KR101672347B1

KR101672347B1 - Infusion preparation

Info

Publication number: KR101672347B1
Application number: KR1020160033024A
Authority: KR
Inventors: 노정열; 김재민; 정지현
Original assignee: 제이더블유생명과학 주식회사
Priority date: 2016-03-18
Filing date: 2016-03-18
Publication date: 2016-11-04

Abstract

The present invention relates to an infusion preparation accommodated in three separated chambers connected and divided to be mixed in use. The preparation comprises: a first chamber liquid including sugar accommodated in a first chamber; a second chamber liquid including amino acid and electrolyte accommodated in a second chamber; and a third chamber liquid including fat emulsion and lecithin accommodated in a third chamber, wherein the fat emulsion comprises fish oil, and the third chamber liquid comprises 35,000-45,000 mg/L of fish oil, and 11,990-15,000 mg/L of lecithin.

Description

INFUSION PREPARATION [0002]

The present invention is directed to a liquid formulation comprising three voids separated by a communicable compartment for use in use.

A liquid preparation containing a sugar, an amino acid, and an electrolyte contained in a liquid bag having two or more chambers is widely used for various purposes such as nutritional management of a patient. Particularly, lipids such as fish oil, olive oil, soybean oil and heavy chain triglyceride oil are widely used in such a liquid preparation (David F. Driscoll, International Journal of Pharmaceutics 379 (2009) 125-130), and these lipids are highly unsaturated fatty acids (Omega-3), eicosapentanoic acid (EPA, C20: 5) and docosahexaenoic acid (DHA, C22: 6) Because it contains.

However, when lipids, especially lipids having a high concentration of long chain fatty acids such as fish oil, are included in the liquid composition, the oil droplet size tends to increase. This is because, when lipids are combined with fish oil, lipophilic components, emulsifiers and hydrophilic components in the lipid chamber to form a micelle structure, micelle size is increased due to a fatty acid having a high carbon number, which is a lipophilic component. When the size of the oil droplet is increased, large particles may block blood vessels and cause embolism-like tendency and other blood circulation disorders may occur.

Specifically, when the three chambers are divided, the size of the emulsion is influenced only by the lecithin and the like in the lipid chamber. In the case where the three liquids of the disappearance are mixed, the emulsion is much more It is increased under the influence of the chemical liquid components. Therefore, it is very difficult to control the content of each component and the content of each component so that the size of the ruins can be appropriately maintained, because the size of the ruins may be affected by the component of the chemical solution stored in each chamber and the minute content of each component to be.

In this regard, according to the test standard PFAT5 (percentage of fat globules with a diameter of > 5 mu m), which is a criterion for evaluating the size of the oil droplet, the oil droplet particle diameter is 5 mu m or more Should be less than 0.05%. Indeed, hepatic histologic deformation was observed in the guinea pig model with TPN of 0.4% or more of PFAT5, and rat model in which TPN of 0.1% or more of PFAT5 was administered resulted in common pathologies in liver and lung, The PFAT5 test standard is closely related to the safety of the product. Thus, a liquid formulation containing fish oil may have safety problems associated with the size of the oil droplet.

On the other hand, a high voltage current measurement method is used to check the leakage of the liquid preparation in the form of a liquid bag. This is a method of measuring the resistance value and the impedance by flowing a high voltage (about 14,000 Volt) from the upper part of the bag to the lower part. If there is no leakage, the current flows along the outer periphery of the bag, and the current flows remotely. If there is leakage, the current flows through the bag and flows through the straight line. In the case of a liquid bag having two or more chambers, a leakage teat for each discrete loss is required. However, current measurement may not be possible at all depending on the composition of the liquid contained in each chamber. As described above, with respect to the disappearance of a composition having a composition which can not be subjected to the leakage test according to the high-voltage current measurement method, only leak inspection through visual confirmation is possible, and this method has a problem of inefficiency and inaccuracy.

David F. Driscoll, International Journal of Pharmaceutics 379 (2009) 125-130

The present invention has high safety by minimizing the oil droplet size of lipid emulsions, particularly fish oil having a concentration of 35,000 mg / L or more, and the leakage measurement by current measurement for each disappearance It is aimed to develop a possible liquid preparation.

In order to solve the above problems, the present invention provides a liquid preparation comprising three fines separated by a communicable compartment to be mixed at the time of use, the liquid preparation comprising: a first feces containing a first elimination solution containing sugar; A second chamber in which a second elimination liquid containing an amino acid and an electrolyte is accommodated; And a third disappearance containing a third disappearance liquid comprising a fat emulsion and lecithin, wherein the fat emulsion comprises fish oil, and the third insoluble liquid comprises 35,000 to 45,000 mg of fish oil / L, and lecithin 11,990 to 15,000 mg / L.

