WO2023287129A1 - Pharmaceutical composition containing omega fatty acid and intravenous fluid preparation containing same - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for improving hyperglycemia in parenteral nutrition therapy, wherein the pharmaceutical composition comprises refined soybean oil, a medium chain triglyceride, refined macadamia nut oil, and refined fish oil, and provides essential fatty acids to patients unreceptive to oral or enteral nutrition while preventing blood sugar increase in patients receiving parenteral nutrition therapy, and improves insulin resistance, thus having the effect of improving hyperglycemia and inflammatory diseases caused by nutritional deficiency, which are side effects of existing TPN therapies.

Description

Pharmaceutical composition containing omega fatty acid and transfusion preparation containing the same

The present invention relates to a pharmaceutical composition capable of supplying nutrients through a vein to patients unable to take oral or enteral nutrition. Specifically, by optimizing the content of omega-3 fatty acids, omega-6 fatty acids, omega-7 fatty acids and omega-9 fatty acids, blood sugar increase is prevented and insulin resistance is improved, which ultimately occurs frequently in TPN intravenous nutrition therapy. It has the characteristic of improving side effects such as hyperglycemia. In addition, the pharmaceutical composition of the present invention has an effect of improving an inflammatory reaction that may occur due to nutritional deficiency and preventing immunosuppression.

Infusion therapy in which infusion preparations are injected through a vein is essential for patients who cannot eat or maintain fasting, and these infusions are classified into basic infusions, nutrient infusions, and special infusions according to their components and roles. Basic fluids supply essential water, electrolytes, and sugars necessary for life support, and include physiological saline solution and aqueous glucose solution. Nutrient fluids provide nutrients such as amino acids, lipids, proteins, vitamins, and minerals to patients who cannot take oral or enteral nutrition. There are high-concentration sugar solution, amino acid solution and lipid solution of various concentrations, etc. Special fluid is a type of fluid that is not classified as basic or nutrient fluid and is used in special cases such as increased external pressure due to cerebral hemorrhage.

Among them, nutrient infusion, i.e., intravenous nutrition (PN), is administered through single bottle administration and 2 chamber (or 2-in-one) formulation, followed by all-in-one (AIO), or 3 -in-1, total nutrient admixture (TNA) formulations have been developed, and 3-chamber bag (3CB) formulations consisting of carbohydrate, protein, and lipid emulsions have become one of the major Total Parenteral Nutrition (TPN) solutions. Among these, intravenous lipid emulsion is a major means of supplying essential fatty acids and non-protein calories in place of carbohydrates. Fat supplied through intravenous nutrition is a component of cell membranes and various hormones. It was developed in the early 1960s, used in earnest for intravenous nutrition from the 1980s, and developed as a component of TPN from the 1990s. , Medium chain triglyceride (MCT), refined olive oil, refined fish oil (Rich in omega-3 fish oil) and omega-3-acid triglyceride are used. , each product aims to supply energy, essential fatty acids, and omega-3 and omega-6 fatty acids.

Such TPN intravenous nutrition therapy is essential for patients who cannot take oral or enteral nutrition, but problems such as infectious complications, catheter-related mechanical side effects, and metabolic side effects such as hyperglycemia and hyperlipidemia occur there is In particular, hyperglycemia is a frequently occurring side effect of TPN where carbohydrates such as glucose are continuously administered. When hyperglycemia occurs, insulin is used to lower blood sugar. There is a demand for an infusion formulation with improved side effects such as hyperglycemia.

[Prior art literature]

[Patent Literature]

(Patent Document 1) Republic of Korea Patent Registration No. 2195090

(Patent Document 2) Korean Patent Registration No. 1672347

(Patent Document 3) Republic of Korea Patent Publication No. 10-2011-0130465

(Patent Document 4) Korean Patent Publication No. 10-2020-0038472

Accordingly, the present inventors confirmed that the side effects of the existing TPN can be improved by using macadamia nut oil as a component of the fat emulsion in the process of researching ways to improve the side effects of the existing TPN such as hyperglycemia. and completed the present invention.

An object of the present invention is to provide a pharmaceutical composition for improving hyperglycemia in intravenous nutrition therapy containing refined soybean oil, medium-chain triglyceride, purified macadamia nut oil and refined fish oil, and to improve hyperglycemia occurring when conventional TPN intravenous nutrition therapy is applied. make it a specific solution.

In order to solve the above problems, the present invention discloses the following means.

In one aspect, the present invention provides a pharmaceutical composition for improving hyperglycemia in intravenous nutrition therapy containing refined soybean oil, medium chain triglycerides, purified macadamia nut oil and refined fish oil.

In another aspect, the present invention provides a pharmaceutical composition for improving inflammation in intravenous nutrition therapy containing refined soybean oil, medium chain triglycerides, purified macadamia nut oil and purified fish oil.

The pharmaceutical composition may contain one or more fatty acids selected from the group consisting of omega-3 fatty acids, omega-6 fatty acids, omega-7 fatty acids and omega-9 fatty acids.

In addition, the omega-7 fatty acids may be included in an amount of 5 to 30 mg/mL.

In addition, the omega-3 fatty acids, omega-6 fatty acids, omega-7 fatty acids, and omega-9 fatty acids may be included in a weight ratio of 0.5 to 1.5: 1.3 to 5.0: 1: 2.5 to 4.0.

