confirmed with a pH meter.

The infusion solution according to this embodiment can be produced according to a conventional method. For example, it can be produced by dissolving the above-mentioned infusion components in distilled water for injection.

Moreover, a commercially available product can be used as the infusion solution according to the present embodiment. Commercially available product names include "Elneopa NF (registered trademark)", "Tripalene (registered trademark)", "Aminotripa (registered trademark)", "Neopalene (registered trademark)", "Mixed (registered trademark)" (stock Company Otsuka Pharmaceutical Factory), “Onepal (registered trademark)”, “Rehabix (registered trademark)”, “PN Twin (registered trademark)” (AY Pharma Co., Ltd.), “Calonary (registered trademark)” (Fuso Pharmaceutical Industry Co., Ltd.) ), “Hycalic (registered trademark)” and “Fulcalic (registered trademark)” (Terumo Corporation).

The effects of the present invention will be described using the following examples and comparative examples. However, the technical scope of the present invention is not limited only to the following examples. Unless otherwise specified, "%" and "parts" mean "mass %" and "mass parts" respectively.

In the following examples and comparative examples, lecithin was used as an emulsifier in preparing fat emulsions. A lecithin containing 0.9% lysophosphatidylcholine was used.

In Tables 1, 4, 7, 11 and 14 below, the emulsifier and lysolecithin contents relative to 10 parts by mass of soybean oil in the fat emulsion were calculated as follows:
When the content of lysophosphatidylcholine is X parts by mass, the content of lecithin is Y parts by mass, and the content of lysophosphatidylcholine in lecithin is Z parts by mass,
Content of lysophosphatidylcholine in fat emulsion: (X+ Z ) parts by mass Content of emulsifier in fat emulsion: (YZ) parts by mass.

(Example 1)
36 g of lecithin, 18 g of lysophosphatidylcholine (lysolecithin), and 150 g of soybean oil were heated and stirred with a homogenizer (manufactured by Nippon Seiki Seisakusho Co., Ltd.) to form a dispersion. An aqueous solution in which 450 g of glucose was dissolved was added to the total amount of this dispersion liquid, and further water was added to make the total amount 1500 mL, and a crude emulsion was obtained with an Adihomomixer (manufactured by Powrex Co., Ltd.). The whole amount of this crude emulsified liquid was placed in a volumetric flask, an aqueous solution in which 450 g of glucose was dissolved was added, and further water was added to make up to 3000 mL. This liquid was emulsified by Starburst (manufactured by Sugino Machine Co., Ltd.) under a pressure of 245 MPa with 15 passes to prepare an emulsified liquid.

This emulsified liquid was sterile-filtered using a prefilter with a pore size of 0.45 μm and a membrane filter with a pore size of 0.22 μm. Next, the filtered emulsified liquid was filled in a container made of polypropylene, and after the container was sealed, nitrogen gas was introduced and autoclave sterilization was performed. Thus, Fat Emulsion 1 was produced.

(Example 2)
A fat emulsion 2 was produced in the same manner as in Example 1, except that the amount of lysophosphatidylcholine (lysolecithin) was changed from 18 g to 12 g.

(Example 3)
12 g of lecithin, 2 g of lysophosphatidylcholine (lysolecithin) and 50 g of soybean oil were heated and stirred with a homogenizer (manufactured by Nippon Seiki Seisakusho Co., Ltd.) to form a dispersion. An aqueous solution in which 150 g of glucose was dissolved was added to the total amount of this dispersion liquid, and further water was added to bring the total amount to 500 mL. The whole amount of this crude emulsified liquid was placed in a volumetric flask, an aqueous solution in which 150 g of glucose was dissolved was added, and further water was added to make up the volume to 1000 mL. This liquid was emulsified by Starburst (manufactured by Sugino Machine Co., Ltd.) under a pressure of 245 MPa with 20 passes to prepare an emulsified liquid.

This emulsified liquid was sterile-filtered using a membrane filter with a pore size of 0.22 μm. Next, the filtered emulsified liquid was filled in a container made of polypropylene, and after the container was sealed, nitrogen gas was introduced and autoclave sterilization was performed. Thus, a fat emulsion 3 was produced.