The liquid preparation of the present invention solves all the problems described above. The liquid formulation of the present invention minimizes the size of the oil droplet even when the lipid emulsion, especially fish oil having a concentration of 35,000 mg / L or more is contained, It is possible to check leakage by high-voltage current measurement for each disappearance.

Hereinafter, the present invention will be described in more detail.

The present invention relates to a liquid preparation comprising three fines separated by a compartment communicable for use in use, wherein when the lecithin contained in the liquid has a specific concentration, it may have a long chain fatty acid such as fish oil It has been experimentally confirmed that the oil droplet size can be minimized even when fat is included.

Specifically, the present invention relates to a liquid preparation comprising a disappearance liquid each of which is contained in three feces separated by a communicable compartment for use in use, the liquid preparation comprising: a first dissolution liquid containing a sugar contained in a first dissolution; A second elimination solution containing an amino acid and an electrolyte contained in the second chamber; And a third insoluble liquid containing a fat emulsion and lecithin accommodated in a third dissolution, wherein the fat emulsion comprises fish oil, and the third insoluble liquid contains 35,000 to 45,000 mg of fish oil based on 1 L / L, and lecithin 11,990 to 15,000 mg / L. The liquid preparation of the present invention may be such that the ratio of the particle diameter of the oil droplet of the emulsion of the third disappearance liquid measured by the PFAT 5 test standard is not less than 0.03%.

The disappearance of the first to third chambers of the liquid agent of the present invention will be described in detail below.

1st disappearance amount

The first elimination solution of the present invention includes sugar.

Examples of the saccharide compounded in the first disappearance liquid include glucose, fructose, reducing sugars such as maltose, non-reducing saccharides such as xylitol, sorbitol and glycerin, and the like. Of these, from the viewpoint of blood glucose level management and the like, it is preferably a reducing sugar, more preferably glucose. Glucose is preferably used more favorably than other sugars because it is most easily absorbed into the body as an amount of basic heat. These sugars may be used singly or in combination of two or more.

The first disappearing liquid may further include an acid, and a leak test may be performed on the first disappearing liquid by including an acid. The acid may be at least one of hydrochloric acid, phosphoric acid, citric acid, ascorbic acid, acetic acid, sulfuric acid, carbonic acid and nitric acid, but is not limited thereto.

The liquid preparation of the present invention can be used as a solution for peripheral vein or as a solution for central vein. When used as a solution for peripheral vein, the first solution contains 80 to 140 mg of acid / L, and 142,990 to 143,010 mg / L per 1 L, and when used as a solution for a central venous vaccine, the first elimination solution contains 150 to 450 mg / L of acid and 461,500 to 462,500 mg / L.

As the solvent of the first disappearance liquid, conventionally used distilled water may be used.

In the liquid preparation of the present invention, the liquid amount of the first disappearing liquid is appropriately set in accordance with the total liquid amount of the liquid preparation, the second disappearing liquid and / or the amount of the third disappearing liquid.

Second disappearance amount

The second disappearing solution of the present invention comprises an amino acid and an electrolyte.

The electrolyte contained in the second disappearance liquid is an electrolyte in the sense of being used in the field of liquids, specifically, an electrolyte (fluid electrolyte) contained in a body fluid (for example, blood, intracellular fluid). It may be a physiologically important electrolyte. More specifically, examples include potassium, calcium, sodium, magnesium, phosphorus, zinc, chlorine and the like.

Examples of the potassium source include potassium chloride, potassium acetate, potassium citrate, potassium glycerophosphate, potassium sulfate, potassium lactate and the like. These potassium sources may be in the form of hydrates. Potassium is formulated so that the concentration in the second disappearance liquid is 40 mEq / L or less (preferably 25 to 40 mEq / L). Further, in the liquid preparation of the invention, the potassium concentration in the mixture of the first disappearing liquid and the second disappearing liquid is preferably 16 mEq / L or higher (preferably 16 to 25 mEq / L, more preferably 16 to 20 mEq / L).

Examples of the calcium source include calcium salts such as calcium gluconate, calcium chloride, calcium glycerophosphate, calcium lactate, calcium pantothenate and calcium acetate. The calcium salt may be in the form of a hydrate (for example, calcium gluconate hydrate). Calcium is formulated so that the concentration in the second disappearance liquid is 15 mEq / L or less (preferably 6 to 12 mEq / L). Further, in the liquid preparation of the invention, the calcium concentration in the mixture of the first disappearing liquid and the second disappearing liquid is 9 mEq / L or less (preferably 3 to 6 mEq / L).