The omega-7 fatty acids include palmitoleic acid (C16: 1n7), vaccenic acid (C18: 1n7), Paulinic acid (C20: 1n7) and rumenic acid (C18: 2n7). ) may be one or more selected from the group consisting of.

The omega-3 fatty acids are alpha-linolenic acid (C18:3n3), stearidonic acid, eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaene It may be at least one selected from the group consisting of acid (Eicosapentaenoic acid, C20:5n3), heneicosapentaenoic acid (HPA), and docosahexaenoic acid (C22:6n3).

The omega-6 fatty acid may be at least one selected from the group consisting of linoleic acid, γ-linolenic acid, calendic acid, dihomo-gamma-linolenic acid, arachidonic acid, docosatetraenoic acid, and docosapentaenoic acid. .

The omega-9 fatty acids include oleic acid (C18: 1n9), elaidic acid (C18: 1n0), gondonic acid (C20: 1n9), mead acid (C20: 3n9), It may be at least one selected from the group consisting of erucic acid (C22:1n9) and nervonic acid (C24:1n9).

The composition may further include one or more additives selected from the group consisting of an emulsifier, an osmotic pressure regulator, a pH regulator, and an antioxidant.

In another aspect, the present invention is an infusion formulation comprising a composition comprising refined soybean oil, medium chain triglycerides, refined macadamia nut oil and refined fish oil, wherein the composition contains 5 to 30 mg/mL of omega-7 fatty acids. In therapy, an infusion preparation for improving hyperglycemia is provided.

The infusion preparation may be contained in a single chamber or in a plurality of chambers spaced apart by communicable compartments to be mixed in use.

In another aspect, the present invention is divided into a first loss, a second loss and a third loss,

The first chamber accommodates a first chamber for supplying amino acids and electrolytes;

The second chamber accommodates the second chamber for supplying sugar,

The third chamber accommodates the third chamber for supplying fat,

The third liquid to be lost includes refined soybean oil, medium chain triglycerides, purified macadamia nut oil and refined fish oil, and the third liquid to be lost is for improving hyperglycemia in intravenous nutrition therapy containing 5 to 30 mg/mL of omega-7 fatty acids. Infusion preparation is provided.

The first loss is L-alanine, L-arginine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine hydrochloride, L-lysine acetate, L-methionine, L-phenylalanine, L-proline, L receiving a first lost liquid containing 80 to 150 mg/mL of amino acids composed of serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, L-glutamic acid and taurine;

The second elimination accommodates a second elimination liquid containing 11 to 45 mg/mL of glucose,

The third chamber contains 5.5 g of refined soybean oil, 5.0 g of medium chain triglycerides, 5.5 g of refined macadamia nut oil, and 4.0 g of refined fish oil based on 100 ml of the infusion liquid preparation.

The third lost liquid may contain 5 to 30 mg/mL of omega-7 fatty acids.

The first lost liquid may further include an electrolyte of calcium chloride dihydrate, sodium glycerol phosphate pentahydrate, sodium acetate trihydrate, magnesium sulfate heptahydrate, potassium chloride or zinc sulfate heptahydrate.

Refined soybean oil, a component of the present invention, has a high essential fatty acid content. Omega-6 fatty acid Linoleic acid (LA) is the most abundant at about 48 to 58%, and contains about 5 to 11% of omega-3 fatty acid α-Linolenic acid (ALA). Linoleic acid (LA) and α-linolenic acid (ALA) are both long-chain fatty acids (LCFAs; 12 or more carbon atoms) and poly-unsaturated fatty acids (PUFAs).

Medium chain triglyceride (MCT), a component of the present invention, is composed of caprylic acid (C8:0) and capric acid (C10:0), which are saturated fatty acids without double bonds. It is stable against oxidation by oxygen and is rapidly oxidized compared to long-chain triglycerides (LCTs) to provide energy readily available to the body.

Refined macadamia nut oil, which is a component of the present invention, is palmitic acid (C16H32O2, 256.4, 7.0-9.0%), palmitoleic acid (C16H30O2, 254.4, 15.0-24.0%), stearic acid , C18H36O2, 284.5, 2.0~4.0%), oleic acid (C18H34O2, 282.5, 53.0~67.0%), and linoleic acid (C18H32O2, 280.5, 1.5~4.0%). In particular, it contains a large amount of oleic acid (C18:1n9), an Omega-9 fatty acid, and palmitoleic acid (C16:1n7), an Omega-7 fatty acid, as mono-unsaturated fatty acid (MUFA). In contrast, refined olive oil, a component of conventional lipid emulsions, contains a large amount (about 56 to 85%) of oleic acid (C18:1n9), which is mainly a mono-unsaturated fatty acid (MUFA).

Refined fish oil, which is a component of the present invention, contains a large amount of omega-3 fatty acids, and marine oils such as anchovy (Engraulidae), horse mackerel (Carangidae), herring (Clupeidae), sea smelt (Osmeride), salmon (Salmonnidae) and It can be obtained by mixing oils of fish rich in fat, such as mackerel (Scombridae).

