JP2010270161A - Side effect-preventing agent in infusion composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a side effect-preventing agent which can inhibit or prevent side effects such as reduced activity of drug-metabolizing enzymes like P450 and other enzymes in a liver as well as overexpression of ABC transporter which are caused by administration of high-calorie infusions or the like, a method of preventing the side effects therewith, and a manufacturing method of an infusion composition in which the side effects are prevented. <P>SOLUTION: The present invention relates to the side effect-preventing agent which is added to the infusion composition to prevent the side effects caused by administration of the infusion composition and comprises a lipid emulsion formulation, the method of preventing the side effects therewith, and the manufacturing method of the infusion composition in which the side effects is prevented. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention provides a side effect inhibitor mixed with the infusion composition in order to suppress or prevent side effects caused by administration of the infusion composition, for example, a decrease in the activity of drug metabolizing enzymes in the liver, and the side effect. It relates to a method for preventing it.

  Cytochrome P450 (hereinafter simply referred to as “P450”) is known as a representative example of a drug-metabolizing enzyme, that is, an enzyme involved in metabolism of a chemical substance such as a pharmaceutical active ingredient compound. This P450 has many molecular species, and each of these molecular species is reported to be involved in the metabolism of various compounds for each molecular species, although there are differences in the enzyme activity (non-native). (See Patent Document 1).

P450 is involved in its metabolism as active pharmaceutical compounds (for example, active compounds such as tricyclic antidepressants, antiepileptics, benzodiazepines, β-blockers, barbital hypnotic hypnotics), etc. Dimethylnitrosamine, which is a low molecular weight carcinogen in the environment, and organic solvents such as benzene.

  When the activity of drug-metabolizing enzymes such as P450 decreases, problems such as excessive drug efficacy and reduced pharmacological effects of prodrugs occur. In particular, drug-metabolizing enzyme activity is underdeveloped at birth, and the ability of newborns and premature infants to metabolize drugs is significantly lower than that of general adults. Therefore, such administration of drugs to newborns and the like is likely to cause serious problems (see Non-Patent Document 2).

  It is known that the activity of P450 decreases for various reasons. For example, when cytokines in the bloodstream increase due to inflammatory diseases, trauma, bacterial infection, etc., P450 activity decreases. In addition, P450 activity decreases due to excessive intake of carbohydrates, lack of fatty acids, and the like (see Non-Patent Document 3). Furthermore, administration of a high-calorie infusion containing normal sugar, amino acid, electrolyte, etc. has been reported to reduce the P450 content in the liver and inhibit drug metabolism (see Non-Patent Documents 4-6).

  In addition, administration of high-calorie fluids may cause hepatomegaly, increased transaminase, and increased alkaline phosphatase and D-bilirubin levels in children, leading to liver damage such as fatty liver and cholestasis. Is known (see Non-Patent Document 7-8).

The cause is increased fat synthesis and fat accumulation in hepatocytes (see Non-Patent Document 9-13). These are closely related to a decrease in β-oxidation of fatty acids in the liver (see Non-Patent Documents 14-16). Enzymes that perform β-oxidation of fatty acids and related enzymes include SCAD (short-chain acyl-Coenzyme A dehydrogenate), MCAD (acyl-coenzyme A dehydrogenase, medium chain), and LCAD (Long-chain acyl-CoA dehydrogenase). ), VLCAD (acyl-coenzyme A dehydrogenase, very long chain), ECH (Enoyl-CoA hydrotase), HAD (3-hydroxyacyl CoA dehydrogenase, L-3-hydroxyacyl-Coenzyme A dehydrogenase, short-chain, HADHSC), HADHB ( β-oxidase of fatty acids such as hydroxyacyl-Coenzyme A dehydrogenase), ACAA2 (Acetyl-CoA acyltransferase 2; aka: 3-oxoacyl CoA thiolase), and LC-ACS (Long-chain acyl-CoA synthetase, aka: fatty acid Coenzyme A ligase, long chain 2 (Facl2)), carnitine palmitoyltransferase I (CPT2), carnitine palmitoyltransferase II (CPTII),
Enzymes associated with β-oxidation of fatty acids are known.

