JP3132085B2 - Fat emulsion - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a fat emulsion useful as a nutritional infusion, particularly as an intravenous nutritional infusion in a disease state.

[0002]

2. Description of the Related Art In general, fat emulsion infusion is used to administer high calories in a short period of time, suppress decomposition of body proteins, and improve nitrogen balance. By the way, the fat conventionally used as the infusion is derived from soybean oil, safflower oil and the like, and its main component is long-chain fatty acid triglyceride (hereinafter referred to as LCT). However, this LCT has disadvantages such as slow metabolism and insufficient utilization of living organisms. This disadvantage is significant, especially during disease states. Therefore, a fat emulsion infusion in which a medium-chain fatty acid triglyceride (hereinafter, referred to as MCT) which has a fast absorption and a good metabolism is mixed with the LCT is being developed.

[0003]

However, the MCT is LC
It is more toxic than T and has the drawback that when administered in large amounts, it causes side effects associated with its rapid absorption and metabolism and a deficiency of essential fatty acids. For this reason, MCT / LC
In the case of the T-mixed emulsion, a detailed study of the composition, blending ratio and the like of MCT is required. Accordingly, an object of the present invention is to provide a nutritional infusion that improves the formulation disadvantages and enhances safety that are found in conventional nutritional infusions, and that is extremely metabolizable during disease states, particularly an intravenous nutritional infusion. It is in.

[0004]

An object of the present invention is to provide a fat emulsion containing MCT and LCT as main components, wherein the MCT-constituting fatty acid has substantially only 8 to 10 carbon atoms. Is approximately 1 to 1 (weight ratio).

[0005] In the present invention, the LCT is one having 1 carbon atom.
6-18 saturated or unsaturated fatty acid triglycerides are exemplified as suitable. LCT contains the LCT as a main component, for example, 95% of the LCT.
It may be used as a vegetable oil containing (by weight) or more, preferably 99% or more (for example, cottonseed oil, soybean oil, corn oil, peanut oil, safflower oil, etc.). Preferred LCTs include soybean oil. As the soybean oil, high-purity refined soybean oil is suitably used, and more preferably, high-purity refined soybean oil (purity: 99.9% or more as triglyceride) obtained by further refining refined soybean oil, for example, by steam distillation. Is used. Fatty acids constituting LCT include, for example, palmitic acid, stearic acid, linoleic acid, linolenic acid, oleic acid and the like.

On the other hand, as the MCT, a triglyceride composed of a saturated fatty acid having 8 to 10 carbon atoms, for example, caprylic acid or capric acid is used. In the present invention, the MCT substantially consists of only the MCT having 8 to 10 carbon atoms. Here, “substantially” means that MCT having a carbon number other than 8 to 10 may be contained in such an amount as not to impair the object of the present invention.

MCTs having 8 to 10 carbon atoms can be produced by a method known per se, for example, by synthesis from glycerol,
It can be obtained by an appropriate means such as partial esterification, transesterification using an enzyme, or fractionation of a fat or oil having a high content. For example, it can be obtained by hydrolysis of cocoa butter or palm fat, fractionation of fatty acids by distillation and re-eswelling with glycerol. They are 80-90%
C ₁₀ fatty acids may be extracted from Cuphea species, including. These triglycerides need not necessarily be of high purity,
Suitable are those containing, for example, at least 90% (by weight), preferably at least 95% (by weight) as a main component.

In the present invention, the composition ratio of MCT and LCT is preferably about 1: 1 (weight ratio).

The fat emulsion of the present invention is prepared from the above-mentioned medium- and long-chain fatty acid triglycerides, an emulsifier, water and appropriate additives by a conventional method. Examples of the emulsifier include phospholipids (egg yolk phospholipids, soybean phospholipids, etc.), nonionic surfactants, and the like. Any emulsifier may be used as long as it is purified for medical use. As the phospholipid, purified phospholipids such as egg yolk lecithin and soybean lecithin are suitable, and can be prepared by a conventional fractionation method using an organic solvent. It is mainly composed of phosphatidylcholine and phosphatidylethanolamine, and also contains other phospholipids such as phosphatidylinositol, phosphatidylserine, sphingomyelin and the like. Phospholipids that do not contain phosphatidylethanolamine may be used. This product can be obtained by subjecting generally available phospholipids such as egg yolk and soybeans to an organic solvent fractionation by a conventional method, and then purifying with an inorganic absorbent such as silica gel or alumina.
The phospholipid thus obtained is mainly composed of phosphatidylcholine, and may contain phosphatidylinositol, phosphatidylserine and sphingomyelin as other phospholipids. Further, phosphatidylcholine itself may be used. The water may be any water suitable for intravenous injection (for example, distilled water for injection, purified water for injection, etc.).