The pharmaceutical composition for improving hyperglycemia in intravenous nutrition therapy containing refined soybean oil, medium-chain triglycerides, refined macadamia nut oil and refined fish oil of the present invention is composed of omega-3 fatty acids, omega-6 fatty acids, omega-7 fatty acids and omega-9 fatty acids. It may include one or more fatty acids selected from the group consisting of

Specifically, the composition of the present invention may include 5.0 g to 6.0 g of refined soybean oil, 4.5 g to 5.5 g of medium chain triglycerides, 5.0 g to 6.0 g of refined macadamia nut oil, and 3.5 g to 4.5 g of refined fish oil, based on a total of 100 mL. And, more specifically, it may contain 5.5 g of refined soybean oil, 5.0 g of medium chain triglyceride, 5.5 g of refined macadamia nut oil, and 4.0 g of refined fish oil based on 100 mL.

The composition of the present invention includes 10 to 20 mg/mL of omega-3 fatty acids, 20 to 50 mg/mL of omega-6 fatty acids, 5 to 30 mg/mL of omega-7 fatty acids, and 30 to 30 mg/mL of omega-9 fatty acids. 70 mg/mL. Preferably, the weight ratio of the omega-3 fatty acids, omega-6 fatty acids, omega-7 fatty acids, and omega-9 fatty acids may be 0.5 to 1.5: 1.3 to 5.0: 1: 2.5 to 4.0.

In the present invention, omega-3 is a series of fatty acids in which the third carbon has a double bond, counting from the methyl group terminal of the fatty acid, and alpha-linolenic acid (C18: 3n3), stearidonic acid (Stearidonic acid), eicosatrienoic acid (ETE), eicosapentaenoic acid (ETA), eicosapentaenoic acid (C20:5n3), heneicosapentaenoic acid (HPA), docosahexaenoic acid (Docosahexaenoic acid, C22:6n3), etc. Omega-3 fatty acids are abundant in canola oil, flaxseed oil, perilla oil, and blue-backed fish, and lower triglyceride levels in the blood by inhibiting the synthesis of triglycerides and VLDL in the liver. Daily supply of omega-3 fatty acids according to the composition of the present invention may be 50 to 200 mg/kg/day.

In the present invention, omega-6 is a series of fatty acids in which the 6th carbon has a double bond, counting from the methyl group terminal of the fatty acid, linoleic acid (C18: 2n6), γ linolenic acid (γaicd, C20: 2n6) , calendic acid, dihomo-gamma-linolenic acid, arachidonic acid (C20:4n6), docosatetraenoic acid, docosapentaenoic acid, and the like. It is contained in large amounts in eggs, dairy products, walnuts, nuts, seeds, soybean oil, safflower oil, and corn oil, and is an important component for skin and hair production, cholesterol metabolism, and maintenance of reproductive function in vivo. Daily supply of omega-6 fatty acids according to the composition of the present invention may be 100 to 500 mg/kg/day.

In the present invention, omega-7 is a fatty acid having a double bond at the 7th carbon, counting from the methyl group terminal of the fatty acid, palmitoleic acid (C16: 1n7), vaccenic acid (C18: 1n7) , Paulinic acid (C20:1n7), and Rumenic acid (C18:2n7). Omega-7s are abundant in sea buckthorn oil, macadamia oil, and avocado oil, and are also present in some marine fish oils, such as fish oil and krill oil. Daily supply of omega-7 fatty acids according to the composition of the present invention may be 25 to 300 mg/kg/day.

In the present invention, omega-9 is a fatty acid having a double bond at the 9th carbon, counting from the methyl group terminal of the fatty acid, oleic acid (C18: 1n9), elaidic acid (C18: 1n9) There are Gondonic acid (C20:1n9), Mead acid (C20:3n9), Erucic acid (C22:1n9), and Nervonic acid (C24:1n9). Omega-9s are found in olive oil, canola oil, and almond oil. Daily supply of omega-9 fatty acids according to the composition of the present invention may be 150 to 700 mg/kg/day.

The pharmaceutical composition comprising refined soybean oil, medium chain triglycerides, refined macadamia nut oil and refined fish oil according to the present invention optimizes the content of omega-3 fatty acids, omega-6 fatty acids, omega-7 fatty acids and omega-9 fatty acids, thereby reducing blood sugar increase. It is possible to prevent and improve insulin resistance, ultimately improving side effects such as hyperglycemia frequently occurring in TPN venous nutrition therapy. In addition, it can exhibit excellent anti-inflammatory effects by lowering ALT (Alanine aminotransferase), AST (Aspartate aminotransferase) and CRP (c-Reactive protein) levels.

The pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the purified soybean oil, medium chain triglyceride, purified macadamia nut oil and purified fish oil for administration. The pharmaceutically acceptable carrier may be saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, and a mixture of one or more of these components, and, if necessary, antioxidants, buffers, Other customary additives such as bacteriostatic agents may be added.

The pharmaceutical composition of the present invention may be administered parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, specifically intravenous administration, more specifically intravenous or peripheral vein administration. can be administered within The dosage can be adjusted in various ranges depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease.

When the pharmaceutical composition of the present invention is formulated as an injection solution, the pharmaceutical composition of the present invention may be mixed in water together with a stabilizer or buffer to prepare a solution or suspension, but the formulation method is not limited thereto. As an example of an injection formulation using the pharmaceutical composition of the present invention, it can be formulated for unit administration in a bottle.