ABC (ATP Binding Cassette) protein is differentiated into various functions of transporter, channel and receptor, and plays an important physiological function. More than 40 AB in humans
C protein has been identified. It has become clear that many ABC proteins are involved in the transport of intrinsic factor substances, foreign substances, and their metabolites that depend on ATP, and are therefore also called ABC transporters (Non-Patent Documents). 17). Some of them cause drug resistance, and if this is overexpressed, the drug action may be attenuated, and the possibility of drug interaction is also considered (Non-patent Document 18). reference).
ABCB1 (MDR1 / Pgp1), ABCC1 (MRP1) and ABCC5a (MRP5) are known as ABC transporters involved in drug resistance.
ABCB1 (MDR1 / Pgp1) has a wide range of substrate specificities and transports hydrophobic compounds with various molecular structures, such as doxorubicin, taxol, vinblastine, and vincristine colchicine, which are known as active ingredients of anticancer drugs. Discharge. When ABCB1 is induced, accumulation of these anticancer agent active ingredient compounds in the cells is reduced due to its action, and the cancer cells acquire resistance (see Non-Patent Document 17).
In ABCC1 knockout mice, transported from the inflammatory cells of leukotriene C ₄ are missing, such as neutrophils, inflammatory response have been reported to decrease significantly (Non-Patent Document 19). From this, it is considered that the inflammatory reaction is worsened by overexpression of ABCC1.
ABCC5a (MRP5) is S- (2,4-dinitrophenyl) -glutathione (DNP-SG), 9- (2-phosphonylmethoxyethyl) adenine (PMEA), an anti-HIV drug, and 6 an anti-leukemic drug. -It has been reported that nucleic acid analogs such as mercaptopurine and thioguanine are transported, and fluorochrome and cGMP are also used as substrates (see Non-Patent Document 20-22). That is, overexpression of ABCC5a promotes the excretion of these drugs out of the cells and attenuates the effects of these drugs.
As described above, when a drug such as an anticancer drug or anti-HIV drug is administered, the expression of an excessive ABC transporter that causes drug resistance should be suppressed. From the perspective of worsening inflammatory response, ABC
Transporter overexpression should be suppressed.
Furthermore, it has been reported that the expression of ABCB1 (MDR1 / Pgp1), one of the ABC transporters, is increased by administration of a high-calorie infusion (see Non-Patent Document 23).

Yoo, J. S. H., Chung, R. C., Wade, D., & Yang, C. S., "Nature of N-nitrosodimethylamine denethylase and its inhibitors", Cancer Res., 47, 3378-3383, 1987 Edited by Ryuichi Kato and Tetsuya Kamataki, “Drug Metabolism (2nd edition)-As the basis of medical pharmacology and toxicology”, Tokyo Kagaku Dojin, published on October 20, 2000, pp157-161 Edited by Ryuichi Kato and Tetsuya Kamataki, “Drug Metabolism (2nd Edition)-As the Basis for Medical Pharmacy and Toxicology”, Tokyo Kagaku Dojin Co., Ltd., published October 20, 2000, pp 131-140 Knodel, RG, Steel, NM, Cerra, FB, Gross, JB, & Solomon, TE, "Effects of parenteral and enteral hyperalimentation on hepatic drug metabolism in the rat", J. Pharmacol. Exp. Ther., 229, 589- 597, 1984 Dickerson, R.N. & Charland, S.L., "The effects of sepsis during parenteral nutrition on hepatic microsomal function in rats", Pharmacotherapy, 22, 1084-1090, 2002 Lu, C. J. H., Redmond, D., Baggs, R. B., Schercter, A. & Gaseiewicz, T. A., "Growth and hepatic composition in the guinea pig after long-term parenteral hyperalimentation", Am. J. Physiol. R388-R397, 1986 Dahms, B.B., Halpin, Jr.T.C., "Serial liver biopsy in parenteral nutrition-associated cholestasis of early infancy", Gastroenterology, 81: 136-144, 1981 Benjamin, D.R., "Hepatobiliary dysfunction in infants and children associated with long-term total parenteral nutrition", A clinico-pathologic study, Am. J. Clin. Pathol., 76: 276-283, 1981 Wolfe, R.R., O'Donnell, T.F., Stone, M.D., et al., "Investigation of factors determining the optimal glucose infusion rate in total parenteral nutrition", Metabolism, 29: 892-900, 1980 Smith, R.S., Burkinshaw, L., Hill, G.L., "Optimal energy and nitrogen intake for gastroenterological patients requireing intravenous nutrition", Gastroenterology, 82: 445-452, 1982 Sax, H.C., Talmini, M.A., Brackett, K., et al., "Hepatic steatosis in total parenteral nutrition: failure of fatty infiltration to correlate with abnormal serum hepatic enzymes levels", Surgery, 100: 697-704, 1986 Reif, S., Tano, M., Oliverio, R., et al., "Total parenteral nutrition-induced steatosis: Reversal by parenteral lipid infusion", J. Parent. Ent. Nutr., 15: 102-104, 1991 Nussbaum, M.S., Fisher, J., "Pathogenesis of hepaticsteatosis during total parenteral nutrition", Surg. Annu., 23: 1-11, 1991 Liver, Vol. 45, No. 2, Yamamoto Keisuke, 66-69, 2004 Spaniol, M., Kaufmann, P., et al., "Mechanisms of liver steatosis in rats with systemic carnitine deficiency due to treatment with trimethylhudraziniumhydraziniumpropionate", J. Lipd Res., 44: 144-153, 2003 Fromentry, B. and Pessayre, D., "Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity", Pharmacol. Ther., 67: 101-154, 1995 Toshihisa Ishikawa, Allikimets, R., Dean, M., Higgins, C., Ling, V. & Wain, H.M., Pharmacokinetics, 15: 8-19, 2000. Iichiro Iiri, Hiroshi Takane, Kenji Otsubo, Mechanism of important drug interactions via transporters, Pharmacy, 54 (11): 2769-2775, 2003 Wijnholds, J., Evers, R., vanLeusden, MR, Mol, CA, Zaman, GJ, Mayer, U., Beijnen, JH, van der Valk, M., Krimpenfort, P. and Borst, P., "Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistanse-associated protein "Nature Med., 3: 1275-1279, 1997 McAleer, MA, Breen, MA, White, NL & Matthews, N. "pABC11 (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells ". J. Biol. Chem. 274: 23541-23548, 1999 Wijnholds, J., Mol, CA, van Deemter, L., de Haas, M., Scheffer, GL, Baas, F., Beijnen, JH, Scheper, RJ, Hatse, S., de Clercq, E., Balzarini , J. & Borst, P. "Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs" Proc. Natl. Acad. Sci. USA 97: 7476-7481,2000 Jedlitschky, G., Burchell, B. & Keppler, D. "The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides" J. Biol. Chem. 275: 30069-30074, 2000 Tazuke, Y., Kiristioglu, I., Heidelberger, K. P., Eisenbraun, M. D. & Teitelbaum, D. H., "Hepatic P-glycoprotein changes with total parenteral nutrition administration", Journal of Parenteral and Enteral Nutrition, 28, 1-6, 2004