Examples of the sodium source include sodium salts such as sodium chloride, sodium lactate, sodium acetate, sodium sulfate, sodium glycerophosphate, sodium citrate, and sodium lactate. In addition, in the case of incorporating phosphorus and calcium and / or magnesium into the liquid preparation of the present invention, sodium citrate is preferably used as (part of) a sodium source in order to prevent them from precipitating. The sodium source may also be in the form of a hydrate. The mixing ratio of sodium to the second disappearance liquid is 50-100 mEq / L, preferably 40-80 mEq / L in the second disappearance liquid. In the liquid preparation of the present invention, the sodium concentration in the mixture of the first disappearing liquid and the second disappearing liquid is set to be in the range of 25 to 50 mEq / L, preferably 30 to 40 mEq / L .

Examples of the magnesium source include magnesium sulfate, magnesium chloride, magnesium acetate and the like. The magnesium source may also be in the form of a hydrate. The mixing ratio of magnesium to the second disappearance liquid is 1 to 20 mEq / L, preferably 5 to 15 mEq / L in the second disappearance liquid. Further, in the liquid preparation of the present invention, the magnesium concentration in the mixed solution of the first disappearing liquid and the second disappearing liquid is set to satisfy the range of 0.5 to 10 mEq / L, preferably 2 to 6 mEq / L .

As the phosphorus source, when an inorganic salt is used, calcium phosphate or magnesium phosphate may precipitate. Therefore, it is preferable to use an organic salt such as sodium glycerophosphate or potassium glycerophosphate. When lecithin is used as an emulsifier in the first chamber, the lecithin is also a phosphorus source. When the required amount of phosphorus can be supplied only from the lecithin-derived phosphorus, it is not necessary to incorporate phosphorus into the second chamber, which is suitable because it does not cause precipitation of calcium phosphate or the like. The compounding ratio of phosphorus to the second disappearance liquid is 0 to 20 mmol / L in the second disappearance solution. In the liquid preparation of the invention, the concentration of phosphorus in the mixture of the first disappearing liquid and the second disappearing liquid is set to satisfy the range of 1 to 20 mmol / L, preferably 5 to 10 mmol / L .

Examples of the zinc source include zinc sulfate and zinc chloride. The zinc source may also be in the form of a hydrate. The mixing ratio of zinc to the second disappearance liquid is 2.5 to 15 mu mol / L in the second disappearance solution. In the liquid preparation of the invention, it is preferable that the zinc concentration in the mixture of the first disappearing liquid and the second disappearance liquid is set to satisfy a range of 1.5 to 9 占 퐉 ol / L.

Examples of the chlorine source include sodium chloride, potassium chloride, magnesium chloride, and calcium chloride. The mixing ratio of chlorine to the second disappearance liquid is 50-100 mEq / L, preferably 40-80 mEq / L in the second disappearance liquid. In the liquid preparation of the present invention, the chlorine concentration in the mixture of the first disappearing liquid and the second disappearing liquid is set to satisfy a range of 25 to 60 mEq / L, preferably 30 to 40 mEq / L .

The electrolyte may include at least one of sodium acetate trihydrate, sodium glycerophosphate pentahydrate, calcium chloride dihydrate, magnesium sulfate heptahydrate, potassium chloride and zinc sulfate heptahydrate.

More specifically, the electrolyte contains 5,570 to 5,670 mg / L of sodium acetate trihydrate, 5,000 to 6,000 mg / L of sodium glycerophosphate, 735 to 745 mg / L of calcium chloride dihydrate based on 1 L of the second disappearance liquid, 2,460 to 2,480 mg / L of magnesium sulfate heptahydrate, 4,450 to 4,510 mg / L of potassium chloride, and 20 to 26 mg / L of zinc sulfate heptahydrate. The fine content of such electrolytes contributes to the oil droplet size reduction effect of the emulsion of the liquid preparation of the present invention.