The dosage of the pharmaceutical composition of the present invention can be calculated based on weight according to the age of the subject to be administered, and as a preferred example, in the case of adults, the dosage of the pharmaceutical composition is 1.0 to 2.0 g/kg/day of fat. The volume of fluid per day can be 5 to 10 mL/kg/day.

In addition, the pharmaceutically effective amount and effective dosage of the pharmaceutical composition of the present invention may vary depending on the formulation method of the pharmaceutical composition, administration method, administration time and / or administration route, etc., and the reaction to be achieved by administration of the pharmaceutical composition Type and degree of administration, type of subject to be administered, age, weight, general health condition, symptom or severity of disease, sex, diet, excretion, drugs used simultaneously or at the same time in the subject, and components of other compositions It may vary according to various factors, including similar factors well known in the medical field, and a person skilled in the art may determine and prescribe the dosage within the desired therapeutic range. For example, administration of the pharmaceutical composition of the present invention may be administered once a day, but is not limited thereto. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. In consideration of all of the above factors, it can be administered in an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by a person skilled in the art to which the present invention belongs.

The pharmaceutical composition of the present invention may further include one or more additives selected from the group consisting of an emulsifier, an osmotic pressure regulator, a pH regulator, and an antioxidant.

The emulsifier is a material that forms stable oil particles and maintains the stability of the formed particles, and may be at least one selected from the group consisting of egg yolk lecithin, hydrogenated egg yolk lecithin, soybean lecithin, hydrogenated soybean lecithin, and sodium oleate. Preferably, it may be egg yolk lecithin and sodium oleate, and may be 0.6 to 1.8% (w/v) of egg yolk lecithin and 0.01 to 0.05% (w/v) of sodium oleate based on 100 ml of the pharmaceutical composition, but is not limited thereto. not.

The osmotic pressure regulator may be at least one selected from the group consisting of sodium chloride, glucose, D-mannitol, sorbitol, trehalose, and glycerol, preferably 1.7 to 2.5% (w/v) of glycerol based on 100 ml of the composition for intravenous administration It can be, but is not limited thereto.

The pH adjusting agent may be at least one selected from the group consisting of sodium hydroxide, hydrochloric acid, phosphoric acid, phosphoric acid salts and citric acid, but is not limited thereto.

The antioxidant may be at least one selected from the group consisting of ascorbic acid, dibutylhydroxyanisole, dibutylhydroxytoluene, sorbitol, and tocopherol, but is not limited thereto.

Another aspect of the present invention for achieving the above object is a transfusion preparation containing refined soybean oil, medium chain triglycerides, refined macadamia nut oil and refined fish oil.

The infusion preparation of the present invention may include a composition containing the omega-3 fatty acids, omega-6 fatty acids, omega-7 fatty acids and omega-9 fatty acids.

The infusion preparation of the present invention contains omega-3 fatty acids, omega-6 fatty acids, omega-7 fatty acids, and omega-9 fatty acids in a weight ratio of 0.5 to 1.5: 1.3 to 5.0: 1: 2.5 to 4.0, thereby preventing an increase in blood sugar and insulin. By improving resistance, side effects such as hyperglycemia that frequently occur in TPN venous nutrition therapy can be improved. In addition, it can exhibit excellent anti-inflammatory effects by lowering ALT (Alanine aminotransferase), AST (Aspartate aminotransferase) and CRP (c-Reactive protein) levels.

The infusion preparation may be included in a single compartment, and the compartment may further include amino acids, electrolytes, and sugars.

In addition, the infusion preparation may be accommodated in a plurality of chambers spaced apart by a communication compartment so as to be mixed during use, and the composition of the present invention may be accommodated in one chamber. Specifically, the infusion solution formulation of the present invention can be accommodated in a chamber divided into a first chamber, a second chamber, and a third chamber, in which the first chamber for supplying amino acids and electrolytes is accommodated, In the second chamber, the second loss liquid for supplying sugar may be accommodated, and in the third chamber, the third loss liquid for supplying fat may be accommodated.

The electrolyte is an electrolyte in the sense used in the fluid field, specifically, an electrolyte contained in body fluids (eg, blood, intracellular fluid), and more specifically, calcium, phosphorus, sodium, magnesium, potassium, zinc, chlorine, etc. However, it is not limited thereto.

The calcium may be calcium gluconate, calcium chloride, calcium glycerophosphate or calcium pantothenate, and the salt may be an inorganic salt including calcium phosphate and magnesium phosphate or an organic salt including sodium glycerophosphate and potassium glycerophosphate, , The sodium may be in the form of sodium chloride, sodium lactate, sodium acetate, sodium sulfate, sodium glycerophosphate, sodium citrate or hydrates thereof, the magnesium may be magnesium sulfate, magnesium chloride or magnesium acetate, the potassium may be potassium chloride, It may be in the form of potassium acetate, potassium glycerophosphate, potassium sulfate, potassium lactate or hydrates thereof, the zinc may be in the form of zinc sulfate, zinc chloride or hydrates thereof, and the chlorine is sodium chloride, potassium chloride, magnesium chloride or calcium chloride It may be, but is not limited thereto.