(Comparative example 1)
36 g of lecithin and 150 g of soybean oil were heated and stirred with a homogenizer (manufactured by Nippon Seiki Seisakusho Co., Ltd.) to form a dispersion liquid. An aqueous solution in which 450 g of glucose was dissolved was added to the total amount of this dispersion liquid, and further water was added to make the total amount 1500 mL, and a crude emulsion was obtained with an Adihomomixer (manufactured by Powrex Co., Ltd.). The whole amount of this crude emulsion was placed in a volumetric flask, an aqueous solution of 450 g of glucose dissolved therein was added, and water was further added to make up the volume to 3000 mL. This liquid was emulsified by Starburst (manufactured by Sugino Machine Co., Ltd.) under a pressure of 245 MPa with 20 passes to prepare an emulsified liquid.

This emulsified liquid was sterile-filtered using a prefilter with a pore size of 0.45 μm and a membrane filter with a pore size of 0.22 μm. Next, the filtered emulsified liquid was filled in a container made of polypropylene, and after the container was sealed, nitrogen gas was introduced and autoclave sterilization was performed. Thus, Comparative Fat Emulsion 1 was produced.

[Test Example 1]
Fat emulsions 1 to 3 and comparative lipid emulsion 1 120 mL (soybean oil content: 6 g) were each mixed with high calorie infusion 1 1500 mL listed in Table 3 to obtain nutritional infusions 1 to 3 and comparative nutritional infusion 1. prepared.

Table 1 shows the contents of glucose, emulsifier and lysolecithin with respect to 10 parts by mass of soybean oil for Fat Emulsions 1 to 3 and Comparative Fat Emulsion 1.

The filter passability of the prepared nutrient infusions 1 to 3 and comparative nutrient infusion 1 was measured using an infusion filter (cylindrical, membrane pore size 0.2 μm, manufactured by Terumo Corporation) and an infusion pump (manufactured by Terumo Corporation). confirmed. The results are shown in Table 2 below.

In nutritional infusions 1 to 3 and comparative nutritional infusion 1, the fat particles in each fat emulsion before mixing with the high-calorie infusion and the fat in each nutritional infusion after 24 hours of mixing the fat emulsion and the high-calorie infusion The average particle size of the particles was measured using Zetasizer Nano (manufactured by Malvern Panalytical). In addition, in the nutrient infusion 1 and the comparative nutrient infusion 1, the number of fat particles having a particle size of 1.5 μm or more after 24 hours and 72 hours after mixing the fat emulsion and the high-calorie infusion was measured using the HIAC light-shielding automatic It was measured using a particle measuring device (manufactured by Beckman Coulter). The results are shown in Table 2 below.

(Example 4)
12 g of lecithin, 4 g of lysophosphatidylcholine (lysolecithin) and 100 g of soybean oil were heated and stirred with a homogenizer (manufactured by Nippon Seiki Seisakusho Co., Ltd.) to form a dispersion. 400 mL of water was added to the total amount of this dispersion, and the total amount was roughly emulsified with a homogenizer (manufactured by Nippon Seiki Seisakusho Co., Ltd.). The whole amount of this crude emulsion was placed in a volumetric flask, and water was added to make up to 1000 mL. This liquid was emulsified by Starburst (manufactured by Sugino Machine Co., Ltd.) under a pressure of 245 MPa with 20 passes to prepare an emulsifier.

This emulsified liquid was sterile-filtered using a membrane filter with a pore size of 0.22 μm. Next, the filtered emulsified liquid was filled in a polypropylene container, sealed, nitrogen gas was introduced, and autoclave sterilization was performed. gone. Thus, a fat emulsion 4 was produced.

(Example 5)
Fat emulsion 5 was prepared in the same manner as in Example 4, except that the amount of lecithin was changed from 12 g to 8 g and the number of passes was changed from 20 to 25.

(Example 6)
In Example 3, lecithin was changed from 12 g to 6 g, lysophosphatidylcholine (lysolecithin) was changed from 2 g to 4 g, soybean oil was changed from 50 g to 100 g, and the number of passes was changed from 20 to 16. prepared a fat emulsion 6 by the same method as in Example 3.

[Test Example 2]
60 mL of fat emulsion 4 (soybean oil content: 6 g) was mixed with 1500 mL of high calorie infusion 2 listed in Table 6 to prepare nutritional infusion 4. Nutritional infusions 5 and 6 were prepared by mixing 20 mL of fat emulsions 5 and 6 (soya oil content: 2 g) with 1500 mL of high calorie infusion 2 listed in Table 6.