The amino acid compounded in the second disappearing solution may be any one which is used in the amino acid solution for nutrition supply to the living body. In the present invention, the amino acid is usually used in the form of a free amino acid, and may be in the form of a pharmaceutically acceptable salt, ester, N-acyl derivative, or dipeptide. L-leucine, L-threonine, L-tryptophan, L-methionine, L-phenylalanine, L-cysteine, L- Tyrosine, L-arginine, L-histidine, L-alanine, L-proline, L-serine, glycine, L-aspartic acid and L-glutamic acid. Specific examples of the salts of amino acids include inorganic acid salts such as L-arginine hydrochloride, L-cysteine hydrochloride, L-glutamic acid hydrochloride, L-histidine hydrochloride and L-lysine hydrochloride; And organic acid salts such as L-lysine acetate and L-lysine malate. Specific examples of the ester of amino acid include L-tyrosine methyl ester, L-methionine methyl ester, L-methionine ethyl ester and the like. Specific examples of the N-acetylamino acid include N-acetyl-L-cysteine, N-acetyl-L-tryptophan, N-acetyl-L-proline and the like. Specific examples of the dipeptide of an amino acid include L-tyrosyl-L-tyrosine, L-alanyl-L-tyrosine, L-arginine-L-tyrosine and L-tyrosine-L-arginine. In particular, L-cysteine is suitably formulated as acetylcysteine in terms of stability. These amino acids may be used singly, but it is preferable to use two or more kinds of amino acids in combination from the viewpoint of nutritional replenishment. Preferably, at least all of the essential amino acids (i.e., nine kinds of L-leucine, L-isoleucine, L-valine, L-lysine, L-threonine, L-tryptophan, L-methionine, L-phenylalanine and L- Amino acids) are exemplified.

The compounding ratio of the amino acid in the second disappearance liquid is preferably in the range of 40,000 to 120,000 mg / L, more preferably 50,000 to 100,000 mg / L, as the total amount of the free amino acids. In the liquid preparation of the present invention, the amino acid concentration in the mixture of the first disappearing liquid and the second disappearing liquid is in the range of 10,000 to 50,000 mg / L, preferably 20,000 to 30,000 mg / L as the total amount of free amino acids Is satisfied.

Specifically, the amino acid is selected from the group consisting of L-isoleucine, L-leucine, L-lysine hydrochloride, L-methionine, L-phenylalanine, L- threonine, L- tryptophan, L- valine, L- arginine, L- , Glycine, L-proline, L-serine, and L-tyrosine.

L-leucine hydrochloride 7,150-7,350 mg / L, L-methionine 3,900-4,100 mg / L, L-isoleucine 7,900-6,100 mg / L, L-leucine 7,200-7,400 mg / / L, L-phenylalanine 5,500 to 5,700 mg / L, L-threonine 4,100 to 4,300 mg / L, L-tryptophan 1,700 to 1,900 mg / L, L-valine 5,700 to 5,900 mg / L, L-arginine 11,400 to 11,600 mg / L, L-histidine 4,700 to 4,900 mg / L, L-alanine 20,600 to 20,800 mg / L, glycine 10,200 to 10,400 mg / L, L-proline 6,700 to 6,900 mg / L, L-serine 4,900 to 5,100 mg / , L-tyrosine 300 to 500 mg / L,

The second disappearing liquid of the present invention may further comprise a pH adjusting agent. It is preferable that the pH of the second disappearance liquid is adjusted to 6.0 to 7.4, preferably 6.5 to 7.2 by pH adjusting agent as necessary. The pH of the second disappearance liquid satisfies the above-mentioned pH range, the stability of the amino acid which easily causes chemical changes such as L-cysteine and L-glutamic acid is promoted, and furthermore, the pH of the mixed solution after mixing with the first disappearance liquid is optimized . &Lt; / RTI >

In particular, the pH adjusting agent may include acetic anhydride. The pH adjusting agent may include 5,700 to 6,300 mg / L of acetic anhydride based on 1 L of the second vanishing solution.

The solvent of the second disappearance liquid may also be conventionally distilled water.

If necessary, a stabilizer may be added to the liquid preparation of the present invention. Examples of the stabilizer incorporated in the liquid preparation of the present invention include sulfite such as sodium hydrogensulfite. The sulfite is added to the second elimination solution to avoid the decomposition of the vitamin B1 contained in the first elimination solution. The blending amount of the sulfite in the second disappearance liquid is, for example, in the range of 20 to 50 mg / L.

In the liquid preparation of the present invention, the liquid amount of the second disappearing liquid is appropriately set in accordance with the total liquid amount of the liquid preparation, the liquid amount of the first disappearing liquid and / or the third disappearing liquid.

3rd disappearance amount

The third scavenging solution of the present invention includes a fat emulsion and lecithin, and more specifically, the fat emulsion may include fish oil.