Specifically, the electrolyte may be at least one selected from the group consisting of calcium chloride dihydrate, sodium glycerophosphate pentahydrate, sodium acetate trihydrate, magnesium sulfate heptahydrate, potassium chloride, and zinc sulfate heptahydrate.

The amino acids include free amino acids and amino acid salt forms. In the form of free amino acids, L-alanine, L-arginine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, taurine, It may be at least one selected from the group consisting of L-threonine, L-tryptophan, L-tyrosine, L-valine and L-glutamic acid. The amino acid salt may be at least one selected from the group consisting of inorganic acid salts such as L-arginine hydrochloride, L-histidine hydrochloride, and L-lysine hydrochloride, L-lysine acetate, and L-lysine malate.

The infusion preparation may contain two or more kinds of amino acids in terms of nutritional supplementation, and essential amino acids L-alanine, L-arginine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine hydrochloride, L -Lyric acid acetate, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, L-glutamic acid and taurine at 80 to 150 mg/mL can

The first loss liquid may further include a pH adjusting agent, and by including the pH adjusting agent, when the first loss liquid is mixed with the second loss liquid and the third loss liquid, the contained amino acids are not destroyed. pH can be maintained. The pH adjusting agent can be selected within the usual range. Preferably, acetic anhydride may be used.

The infusion preparation contains sugar, and may be a reducing sugar such as glucose, fructose, maltose, and a non-reducing sugar such as xylitol and sorbitol, preferably containing 11 to 45 mg/mL of glucose, which is most easily absorbed by the body. can do.

The second lost liquid may further include a pH adjusting agent, and the pH adjusting agent may be hydrochloric acid, phosphoric acid, acetic acid, citric acid, or sulfuric acid.

The third elimination liquid contains oil, an emulsifier, an osmotic pressure regulator, a pH regulator, and an antioxidant, and is the composition for intravenous administration of the present invention.

The intravenous administration composition of the present invention, which is the third loss solution, may be used alone or mixed with the first loss solution and the second loss solution according to the condition of the subject requiring administration of the fluid.

When the composition for intravenous administration of the present invention is mixed with the first loss solution and the second loss solution, the mixing ratio and total dose are appropriately adjusted according to the nutritional status and calorie requirement of each patient, and the composition is administered through a central vein or a peripheral vein. It can be. When the infusion formulation of the present invention is administered through a central vein, the volume ratio of the first lost fluid, the second lost fluid, and the third lost fluid may be 2.66 : 1.59 : 1.00. The volume ratio of the second loss liquid and the third loss liquid may be 2.24:3.86:1.00. However, the volume ratio of the first lost liquid, the second lost liquid, and the third lost liquid is not limited thereto, and may be variously partitioned according to nutritional calorie standards.

The infusion formulation of the present invention can supply calories, amino acids, and essential fatty acids to patients who need jugular vein nutrition because oral or gastrointestinal nutrition is impossible, insufficient, or limited. In addition, the infusion preparation of the present invention can be used to manage nutrition of major trauma surgery patients such as cancer, AIDS, ischemic bowel disease, malabsorption, bronchial block/removal, intestinal obstruction, severe liver dysfunction, and severe acute pancreatitis.

The pharmaceutical composition comprising refined soybean oil, medium chain triglycerides, refined macadamia nut oil and refined fish oil of the present invention can provide essential fatty acids to patients unable to take oral or enteral nutrition. More specifically, it can be useful in the medical field by preventing an increase in blood sugar in patients receiving intravenous nutrition therapy, improving insulin resistance, improving hyperglycemia, a side effect of conventional TPN therapy, and improving inflammation levels. can

1 is a graph showing the results of an oral glucose tolerance test performed on the first day after administration of the compositions of Examples and Comparative Examples to rats.

Figure 2 is a graph showing the results of oral glucose tolerance test performed on the 22nd day after administration of the compositions of Examples and Comparative Examples to rats.

3 is a graph showing the results of an oral glucose tolerance test performed for 30 days after administering the compositions of Examples and Comparative Examples to beagle dogs.

Figure 4 is a graph showing the results of inflammation levels measured after administering the compositions of Examples and Comparative Examples to beagle dogs.

Hereinafter, the present invention will be described in detail by examples. However, the following examples are only to illustrate the present invention, and the content of the present invention is not limited to the following examples.

Examples 1 to 3. Preparation of pharmaceutical compositions containing purified macadamia nut oil

Two manufacturing tanks were prepared and one was used as a water phase manufacturing tank and the other was used as an oil phase manufacturing tank. Water for injection and glycerol, an osmotic pressure regulator, are mixed in a water phase preparation tank, and refined soybean oil, medium chain triglyceride, refined macadamia nut oil, refined fish oil, lecithin, sodium oleate, and α-tocopherol are added to the oil phase preparation tank, and homomixer for about 20 minutes. were mixed homogeneously. After transferring the mixed solution in the tank for preparing the oil phase to the tank for preparing the aqueous phase, it was emulsified once using an emulsifier, and then the pH was adjusted to about 9.3 by adding sodium hydroxide as a pH adjusting agent. After adjusting the pH, the mixture was emulsified 5 times using an emulsifier. The emulsified liquid was filled in a plastic container for infusion and sterilized at 121 ° C. Specific compositions of Examples 1 to 3 are shown in Table 1.