Table 4 shows the contents of glucose, emulsifier and lysolecithin with respect to 10 parts by mass of soybean oil for fat emulsions 4 to 6.

Filter passability of the prepared nutrient infusions 4 to 6 was confirmed using an infusion filter (cylindrical, membrane pore size 0.2 μm, manufactured by Terumo Corporation) and an infusion pump (manufactured by Terumo Corporation). The results are shown in Table 5 below.

In nutritional infusions 4 to 6, the average particle size of the fat particles in each fat emulsion before mixing with the high-calorie infusion and the fat particles in each nutritional infusion after 24 hours of mixing the fat emulsion and the high-calorie infusion , was measured using a Zetasizer Nano (manufactured by Malvern Panalytical). The results are shown in Table 5 below.

(Example 7)
24 g of lecithin, 12 g of lysophosphatidylcholine (lysolecithin) and 100 g of soybean oil were heated and stirred with a homogenizer (manufactured by Nippon Seiki Seisakusho Co., Ltd.) to form a dispersion. 400 mL of water was added to the total amount of this dispersion, and the total amount was roughly emulsified with a homogenizer (manufactured by Nippon Seiki Seisakusho Co., Ltd.). The whole amount of this crude emulsion was placed in a volumetric flask, and water was added to make up to 1000 mL. This liquid was emulsified by Starburst (manufactured by Sugino Machine Co., Ltd.) under a pressure of 245 MPa with 15 passes to prepare an emulsifier.

This emulsified liquid was sterile-filtered using a membrane filter with a pore size of 0.22 μm. Next, the filtered emulsified liquid was filled in a polypropylene container, sealed, and then nitrogen gas was introduced, followed by high-pressure steam sterilization. gone. Thus, a fat emulsion 7 was produced.

(Example 8)
48 g of lecithin, 24 g of lysophosphatidylcholine (lysolecithin), and 200 g of soybean oil were heated and stirred with a homogenizer (manufactured by Nippon Seiki Seisakusho Co., Ltd.) to form a dispersion. 400 mL of water was added to the total amount of this dispersion, and the total amount was roughly emulsified with a homogenizer (manufactured by Nippon Seiki Seisakusho Co., Ltd.). The whole amount of this crude emulsion was placed in a volumetric flask, and water was added to make up the volume to 2000 mL. This liquid was emulsified by Starburst (manufactured by Sugino Machine Co., Ltd.) under a pressure of 245 MPa with 15 passes to prepare an emulsifier.

This emulsified liquid was sterile-filtered using a membrane filter with a pore size of 0.22 μm. Next, the filtered emulsified liquid was filled in a polypropylene container, sealed, and then nitrogen gas was introduced, followed by high-pressure steam sterilization. gone. Thus, a fat emulsion 8 was produced.

(Example 9)
Fat emulsion 9 was produced in the same manner as in Example 7, except that the amount of lecithin was changed from 24 g to 12 g.

(Example 10)
A fat emulsion 10 was produced in the same manner as in Example 3, except that the amount of lysophosphatidylcholine (lysolecithin) was changed from 2 g to 10 g.

[Test Example 3]
60 mL of fat emulsion 7-9 (soybean oil content: 6 g) was mixed with 1500 mL of high calorie infusion 1 listed in Table 3, respectively, to prepare nutritional infusions 7-9. 120 mL of fat emulsion 10 (soybean oil content: 6 g) was mixed with 1500 mL of high calorie infusion 1 listed in Table 3 to prepare nutritional infusion 10. Also, 60 mL of fat emulsion 8 was mixed with 1500 mL of high calorie infusion 2 listed in Table 6 to prepare nutritional infusion 11.

Table 7 shows the contents of glucose, emulsifier and lysolecithin with respect to 10 parts by mass of soybean oil for fat emulsions 7 to 10.

Filter passability of the prepared nutrient infusions 7 to 11 was confirmed by gravity using an infusion filter (cylindrical, membrane pore size 0.2 μm, manufactured by Terumo Corporation). The results are shown in Tables 8 and 9 below.