The third elimination liquid may contain 35,000 to 45,000 mg / L of fish oil and 11,990 to 15,000 mg / L of lecithin based on 1 L. Specifically, the third disappearance liquid may include 35,000 to 45,000 mg / L of fish oil, Lactin 11,990 mg / L to 12,010 mg / L may be included. Thus, it has been experimentally confirmed that when the lecithin has a specific concentration, the oil droplet size can be minimized even when fat having a long chain fatty acid such as fish oil is included.

The fat emulsion formulated in the third insoluble liquid is an underwater type emulsion prepared by dispersing the fat in water using an emulsifier. The preparation of the fat emulsion can be carried out according to a conventional method. For example, the oil emulsion can be prepared by adding oil and a preservative to water, stirring the emulsion to prepare a crude emulsion (crude emulsion), and then emulsifying the emulsion by a conventional method such as a high-pressure emulsification method.

The preservation includes fish oil (cod liver oil, etc.), and may further include edible oil. (Trade name: "Panaceate" (manufactured by Nihon Yucca), triglycerides of fatty acids having 8-10 carbon atoms (commercially available from Nippon Oil & Fats Co., Ltd.), vegetable oils (soybean oil, olive oil, cottonseed oil, safflower oil, corn oil, palm oil, , "ODO" (manufactured by Nisshin Seiyaku Co., Ltd.), "Coconnaad" (manufactured by Kao Corporation), "Miglyol" (manufactured by Mitsubo Electronics), etc.], chemically synthesized triglycerides [2-linoleoyl-1,3 -Dioctanoyl glycerol (8L8), 2-linoleoyl-1,3-dideckanoyl glycerol (10L10), etc.]. These may be used singly or in combination of two or more kinds.

Particularly, the third disappearance liquid preferably contains 55,000 to 65,000 mg / L of soybean oil and 45,000 to 55,000 mg / L of heavy chain triglyceride, based on 1 L, and more preferably the soybean oil, heavy chain triglyceride and olive oil. , And 45,000 to 55,000 mg / L of olive oil. Thus, the liquid preparation of the present invention has a ratio of omega 6 (omega 6) to omega 3 (omega 3) omega 6: omega 3 = 2.1: 1, by having four omega oils such as fish oil, soybean oil, heavy chain triglyceride and olive oil . In the case where the ratio of omega 6 (omega 6) to omega 3 (omega 3) is in the range of 2: 1 to 4: 1, the immunoregulatory reaction is performed. The composition of the present invention can have a composition close to an ideal ratio in immunomodulation as well as contributing to the effect of minimizing the oil droplet size of the emulsion due to the synergistic effect with the content of the lecithin.

The lecithin used as an emulsifier may be egg yolk phospholipid (egg yolk lecithin), hydrogenated egg yolk phospholipid, soybean phospholipid (soy lecithin), hydrogenated soy phospholipid, and the like. These may be used singly or in combination of two or more kinds.

The ratio of the oil and fat to be used for preparing the oil-in-fat emulsion is not particularly limited as long as an oil-in-water type oil-emulsion can be obtained. Usually, the fat is used in a proportion of about 0.5 to 6 w / v%, preferably about 1 to 5 w / v%, in the resulting fat emulsion. The emulsifier is usually used in an amount of about 0.01 to 2 w / v%, preferably about 0.05 to 1 w / v%, in the resulting fat emulsion.

The acid in the first chamber and the lecithin in the third chamber may be contained in a weight ratio of 40: 1 to 120: 1, and the oil droplet size reduction effect of the emulsion of the present invention is further increased.

One embodiment of the production method of the fat emulsion particularly suitable for the present invention is as follows. That is, at least one selected from glycerin and glucose is added to water and an emulsifier is added to water, and then the mixture is stirred to prepare a crude emulsion, and then the crude emulsion is emulsified by a conventional method such as a high-pressure emulsification method. When the high-pressure emulsification method is adopted, this method is carried out by using an emulsifying machine such as a Manton Gaulin homogenizer, for example, about 2-50 times under the condition of about 20 to 700 kg / cm 2, Can be carried out by passing it about 3 to 20 times. On the other hand, in this method, glycerin and / or glucose may be present at the time of emulsification. For example, glycerin and / or glucose may be added to the crude emulsion prepared using a fat and an emulsifier to emulsify. The amount of glycerin and / or glucose to be used is usually such that the obtained fat emulsion contains about 30 to 70 w / v%, preferably about 40 to 60 w / v% of glycerin and / or glucose.