The content of each component of the fat emulsion according to the present invention is, for example, from 1 to 50 for an oil component (triglyceride).
% (W / v), preferably 5 to 50% (w / v), 1 to 500 parts of an emulsifier with respect to 100 parts of an oil component (preferably,
1 to 50 parts) and an appropriate amount of water.

In addition, if necessary, further emulsifying aids (for example, C6 to C2 in an amount of up to 0.3% (w / v)).
2, preferably 12 to 20 fatty acids or pharmacologically acceptable salts thereof], stabilizer [for example, 0.5% (w
/ V) or less, preferably 0.1% (w / v) or less of cholesterol, or 5% (w / v) or less, preferably 1% (w / v) or less of phosphatidic acid, etc.] ,
Polymeric substances [for example, 0.1 to 5% (w / v), preferably 0.5 to 1% (w / v) of albumin, dextran, vinyl polymer, nonionic surfactant, gelatin,
Hydroxyethyl starch and the like], glycerin, glucose and the like can also be added.

As the emulsifying aid, any fatty acid having 6 to 22 carbon atoms can be used as long as it can be added to pharmaceuticals. This fatty acid may be linear or branched, but may be linear stearic acid, oleic acid, linoleic acid,
It is preferable to use palmitic acid, linolenic acid, myristic acid and the like. As these salts, physiologically acceptable salts, for example, alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, magnesium salt, etc.) can be used.

Furthermore, an aliphatic amine may be used as an emulsifying aid. Specifically, those having 2 to 22 carbon atoms are exemplified. Any of these aliphatic amines can be used as long as they can be added to pharmaceuticals. This aliphatic amine is linear,
It may be branched, but it is preferable to use linear ethylamine, propylamine, octylamine, stearylamine, oleylamine and the like. The addition amount is, for example, about 0.0001 to 0.01% (w / v). When the emulsification is insufficient, various known emulsification aids can be further used.

Any stabilizer can be used as long as it can be used as a pharmaceutical.

The following are preferred as the albumin, vinyl polymer and nonionic surfactant used as the polymer substance according to the present invention. That is, as the albumin, a human-derived one is preferable from the problem of antigenicity.
Examples of the vinyl polymer include polyvinylpyrrolidone. As the nonionic surfactant, polyalkylene glycol (for example, having an average molecular weight of 1,000 to 1)
0,000, preferably 4,000 to 6,000 polyethylene glycol), polyoxyalkylene copolymer (for example, polyoxyethylene-polyoxypropylene copolymer having an average molecular weight of 1,000 to 20,000, preferably 6,000 to 10,000), hydrogenated castor oil polyoxy Alkylene derivatives [eg, hydrogenated castor oil polyoxyethylene- (20) -ether,-(40) -ether,-(100) -ether, etc.), castor oil polyoxyalkylene derivatives [eg, castor oil polyoxyethylene -(20) -ether,-(40) -ether,-(100) -ether, etc.] and the like.

The fat emulsion of the present invention is produced, for example, by the following method. First, a predetermined amount of an oil component (for example, soybean oil and MCT having 8 to 10 carbon atoms ), an emulsifier (preferably phospholipid) and other additives described above are mixed and heated to form a solution, and a conventional homogenizer is used. The mixture is then homogenized, and water containing a necessary amount of an isotonic agent, a stabilizer and the like is added thereto, and the mixture is homogenized again by a homogenizer or ultrasonic treatment to obtain an oil-in-water emulsion. Depending on the production convenience, additives such as a stabilizer and a tonicity agent may be added after the formation of the fat emulsion.

The fat emulsion thus obtained is very fine, and the fat particles have an average particle size of about 0.05 to 0.5.
It is about μm.

The fat emulsion of the present invention may optionally contain other known additives (animal and vegetable fats and oils, stabilizers, etc.) and nutrient infusion components such as sugars, amino acids, vitamins and electrolytes.

The fat emulsion of the present invention and its contents include, for example, liver dysfunction, surgical diseases (including burns, burns, and trauma), post-operative recovery, sepsis, surgical invasion, and reduction of carnitine at the cellular level. For nutritional calorie supplementation, such as nutritional infusions, conditions that impose a burden on the oxidation process of long-chain fatty acids, diabetes, liver cirrhosis, other conditions with reduced tolerance to fat, and other metabolic functions .