In nutritional infusions 7 to 11, the average particle size of the fat particles in each fat emulsion before mixing with the high-calorie infusion and the fat particles in each nutritional infusion after 24 hours of mixing the fat emulsion and the high-calorie infusion , was measured using a Zetasizer Nano (manufactured by Malvern Panalytical). In the nutrient infusion solution 7, the number of fat particles having a particle size of 1.5 μm or more after 24 hours of mixing the fat emulsion and the high-calorie infusion solution was measured using a HIAC light-shielding automatic particle analyzer (manufactured by Beckman Coulter). was measured using The results are shown in Tables 8 and 9 below.

[Test Example 4]
100 mL of fat emulsion 8 (soya oil content: 10 g) was mixed with 1500 mL of high calorie infusion 2 listed in Table 6 to prepare nutritional infusion 12.

Filter passability of the prepared nutrient infusion solution 12 was confirmed by gravity using an infusion filter (cylindrical, membrane pore size 0.2 μm, manufactured by Terumo Corporation). The results are shown in Table 10 below.

In the nutritional infusion solution 12, the average particle size of the fat particles in the fat emulsion before mixing with the high-calorie infusion solution and the fat particles in the nutritional infusion solution after 24 hours of mixing the fat emulsion and the high-calorie infusion solution were measured by Zetasizer Nano. (manufactured by Malvern Panalytical). The results are shown in Table 10 below.

(Discussion)
As shown in Table 2, nutritional infusions 1 to 3 containing a predetermined amount of lysophosphatidylcholine (lysolecithin) all passed through the infusion filter, but comparative nutritional infusion 1 that did not contain a predetermined amount of lysophosphatidylcholine (lysolecithin) , the infusion filter was clogged and blocked, and the entire volume did not pass. Without a predetermined amount of lysophosphatidylcholine (lysolecithin), metal ions, electrolytes, amino acids, etc. in high-calorie infusions are thought to cause aggregation of fat particles. As a result, an increase in the particle size of fat particles and the formation of coarse particles occur, which is considered to be a cause of clogging of the infusion filter.

Fat emulsion 1 was produced by performing emulsification 15 times, and the average particle size of the fat particles was 58 nm. Comparative fat emulsion 1 was prepared by emulsifying 20 passes, and the average particle size of the fat particles was 70 nm. Therefore, it can be seen that when a predetermined amount of lysophosphatidylcholine (lysolecithin) is used, the average particle size of fat particles can be reduced with a smaller number of emulsifications (Table 1).

Fat emulsion 4 was prepared by emulsifying 20 passes, and the average particle size of the fat particles was 100 nm. Fat emulsion 5 was produced by performing emulsification 25 times, and the average particle size of the fat particles was 113 nm. Therefore, it can be seen that the larger the amount of emulsifier, the smaller the average particle size of the fat particles can be achieved with fewer emulsifications (Table 4).

Fat emulsion 6 was prepared by performing emulsification with 16 passes, and the average particle size of the fat particles was 112 nm. Compared with fat emulsion 5, it can be seen that the average particle size of fat particles can be reduced with a smaller number of emulsifications even when glucose is used (Table 4).

Fat emulsions 7-9 contain almost twice the concentration of soybean oil, emulsifier and lysophosphatidylcholine (lysolecithin), without glucose, compared to fat emulsions 1-3. As shown in Table 8, even nutritional infusions 7 to 9 using fat emulsions 7 to 9 all passed through the infusion filter.

(Comparative example 2)
A comparative fat emulsion 2 was produced in the same manner as in Comparative Example 1, except that the amount of lecithin was changed from 36 g to 72 g and the number of passes was changed from 20 to 16.

[Test Example 5]
Animal experiments were performed using comparative fat emulsions 1 and 2. Seven-week-old male SD rats (Charles River Laboratories Japan, Inc.) were used as animals. A catheter was placed in the external jugular vein, and comparative lipid emulsion 1 or 2 was administered continuously for 14 days without restraint (n=6-7). The fat dose was adjusted to 1.4 g/kg body weight/day, and the total calorie dose was adjusted to 207 kcal/kg body weight/day. On the first day of administration, the amount of fat administered and the amount of total calories administered were halved. As a control, Intralipos Infusion 10% (manufactured by Otsuka Pharmaceutical Factory Co., Ltd.) was used.

Table 11 shows the contents of glucose, emulsifier and lysolecithin with respect to 10 parts by mass of soybean oil for Comparative Fat Emulsions 1 and 2 and Intralipos Infusion 10%.