If necessary, various additives known to be additionally compoundable in the fat emulsion may be further added. As the additive, for example, a pH adjusting agent can be mentioned. As the pH adjuster, an acid such as hydrochloric acid, an alkali such as sodium hydroxide, potassium hydroxide, etc., or an organic acid or an amino acid can be used. Examples of the organic acid include acetic acid, lactic acid, citric acid, malic acid, succinic acid and the like. Examples of amino acids include L-histidine and L-lysine. Of these, the oil-soluble material can be used in advance in an oil-based component constituting the emulsion. The water-soluble material may be added to the water for injecting water or added to the aqueous phase of the resulting fat emulsion. These addition amounts may be appropriately set and may be the same as those conventionally known.

Specifically, the third disappearance liquid includes sodium oleate, and preferably contains 290 to 310 mg / l of sodium oleate. The sodium oleate also contributes to the effect of minimizing the oil droplet size of the emulsion of the present invention.

The third disappearing liquid may further comprise at least one of an antioxidant, an isotonizing agent and a pH adjusting agent. The third disappearing liquid may contain 190 to 210 mg / L of an antioxidant, 20,000 to 30,000 mg of an isotonic agent / L, and 5 to 35 mg / L of a pH adjusting agent.

As the solvent of the third disappearance liquid, distilled water usually used can be used.

In the liquid preparation of the present invention, the liquid amount of the third disappearing liquid is appropriately set in accordance with the total liquid amount of the liquid preparation, the liquid amount of the first disappearing liquid and / or the second disappearing liquid.

On the other hand, both of the first to third disappearance liquids can be produced in accordance with a known method for producing a sap. For example, it can be prepared by dissolving each of the above-mentioned components in distilled water for injection. The fat-soluble component is preferably used after being emulsified, for example, as described above.

A mixed solution of the first to third insoluble liquids

The liquid preparation of the present invention is used by mixing a first disappearance liquid to a third disappearance liquid at the time of use.

In the liquid preparation of the present invention, the volume ratio of the first to third disappearing liquids is appropriately set in accordance with the liquid amount of the first to third insoluble liquids described above, and the stability of each component contained therein, From the viewpoint of the osmotic pressure setting, for example, the volume ratio of the first dissolution liquid: the second dissolution liquid: the third dissolution liquid is 30.2: 50.8: 19.0 for the central vein and 54.4: 31.5: 14.1 for the distal vein) .

The amount of heat in the mixed solution is preferably 300 to 1500 kcal / L, more preferably 600 to 1200 kcal / L. More specifically, it is preferable that the central vein solution is about 1100 Kcal and the peripheral vein solution is about 700 Kcal based on 1 L of the mixed solution.

The proportion of fat in the above amount of heat is preferably 40% or less, and more preferably 20 to 40%. The content of sugar, fat and amino acid in the above calories is preferably 40 to 60%, fat: 20 to 40%, amino acid: 10 to 30%, sugar: 45 to 55%, fat: 25 To 35% and an amino acid content of 15 to 25%.

On the other hand, the approximate calorie can be obtained by multiplying the amount of sugar (g) of each component by 4, the fat by 9, and the amino acid by 4, respectively. That is, a calorie of 1 g per gram is about 4 kcal, a calorie of 1 g of lipid is about 9 kcal, a calorie of 1 g of amino acid is about 4 kcal, and a calorie can be obtained based on this. The above-mentioned " heat quantity in the mixed liquid " is based on the value calculated by this calculation.

Usage of liquid formulation

The liquid preparation of the present invention can be used for nutritional management of patients before and after surgery when the oral intake is insufficient and the patient is in a state of low hypoproteinemia or mild low nutritional state or invasive period And is suitably used for the purpose of nutritional management of a patient (preferably, a patient who has undergone digestive surgery) who has difficulty in oral nutrition due to surgery or digestive system diseases. By administering the liquid preparation of the present invention to the patient for 1 to 14 days after the surgery, preferably for 1 to 3 days after the surgery, the nutritional status of the patient can be maintained soundly. The dose and the administration rate can be appropriately set after considering the symptom and age of each patient. In particular, the liquid preparation of the present invention can maintain the nutritional status of the patient by the administration period and the liquid preparation only.

Sap container

The container for accommodating the first to third elimination liquids is not particularly limited as long as it has three communicable chambers. For example, a container having a partition wall formed by an easy peel seal (Japanese Patent Application Laid-Open No. 2-4671 Japanese Unexamined Utility Model Publication No. 5-5138, etc.), a partition wall formed by inserting a seal between clips (Japanese Unexamined Patent Publication No. 63-309263, etc.), and various communication means capable of opening the partition wall Japanese Unexamined Patent Publication (Kokai) No. Sho 63-20550, etc.), and the like, separated from each other by a communicable partition wall. Of these, a sapphire bag in which a partition is formed by an easy peel seal is suitable for mass production and is easy to perform a communication operation. Examples of the material of the container include various gas permeable plastics commonly used in medical containers and the like, such as polyethylene, polypropylene, polyvinyl chloride, crosslinked ethylene-vinyl acetate copolymer, ethylene -olefin copolymer, And a flexible plastic such as a laminate.