An object of the present invention is to prevent side effects caused by administration of high-calorie infusions, in particular, to suppress a decrease in activity of various enzymes such as drug metabolizing enzymes such as P450 in the liver and β-oxidase involved in fatty acid oxidation. Another object of the present invention is to provide a novel side effect inhibitor capable of suppressing the overexpression of ABC transporters involved in drug resistance in cells, a new infusion composition using the same, and a method for preparing them.

The inventor has conducted various studies on the technical means that can achieve the above object, and as a result, the above-mentioned side effects caused by administration of a high calorie infusion containing normal sugar, amino acid, electrolyte, etc. are caused by adding a fat emulsion to the infusion. The knowledge that it can be effectively prevented or suppressed by blending was obtained. In addition, administration of a high-calorie infusion solution containing this fat emulsion can maintain the activity of various enzymes including drug metabolizing enzymes in the liver, and does not cause overexpression of ABC transporter. The present inventors have found the fact that the onset of various clinical symptoms can be prevented or alleviated. In particular, it has been found that the maintenance of the activity of drug metabolizing enzymes or the prevention of the decrease in activity by administration of an infusion solution containing this fat emulsion can be expected to have a particularly beneficial effect on newborns, premature infants, etc. with low drug metabolizing enzyme activity. .

  The present invention has been completed as a result of further research based on these findings. The gist of the present invention is as described in the following items 1-17.

Item 1. A side-effect preventing agent, which comprises a fat emulsion, which is added to the infusion composition in order to prevent side effects caused by administration of the infusion composition.

  Item 2. The side effect inhibitor according to Item 1, wherein the side effect is a decrease in activity of a drug metabolizing enzyme in the liver.

Item 3. The side-effect preventing agent according to Item 1, wherein the side effect is a decrease in the activity of β-oxidase and related enzymes involved in fatty acid oxidation in the liver.

  Item 4. The side effect inhibitor according to Item 1, wherein the side effect is overexpression of an ABC transporter involved in drug resistance in cells.

Item 5. The side effect inhibitor according to any one of Items 1-4, wherein the fat emulsion is obtained by emulsifying soybean oil using egg yolk lecithin as an emulsifier.

Item 6. The side-effect preventing agent according to any one of Items 1-5, wherein the fat emulsion has an average particle size of 0.17 μm or less.

  Item 7. The side-effect preventing agent according to any one of Items 1-6, wherein the infusion composition contains a sugar, an amino acid, and an electrolyte.

Item 8. The side effect inhibitor according to Item 7, wherein the infusion composition further contains at least one phosphorus component selected from the group consisting of polyhydric alcohols or sugar phosphates and salts thereof.