Comparative lipid emulsion 1, comparative lipid emulsion 2, or 10% intralipos infusion was administered from the side tube of high-calorie infusion 2 without passing through an infusion filter. After 14 days of administration, blood was collected from the abdominal aorta and serum was separated. Concentration results for serum components (free cholesterol, phospholipids, free fatty acids and triglycerides) and fatty acid fraction (eicosatrienoic acid/arachidonic acid [T/T ratio]) are shown in Table 12 below.

The average particle size of fat particles in Comparative Fat Emulsion 2 and Intralipos Infusion 10% was measured using Zetasizer Nano (manufactured by Malvern Panalytical).

(Discussion)
The mass ratio of the emulsifiers contained in Comparative Fat Emulsion 1, Comparative Fat Emulsion 2 and Intralipos Infusion 10% is about 2:4:1 with equal weight of soybean oil (Table 11). As shown in Table 12, the amounts of free cholesterol, phospholipids and free fatty acids are significantly high when Comparative Fat Emulsion 2, which contains the largest amount of emulsifier, is used (Tukey test). In Comparative Fat Emulsion 1, which has half the amount of emulsifier than in Comparative Fat Emulsion 2, these increases in these amounts are not seen and are believed to be due to the amount of emulsifier. When Comparative Fat Emulsion 2 was used, an excessive amount of the emulsifier was added to the soybean oil, and therefore there was lecithin that was not emulsified, which caused an increase in serum components.

The T/T ratio is an indicator of essential fatty acid deficiency. As shown in Table 12, comparative nutritional infusions 2 to 4 had low T/T ratios, indicating that the rats were not deficient in essential fatty acids and sufficient fatty acids were administered to the rats.

[Test Example 6]
A test solution 1 was prepared by putting 25 mg of lecithin and 50 mL of physiological saline into a test tube and mixing well by inversion.

50 mg of lysophosphatidylcholine (lysolecithin) and 50 mL of physiological saline were placed in a test tube and mixed well by inversion to prepare a 0.1% lysophosphatidylcholine (lysolecithin) solution. A 0.1% lysophosphatidylcholine (lysolecithin) solution was diluted 2-fold, 20-fold, and 200-fold with physiological saline, and well mixed by inversion to prepare test solution 2, test solution 3, and test solution 4.

Each of the fat emulsions 1 to 3 was diluted 12-fold with physiological saline to prepare test solutions 5, 6 and 7. Test solution 8 was prepared by diluting 10% intralipos infusion solution 24-fold with physiological saline.

12 mL of 0.1% lysophosphatidylcholine (lysolecithin) solution was added to 1 mL of Intralipos infusion 10%, and physiological saline was added to make 24 mL, and the mixture was inverted 1-2 times to prepare test solution 9. A test solution 10 was prepared by diluting the comparative fat emulsion 1 12-fold with physiological saline. To 2 mL of Comparative Fat Emulsion 1, 12 mL of 0.1% lysophosphatidylcholine (lysolecithin) solution was added, and physiological saline was added to make 24 mL.

4 mL of each of the prepared test solutions 1 to 11 and 80 μL of defibrinated rabbit blood were mixed and incubated at 37° C. for 1 hour. After that, it was centrifuged at 750×g for 5 minutes and the supernatant was collected. The collected supernatant was centrifuged at 5000×g for 20 minutes using Amicon (registered trademark) Ultra-15 (100K) (manufactured by Merck), and the absorbance at 576 nm was measured. The hemolysis rate (%) was calculated using the following formula. The results are shown in Table 13 below.

(Discussion)
As shown in Table 13, the hemolytic activity of lysophosphatidylcholine (lysolecithin) alone depends on its concentration, and non-hemolytic activity does not occur unless it is diluted to a concentration of 0.0005% (test solution 4).

Test solution 2 containing 0.05 w/v % lysophosphatidylcholine (lysolecithin) showed 92.3% hemolysis, whereas 0.05 w/v % lysophosphatidylcholine (lysolecithin) and 0.1 w/v % of lecithin was non-hemolytic due to emulsification.