Comparative Example 1. Preparation of Pharmaceutical Composition Containing Refined Olive Oil

Two production tanks were prepared in the same manner as in the example, one was used as a water phase production tank, and the other was used as an oil phase production tank. Water for injection and glycerol, an osmotic pressure regulator, are mixed in a water phase preparation tank, and refined soybean oil, medium chain triglyceride, refined olive oil, refined fish oil, lecithin, sodium oleate, and α-tocopherol are added to the oil phase preparation tank and mixed with a homomixer for about 20 minutes. Mixed homogeneously. After transferring the mixed solution in the tank for preparing the oil phase to the tank for preparing the aqueous phase, it was emulsified once using an emulsifying machine, and the pH was adjusted to about 9.3 by adding sodium hydroxide as a pH adjusting agent. After adjusting the pH, the mixture was emulsified 5 times using an emulsifier. The emulsified liquid was filled in a plastic container for infusion and sterilized at 121 ° C. The composition obtained in this way corresponds to Omap One Lipid Inj., a product currently on the market, and the specific composition is shown in Table 1.

Raw material amount (g/L)	Example 1	Example 2	Example 3	Comparative Example 1
refined soybean oil	70	55	50	60
medium chain triglycerides	70	50	20	60
refined olive oil	0	0	0	50
Refined Macadamia Nut Oil	20	55	90	0
refined fish oil	40	40	40	30
egg yolk phospholipid	12	12	12	12
glycerol	25	25	25	25
sodium oleate	0.3	0.3	0.3	0.3
α-tocopherol	0.194	0.194	0.194	0.194
sodium hydroxide	Appropriate amount	Appropriate amount	Appropriate amount	Appropriate amount
water for injection	Appropriate amount	Appropriate amount	Appropriate amount	Appropriate amount

Experimental Example 1. Fatty acid content analysis The compositions of Examples and Comparative Examples were subjected to a fatty acid analysis test according to a gas chromatography method, and the results are shown in Table 2.

Fatty acids (g/L)	Example 1	Example 2	Example 3	Comparative Example 1
Capric acid	27.0	18.5	7.7	24.1
Palmitic acid		17.2		16.7
Palmitoleic acid	8.4	15.0	24.8
Stearic acid		5.2		5.8
Oleic acid	31.0	46.2	62.8	54.9
Oleic acid isomer		3.2		2.0
Linoleic acid	40.7	28.6	32.1	37.1
Linolenic acid		3.0		5.2
Stearidonic acid		1.1		0.8
Arachidonic acid		0.7		0.8
EPA	7.8	6.7	8.3	5.9
DPA		0.8		0.6
DHA	4.7	4.7	4.7	3.7
total ω3	12.5	16.3	13.0	16.2
total ω6	40.7	29.3	32.1	37.9
total ω7	8.4	15.0	24.8	0.0
total ω9	31.0	46.2	62.8	54.9
ω6:ω3 Ratio	3.26	1.80	2.47	2.34
essential fatty acids	40.7	31.6	32.1	42.3

Experimental Example 2. Evaluation of blood sugar control efficacy using rats

In order to evaluate the blood glucose control efficacy of the composition of the present invention, rats (SD rats, male, 7 weeks old, 164.5-body weight) were purchased from Orient Bio and an oral glucose tolerance test was performed.

Specifically, 20 mL/kg of the compositions of Examples 1 to 3 and Comparative Example at a rate of 0.05 mL/min was intravenously administered once/day using a femoral vein catheter for 22 days. On the first day and the 22nd day of administration, glucose was orally administered at a dose of 2 g/kg 1 hour after administration of the composition, and 30 and 60 minutes later, the rat's blood sugar was measured and recorded using a blood glucose meter. On the 22nd day, blood glucose was measured 30 and 240 minutes after glucose administration. At this time, as a positive control group, 6 unit/kg (day 1) or 3 unit/kg (day 22) of insulin in Comparative Example was mixed and injected into the catheter.

The results are shown in Table 3, Table 4, and FIGS. 1 and 2, and are shown as the average and standard deviation of blood glucose for each test group and each blood collection time, and statistical significance was obtained after student's t test analysis between groups (*p< 0.05, **p<0.01, ***p<0.001)

Time	Changes of blood glucose versus 0 min (%mean±S.E.)
	G1 (saline solution)	G2 (Comparative example)	G3 (Example 1)	G4 (Example 2)	G5 (Example 3)	G6 (Comparative example + insulin)
0min	100	100	100	100	100	100
30min	175.4±12.93	169.72±14.99	134.36±19.71	151.51±8.21	157.62±13.79	136.32±12.38
60min	146.58±7.45	205.57±13.46	150.17±17.68	170.82±7.79	181.23±17.08	100.85±12.81

As can be seen in Table 3 and Figure 1, as a result of the oral glucose tolerance test performed on the first day of administration, blood glucose increased when glucose was administered. Significantly in Examples 1 to 3 compared to Comparative Example 60 minutes after glucose administration It was confirmed that the blood sugar increase rate was improved.