The filling and storage of the first to third insoluble liquids in the container can be carried out according to a usual method. For example, a method of filling each of the insoluble liquids in an inert gas atmosphere, closing the lid, and sterilizing by heating . Here, the heat sterilization may be carried out by known methods such as high pressure steam sterilization and hot water shower sterilization, and may be carried out in an inert gas atmosphere such as carbon dioxide or nitrogen, if necessary.

Furthermore, in order to reliably prevent deterioration, oxidation, and the like of the first to third elimination liquids contained in the container, it is preferable that the container is packaged in an oxygen-barrier outer bag together with the oxygen scavenger. Particularly, when a sapphire bag having a partition formed by an easy peel seal is employed as a container, the sapphire bag is folded in an easy peel seal portion so as to prevent the partition wall from being communicated by external pressure For example, an easy peel seal, in a folded state. In addition, it may be packed with an inert gas if necessary.

As the material of the oxygen-barrier outer bag suitable for the packaging, films and sheets of various materials generally used in general can be used. Specific examples thereof include films, sheets, and the like made of a material comprising at least one of ethylene, vinyl alcohol copolymer, polyvinylidene chloride, polyacrylonitrile, polyvinyl alcohol, polyamide, .

As the deoxidizing agent, there may be used various known ones such as iron compounds such as iron hydroxide, iron oxide, and iron carbide as effective components, and those using low molecular weight phenol and activated carbon. Representative examples of commercially available products include "Agirez" (manufactured by Mitsubishi Gas Gas Company), "Modorane" (manufactured by Nippon Kayaku), "Sekuk" (manufactured by Nippon Soda Co., Ltd.), "Tamotsu" ), &Quot; KEY PIT " (manufactured by Doren Shisha), and the like.

Example

Hereinafter, the present invention will be described in detail, but the present invention is not limited to the following examples.

Example 1 Preparation of liquid formulations

1. Preparation of the 1st disappearance liquid

According to the composition shown in Table 1, glucose disulfide hydrate and hydrochloric acid were completely dissolved in the water for injection to prepare the first disappearance liquid.

2. Preparation of second disappearance liquid

According to the composition shown in Table 1, the amino acid and the electrolyte were completely dissolved in the water for injection, and the pH was adjusted using acetic anhydride (pH adjuster) to prepare the second disappearance liquid.

3. Preparation of the third disappearance liquid

According to the composition shown in Table 1, the water and oil phases were prepared in two preparation tanks respectively, and the water phase and the oil phase were emulsified using an emulsifier and the pH was adjusted using 1N sodium hydroxide (pH adjusting agent). The aqueous phase preparation was prepared by completely dissolving glycerin and sodium oleate in the water for injection, and mixing the purified oil with purified soybean oil, medium triglyceride, purified olive oil, purified fish oil, tocopherol and yolk phospholipid.

4. Preparation of liquid formulations

The first elimination liquid, the second elimination liquid, and the third disappearance liquid obtained in the above were filled into respective chambers of a polyethylene third chamber vessel partitioned into three discharge chambers, The overlap of the multilayered film was sealed together with the oxygen scavenger and sterilized by high pressure steam according to a conventional method to obtain a solution for a central venous injection.

(Table 1)

Example 2 Preparation of a liquid preparation

A preparation for a peripheral vein was prepared in the same manner as in Example 1, except that the components and contents in Table 2 were used.

(Table 2)

Comparative Example 1 Preparation of liquid formulations

The preparation for the central vein was prepared in the same manner as in Example 1, except that the ingredients and the contents in Table 3 were used.

(Table 3)

Comparative Example 2 Preparation of liquid preparation

A preparation for a peripheral vein was prepared in the same manner as in Example 1, except that the ingredients and contents in Table 4 were used.

(Table 4)

Experimental Example One. Emulsion Oil Droplet measurement experiment

In the above Examples 1 and 2 and Comparative Examples 1 and 2, an oil droplet measurement experiment was carried out in the following manner.