The fat emulsion of the present invention is 10% w / v per day and 100 to 100% as a fat emulsion depending on the condition of the patient.
About 1000 ml (10 to 100 g as fat and oil, 90 to 900 cal as calories) is usually administered by intravenous administration (intravenous drip).

[0021]

Industrial Applicability The fat emulsion of the present invention is a superior energy substrate as compared with conventional nutritional infusions, has a rapid metabolism in the body, and has safety. It is extremely useful as a nutritional infusion for intravenous injection.

[0022]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

Example 1 [Raw materials] MCT; MCT was 77% caprylic acid and 2% capric acid.
It is a fat that is randomly esterified with glycerin at a rate of 3%. It is a colorless to slightly yellow transparent liquid. The solubility in water is 60 mg / dl, the freezing point is -14 ° C, and the calorie is 8.3 kcal / g. [Composition] Consist of 50 g of MCT, 50 g of soybean oil, 12 g of egg yolk phospholipid, 22.1 g of glycerin and an appropriate amount of water for injection, and the total amount is 1 L. After blending the above raw materials and lightly emulsifying with a homomixer by a conventional method, a high-pressure homogenizer (20
(0 to 250 kg / cm ² ), and homogenized so that the emulsified particle diameter becomes about 0.2 μm.
3).

Experimental Example 1 (toxicity) (1) Fat emulsion [MCT / LCT] prepared in Example 1 using 200 to 250 g of male Wistar rats
(1: 1) emulsion] and a fat emulsion having each composition shown in Table 1 were intravenously administered, and toxicity was examined. Table 1 shows the respective LD ₅₀ values. C ₈ emulsion is highly toxic, LD
_{The 50} value was 20 ml / kg. On the other hand, toxicity to C ₁₀ emulsion is maintained at toxic LCT emulsion, it could be administered 100 ml / kg or more. As a result, a mixed MC of C ₈ and C ₁₀
At T, the toxicity tends to decrease, and the LD ₅₀ value is 30.
ml / kg was LD ₅₀ value. However, it was determined that the MCT single emulsion was still too toxic for clinical use. Therefore, the MCT and LCT 1: was administered mixed emulsion at 1, significantly weakens toxic, 8 g / kg is the LD ₅₀ value as MCT, could be prepared less toxic emulsion.

[0025]

[Table 1]

(2) MC commercially available in Germany
To compare the toxicity with the T-containing fat emulsion in detail, a Wistar male rat of 200 to 250 g was intravenously administered with a 10% MCT fat emulsion having the composition shown in Table 2, and the toxicity was examined. Table 3 shows the results. Conventional MCT
Of the present invention, the MCT substantially consisting of C ₈ and C ₁₀
Was significantly less toxic.

[0027]

[Table 2]

[0028]

[Table 3]

Experimental Example 2 (rat cecal ligation peritonitis model
Examination of MCT / LCT Mixing Ratio) Using 200 to 250 g of male Wistar rats, the cecum was excised 12 hours after ligation of the cecum. Emulsions to be tested include MCT single emulsion, MCT / LCT (3:
1) Emulsion, MCT / LCT (1: 1) emulsion, MCT / L
A CT (1: 3) emulsion and an LCT single emulsion were used. An infusion containing each fat emulsion was administered for 3 days by a catheter inserted into the central vein. Calorie administration: 150 Kcal / kg / day Fat / non-protein calories: 50% Non-protein calories / nitrogen ratio: 95

FIG. 1 shows the cumulative nitrogen balance of each fat emulsion for three days after administration. From the results shown in FIG. 1, MCT / L
It can be seen that the administration of the CT (1: 1) emulsion has the least decrease in nitrogen balance.

[Brief description of the drawings]

FIG. 1 shows the cumulative nitrogen balance for three days of administration of each fat emulsion.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Shunichi Abe 2-25-1, Invitation Otani, Hirakata City, Osaka Prefecture Inside the Midori Cross Research Institute, Inc. (72) Inventor Shinichi Sakabe 2-25-2, Invitation Otani, Hirakata City, Osaka Prefecture No. 1 Inside Midori Cross Research Laboratory Co., Ltd. (56) References JP-A-58-41825 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 9/107, 47/14, 31/23

Claims (2)

(57) [Claims] 1. A fat emulsion comprising a medium-chain triglyceride and a long-chain triglyceride as main components,
Medium-chain triglycerides are combined with caprylic acid and capric acid.
A fat emulsion characterized by being a mixed medium-chain fatty acid triglyceride . 2. The fat emulsion according to claim 1, wherein the composition ratio of the medium-chain fatty acid triglyceride to the long-chain fatty acid triglyceride is approximately 1 to 1 (weight ratio).