Time	Changes of blood glucose versus 0 min (%mean±S.E.)
	G1 (saline solution)	G2 (Comparative example)	G3 (Example 1)	G4 (Example 2)	G5 (Example 3)	G6 (Comparative example + insulin)
0min	100	100	100	100	100	100
30min	121.58±10.52	115.69±4.85	125.02±31.54	100.49±1.35	106.18±13.82	124.29±5.24
240min	115.69±7.75	125.66±6.40	126.88±9.49	98.33±3.50	113.78±2.20	23.33±13.81

As can be seen in Table 4 and Figure 2, as a result of the oral glucose tolerance test performed on the 22nd day of administration, the blood glucose increase rate was significantly improved in Example 2 compared to the comparative example 30 and 240 minutes after glucose administration. I was able to confirm.

Experimental Example 3. Evaluation of blood sugar control efficacy using beagle dogs

In order to further evaluate the blood sugar control efficacy of Example 2, which showed the best effect in long-term (22 days) administration in Experimental Example 2, a beagle dog (male, 10 months old, 9 ~ 13 kg body weight) was purchased from Orient Bio. 2-hour postprandial blood glucose was measured on the 6th and 30th days of administration.

Specifically, 9.25 mL/kg of the compositions of the negative control group (saline), Comparative Example 1 and Example 2 at a rate of 3 mL/hr was intravenously administered once/day using a radial vein catheter for 30 days. For blood glucose measurement 2 hours after a meal, feed was provided 2 hours after composition administration, and blood was collected 2 hours after the completion of feed intake for each individual, and blood glucose was measured and recorded using a blood glucose meter. The results are shown in Table 5 and FIG. 3, and are shown as the average and standard deviation of blood glucose for each test group and each blood collection time, and statistical significance was obtained after student's t test analysis between groups (*p<0.05, **p< 0.01, ***p<0.001)

Day	Postprandial glucose versus day 0 (%mean±S.D.)
	G1 (saline solution)	G2 (Comparative example)	G4 (Example 2)
0	100	100	100
6	113.7±18.93	108.5±11.62	91.4±14.23
30	120.2±27.14	133.3±16.06	107.8±11.33

As can be seen in Table 5 and FIG. 3, on the 6th day of administration, compared to the negative control group (saline) and Comparative Example, the 2-hour postprandial blood glucose increase rate of the Example 2 treatment group was significantly improved, and even on the 30th day of administration, Comparative Example Compared to Example 2, the 2-hour postprandial blood glucose increase rate was significantly improved. These results mean that the composition of the present invention has excellent short-term and long-term blood sugar improving efficacy.

Experimental Example 4. Inflammation level measurement

In the same manner as in Experimental Example 3, the compositions of the negative control group (saline), Comparative Example 1 and Example 2 were administered to beagle dogs for 30 days, and on the 16th and 31st days of administration, blood was collected immediately before administration of the composition, and the serum was separated The levels of inflammatory markers c-reactive protein (CRP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured. CRP was measured using Abcam's kit (catalog number: ab157698), and ALT and AST levels were measured using a DCA Vantage analyzer (SIEMENS). The results are shown in Table 6 and FIG. 4, and are shown as the average and standard deviation of blood glucose for each test group and each blood collection time, and statistical significance was obtained after student's t test analysis between groups (*p<0.05, **p< 0.01, ***p<0.001)

-	Day 16			Day 31
	G1 (saline solution)	G2 (Comparative example)	G4 (Example 2)	G1 (saline solution)	G2 (Comparative example)	G4 (Example 2)
CRP (mean±S.D.)	6.86±4.21	11.79±8.17	7.47±5.60	10.87±9.90	21.69±11.31	5.38±1.93
ALT (%mean±S.D.)	144.38±14.53	115.88±11.46	103.88±17.57	134.52±29.11	99.27±9.43	92.85±9.60
AST (%mean±S.D.)	116.40±21.66	96.53±21.12	89.75±14.02	124.73±26.12	109.45±21.78	96.38±15.85

As can be seen in Table 6 and FIG. 4, a significant ALT reduction was confirmed in Comparative Example 1 and Example 2 compared to the negative control group (saline) on the 16th day from the start of administration, and the significance of Example 2 compared to the negative control group (saline) Decreased AST was confirmed. On the 31st day of administration, the CRP level was significantly decreased in the Example 2 treatment group compared to the Comparative Example, and the ALT level was significantly decreased in the Comparative Example and Example 2 treatment group compared to the negative control group (saline). These results mean that the composition of the present invention can also exhibit anti-inflammatory effects.

Experimental Example 4. Stability test

The composition of Example 2 was subjected to an accelerated stability test at a temperature of 40 ° C ± 2 ° C and a relative humidity of 25% or less, and it was confirmed that it was suitable for all tested items, and the results are shown in Table 7.