On the other hand, test solution 9 (0.05 w/v% lysophosphatidylcholine (lysolecithin) added), which is a mixed solution of 10% Intralipos infusion and lysophosphatidylcholine (lysolecithin), had a hemolysis rate of 72.6%. . Further, Test Example 11 (0.05 w/v% lysophosphatidylcholine (lysolecithin) was added), which is a liquid mixture of comparative fat emulsion 1 and lysophosphatidylcholine (lysolecithin), had a hemolysis rate of 100%.

From the above, it can be seen that the hemolytic property of lysoletin is not improved simply by mixing lysophosphatidylcholine (lysolecithin) with a fat emulsion containing no lysolecithin. However, by emulsifying lysophosphatidylcholine (lysolecithin) together with oils and fats and emulsifiers (excluding lysolecithin), the hemolysis rate of the fat emulsion can be reduced to 2% or less (non-hemolytic).

[Test Example 7]
Animal experiments were conducted using lipid emulsions 1 and 2. Seven-week-old male SD rats (Charles River Laboratories Japan, Inc.) were used as animals. A catheter was placed in the external jugular vein, and administration was continued for 14 days without restraint (n=8). The fat dose was adjusted to 2.0 g/kg body weight/day, and the total amount of calories administered was adjusted to 302 kcal/kg body weight/day. On the first day of administration, the amount of fat administered and the amount of total calories administered were halved. As a control, Intralipos Infusion 20% (manufactured by Otsuka Pharmaceutical Factory Co., Ltd.) was used.

Table 14 shows the contents of glucose, emulsifier and lysolecithin with respect to 10 parts by mass of soybean oil for Fat Emulsions 1 and 2 and Intralipos Infusion 20%.

120 mL of fat emulsions 1 and 2 (soybean oil content: 6 g) were mixed with 1430 mL of high calorie infusion 1 to prepare nutritional infusions 13 and 14, respectively. Nutrient infusion solution 13 or 14 was administered through an infusion filter (cylindrical, membrane pore size 0.2 μm, manufactured by Terumo Corporation). Intralipos infusion 20% did not pass through the infusion filter, so it was administered from the side tube of high-calorie infusion 1 without passing through the infusion filter. After 14 days of administration, blood was collected from the abdominal aorta and serum was separated. Concentration results of serum components (total bilirubin, LDH and potassium) are shown in Table 15 below.

The average particle size of fat particles in Intralipos Infusion 20% was measured using Zetasizer Nano (manufactured by Malvern Panalytical).

As shown in Table 15, in nutritional infusions 13 and 14, the values of total bilirubin, LDH, and potassium, which are indicators of hemolysis, are not significantly different from comparative nutritional infusion 5, which does not contain a hemolytic component. is known (Tukey test). Therefore, it can be seen that fat emulsions 1 and 2 do not exhibit hemolysis.

Therefore, the fat emulsions of Examples contain lysophosphatidylcholine (lysolecithin) in an amount exhibiting hemolysis when used alone, but are emulsified so that they can be used both in vitro (Test Example 6) and in vivo (Test Example 7). ) does not exhibit hemolysis.

Claims (6)

Contains fats, lysophosphatidylcholine and emulsifiers (except lysophosphatidylcholine),
A fat emulsion, wherein the content of the lysophosphatidylcholine is 0.40 to 2.10 parts by mass and the content of the emulsifier is 0.40 to 3.00 parts by mass with respect to 10 parts by mass of the oil. 2. The emulsifier according to claim 1, wherein the emulsifier is at least one selected from the group consisting of egg yolk phospholipids, hydrogenated egg yolk phospholipids, soybean phospholipids, hydrogenated soybean phospholipids, phosphatidylcholine, phosphatidylethanolamine and phosphatidylglycerol. fat emulsion. 3. The fat emulsion according to claim 1 or 2, wherein said oil is at least one selected from the group consisting of vegetable oil, fish oil, medium-chain fatty acid triglycerides and chemically synthesized triglycerides. The fat emulsion according to any one of claims 1 to 3, which has a hemolysis rate of 2% or less. A nutritional infusion containing the lipid emulsion according to any one of claims 1 to 4. It has two rooms separated by an isolation wall that can be opened when used,
One chamber accommodates the fat emulsion according to any one of claims 1 to 4,
6. The nutritional infusion solution according to claim 5, wherein the other compartment contains an infusion solution containing at least one of amino acids, electrolytes, vitamins and trace elements.

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