Experimental Method

Using an Accusizer, dilute 100 ㎕ of 5.0 ㎛ standard into 100 ㎖ and measure 500 ㎕ of 10.0 ㎛ standard to dilute to 50 ml and use as standard value. Approximately 3 mL of the fat emulsion alone and the particle size of all the fluids were measured. Emulsion Residues (Oil Droplet) The values obtained by measuring the ratio of particles having a diameter of 5 占 퐉 or more are shown in Table 5.

Experiment result

(Table 5)

The oil droplet preferably has an oil droplet particle diameter of not less than 5 μm, preferably not more than 0.05%. In case of mixed oil droplets, the oil droplet size is increased due to the influence of not only lipids but also electrolytes. % Or less.

According to the experimental results, the proportions of the oil droplet particle diameters of the oil emulsions of Examples 1 and 2 were 5% or more and 0.02% or 0.01%, respectively, and that of Comparative Example 1 and Comparative Example 2 Was significantly lower.

Also, even in the mixed liquor, the ratios of the oil droplet particle diameters of the emulsions of Examples 1 and 2 to those of 5 占 퐉 or more were 0.09% and 0.08%, respectively, which were significantly lower than those of Comparative Example 1 and Comparative Example 2 .

It can be confirmed that the ratio of the oil droplet particle diameter of the oil emulsion to the oil emulsion particle diameter of 5 mu m or more is significantly reduced in the examples of the oil emulsion and the mixed emulsion.

Experimental Example 2. High voltage Through current measurement Leak test (leak test)

In the above Examples 1 and 2 and Comparative Examples 1 and 2, a leak test was performed in the following manner.

Example 1, Example 2, Comparative Example 1, and Comparative Example 2 were prepared and then packed into a bag having 5 to 10 탆 and 40 탆 leak generated arbitrarily. The bag was passed through a leak tester to check for leakage. The results are as follows.

(Table 6)

O: leak check, X: leak not confirmed

As a result of the experiment, it was possible to confirm whether the liquid solution of the present invention leaked only at 5 to 10 mu m.

Claims

Claims 1. A liquid preparation comprising a disappearance liquid each of which is contained in three fines separated by a communicable compartment to be mixed in use,
The first disappearance is a first elimination liquid containing 462,000 mg / L or 143,000 mg / L glucose monohydrate based on 1 L;
L-lysine hydrochloride 7,250 mg / L, L-methionine 4,000 mg / L, L-phenylalanine 5,600 mg / L, L-isoleucine 7,600 mg / L-arginine 4,800 mg / L, L-alanine 20,700 mg / L, L-tryptophan 1,800 mg / L, L-valine 5,800 mg / L, L-arginine 11,500 mg / / L, L-proline 6,800mg / L, L-serine 5,000mg / L, L-tyrosine 400mg / L, sodium acetate trihydrate 5,620mg / L, sodium glycerophosphate 4,180mg / L, calcium chloride dihydrate 740mg / , 2,470 mg / L of magnesium sulfate heptahydrate, 4,480 mg / L of potassium chloride and 23 mg / L of zinc sulfate heptahydrate; And
The third fate includes a third insoluble liquid comprising 40,000 mg / L fish oil, 60,000 mg / L soybean oil, 50,000 mg / L heavy chain triglyceride, 50,000 mg / L olive oil, 12,000 mg / L lecithin and 300 mg / L sodium oleate Wherein the liquid preparation is a liquid preparation.

delete

The method according to claim 1,
Wherein the third disappearance liquid further comprises at least one of tocopherol 200 mg / L, glycerin 25,000 mg / L and sodium hydroxide 14.4 mg / L based on 1L.

The method of claim 4,
Wherein the third disappearance liquid further comprises 200 mg / L of tocopherol, 25,000 mg / L of glycerin and 14.4 mg / L of sodium hydroxide based on 1 L.

delete

The method of claim 5,
The liquid preparation is a peripheral intravenous liquid preparation,
Wherein the first elimination liquid contains 120 mg / L of hydrochloric acid and 143,000 mg / L of grape diary hydrate based on 1 L.

The method of claim 5,
The liquid preparation is a liquid preparation for central vein,
Wherein the first elimination liquid contains 330 mg / L of hydrochloric acid and 462,000 mg / L of glucose monohydrate based on 1 L.

delete

The method according to claim 8 or 9,
Wherein the second disappearance liquid further comprises 6,180 mg / L acetic anhydride based on 1 L.

The method according to claim 1,
Wherein the ratio of the oil droplet particle diameter of the emulsion of the third disappearance liquid, which is measured according to the PFAT 5 test standard, is 5 占 퐉 or more is 0.03% or less.