Test Items and Criteria			point of manufacture	accelerated 2 months	accelerated 4 months	accelerated 6 months
appearance		milky emulsion	fitness	fitness	fitness	fitness
pH		6.0 to 9.0	8.32	7.91	7.51	7.02
Tocopherol		155 to 233 mg/ml	176.30	182.87	178.65	183.98
free fatty acids		Less than 8.0 mEq/L	3.07	3.23	4.97	7.00
Particle size (more than 1.5㎛)		2% or less	0.07	0.00	0.00	0.00
Particle size (more than 5.0㎛)		0% or less	0.00	0.00	0.00	0.00
fatty acid (mg/ml)	Caprylic	21 to 31 mg/ml	24.0	26.2	26.4	27.8
fatty acid (mg/ml)	Capric	14 to 20 mg/ml	16.8	17.5	17.8	18.4
fatty acid (mg/ml)	Palmitoleic	12 to 18 mg/ml	15.2	15.2	15.3	15.7
fatty acid (mg/ml)	Oleic	27 to 55 mg/ml	45.2	46.1	46.6	46.5
fatty acid (mg/ml)	Linolenic	24 to 36 mg/ml	29.6	30.2	30.4	29.9
fatty acid (mg/ml)	EPA	6 to 8 mg/ml	7.7	7.8	7.0	7.1
fatty acid (mg/ml)	DHA	4 to 6 mg/ml	4.8	4.8	5.1	4.7

Since the pharmaceutical composition and infusion preparation according to the present invention can supply calories, amino acids, and essential fatty acids to patients who cannot take oral or enteral nutrition, they can be used as medicines in the pharmaceutical industry and medical field.

Claims (15)

1. A pharmaceutical composition for improving hyperglycemia and inflammation in intravenous nutrition therapy comprising refined soybean oil, medium chain triglycerides, purified macadamia nut oil and refined fish oil.
2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains one or more fatty acids selected from the group consisting of omega-3 fatty acids, omega-6 fatty acids, omega-7 fatty acids and omega-9 fatty acids.
3. The pharmaceutical composition according to claim 2, wherein the omega-7 fatty acid is 5 to 30 mg/mL.
4. The pharmaceutical composition according to claim 2, wherein the composition comprises omega-3, omega-6, omega-7 and omega-9 fatty acids in a weight ratio of 0.5 to 1.5: 1.3 to 5.0: 1: 2.5 to 4.0.
5. The method of claim 2, wherein the omega-7 fatty acids are palmitoleic acid (C16: 1n7), vaccenic acid (C18: 1n7), Paulinic acid (C20: 1n7) and rumenic acid (Rumenic acid). acid, C18: 2n7) of at least one member selected from the group consisting of, a pharmaceutical composition.
6. The method of claim 2, wherein the omega-3 fatty acids are alpha-linolenic acid (α-Linolenic acid, C18:3n3), stearidonic acid, eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA) ), Eicosapentaenoic acid (C20: 5n3), Henicosapentaenoic acid (HPA), and Docosahexaenoic acid (C22: 6n3)) At least one selected from the group consisting of, pharmaceutical enemy composition.
7. The method of claim 2, wherein the omega-6 fatty acid is from the group consisting of linoleic acid, γ-linolenic acid, calendic acid, dihomo-gamma-linolenic acid, arachidonic acid, docosatetraenoic acid and docosapentaenoic acid. At least one selected, pharmaceutical composition.
8. The method of claim 2, wherein the omega-9 fatty acid is oleic acid (C18: 1n9), elaidic acid (C18: 1n0), gondonic acid (C20: 1n9), mead acid (Mead acid) , C20: 3n9), erucic acid (Erucic acid, C22: 1n9) and nervonic acid (Nervonic acid, C24: 1n9) at least one selected from the group consisting of, a pharmaceutical composition.
9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the composition further comprises at least one additive selected from the group consisting of an emulsifier, an osmotic pressure regulator, a pH regulator, and an antioxidant.
10. An infusion preparation comprising a composition comprising refined soybean oil, medium-chain triglycerides, refined macadamia nut oil and refined fish oil, wherein the composition contains 5 to 30 mg/mL of omega-7 fatty acids for the treatment of hyperglycemia and inflammation in intravenous nutrition. Infusion preparation for improvement.
11. The infusion preparation according to claim 10, which is accommodated in a single chamber.
12. The infusion preparation according to claim 10, wherein the infusion preparation is accommodated in a plurality of chambers spaced apart by communicable compartments so as to be mixed during use.
13. 13. The method of claim 12, wherein the chamber is divided into a first chamber, a second chamber and a third chamber,

    The first chamber accommodates a first chamber for supplying amino acids and electrolytes;

    The second chamber accommodates the second chamber for supplying sugar,

    The third chamber accommodates the third chamber for supplying fat,

    The third loss liquid includes refined soybean oil, medium chain triglyceride, purified macadamia nut oil and refined fish oil, and the third loss liquid contains 5 to 30 mg/mL of omega-7 fatty acids.
14. According to claim 13,

    The first loss is L-alanine, L-arginine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine hydrochloride, L-lysine acetate, L-methionine, L-phenylalanine, L-proline, L receiving a first lost liquid containing 80 to 150 mg/mL of amino acids composed of serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, L-glutamic acid and taurine;

    The second elimination accommodates a second elimination liquid containing 11 to 45 mg/mL of glucose,

    The third chamber contains 5.5 g of refined soybean oil, 5.0 g of medium chain triglycerides, 5.5 g of purified macadamia nut oil, and 4.0 g of refined fish oil based on 100 ml of the infusion solution.

    Wherein the third loss solution contains 5 to 30 mg/mL of omega-7 fatty acids.
15. According to claim 14,

    The first loss solution further comprises an electrolyte of calcium chloride dihydrate, glycerol sodium phosphate pentahydrate, sodium acetate trihydrate, magnesium sulfate heptahydrate, potassium chloride or zinc sulfate heptahydrate.

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