Item 9. The side effect inhibitor according to Item 7 or 8, wherein the infusion composition further contains at least one coloring agent selected from the group consisting of sodium bisulfite, thioglycerol, and dithiothreitol. .

  Item 10. The side effect inhibitor according to Item 1-9, wherein the pH of the infusion composition containing the side effect inhibitor is adjusted from 5.0 to 8.0.

  Item 11. The side effect inhibitor according to Item 10, wherein the pH is adjusted by adding citric acid.

Item 12. The side-effect preventing agent according to Item 1, wherein the infusion composition containing the side-effect preventing agent has the following composition:
Oil 5-50g / L
Emulsifier 0.5-10g / L
Sugar 50-250g / L
L-isoleucine 0.5-5g / L
L-Leucine 0.5-7g / L
L-Valine 0.5-5g / L
L-Lysine 0.5-7g / L
L-methionine 0.1-4g / L
L-Phenylalanine 0.3-5g / L
L-Threonine 0.3-5g / L
L-tryptophan 0.1-1g / L
L-Arginine 0.3-7g / L
L-Histidine 0.2-3g / L
Glycine 0.2-3g / L
L-Alanine 0.3-5g / L
L-proline 0.2-5g / L
L-Aspartic acid 0.03-2g / L
L-Serine 0.2-3g / L
L-tyrosine 0.03-0.5g / L
L-glutamic acid 0.03-2g / L
L-cysteine 0.03-1g / L
Sodium 15-60mEq / L
Potassium 10-50mEq / L
Calcium 3-15mEq / L
Magnesium 2-10mEq / L
Chlorine 0-80mEq / L
Phosphorus 1-15mEq / L
Zinc 0-30 μmol / L.

  Item 13. The side effect inhibitor according to Item 12, wherein the infusion composition containing the side effect inhibitor further contains vitamins and trace elements.

  Item 14. A method for preventing side effects caused by administration of an infusion composition, which further comprises adding a fat emulsion to the infusion composition.

Item 15. A method for producing an infusion composition with reduced side effects, comprising adding a fat emulsion to the infusion composition.
Item 16. Item 14 or Item 15 wherein the amount of fat emulsion added to the infusion composition is 5 to 50% by weight
The method described in 1.

  Hereinafter, the side effect inhibitor of the present invention and the high-calorie infusion composition containing the same will be described in detail.

(1) The side effect inhibitor of the present invention The side effect inhibitor of the present invention comprises a fat emulsion, that is, an emulsion obtained by emulsifying fats and oils in water using an emulsifier. The fat emulsion can be prepared according to a conventional method. For example, a fat emulsion can be prepared by adding fats and oils and an emulsifier to water, stirring to prepare a crude emulsion, and then emulsifying the crude emulsion by a conventional method such as a high-pressure emulsification method.

As fats and oils, any fats and oils can be used as long as they are edible oils. Examples of the oil include vegetable oil (
Soybean oil, cottonseed oil, safflower oil, corn oil, coconut oil, perilla oil, sesame oil, etc.), fish oil (eg, cod liver oil), medium chain fatty acid triglycerides (triglycerides of fatty acids with 8-10 carbon atoms) [commercial product name: Panaceto "(manufactured by Nippon Oil & Fats Co., Ltd.)," ODO "(manufactured by Nisshin Oil Co., Ltd.)," Coconard "(manufactured by Kao Corporation)," Miglyol "(Mitsuba Trading Co., Ltd.), etc.], chemically synthesized triglycerides [2-linole oil-1 , 3-dioctanoylglycerol (8L8), 2-linoleoyl-1,3-didecanoylglycerol (10L10), and the like]. These can be used alone or in combination of two or more.

As the emulsifier, for example, various emulsifiers known to be used in pharmaceutical preparations can be used. Examples of the emulsifier include egg yolk phospholipid, hydrogenated egg yolk phospholipid, soybean phospholipid, hydrogenated soybean phospholipid and the like, and nonionic surfactants (commercial product name: “Pluronic F68” (manufactured by BASF), “HCO- 60 "(Nikko Chemicals Co., Ltd.) etc.]. These can be used alone or in combination of two or more. Particularly preferred oils and fats are soybean oil, and particularly preferred emulsifiers are egg yolk phospholipid (egg yolk lecithin).

The ratio of the fats and emulsifiers used in the preparation of the fat emulsion is not particularly limited as long as an oil-in-water fat emulsion is obtained. Usually, fats and oils are used in the resulting fat emulsion at a rate of about 0.1 to 30 W / V% (hereinafter, unless otherwise specified,% indicates W / V%), preferably about 1 to 20%. The emulsifier is used in a range of about 0.01 to 10%, preferably about 0.05 to 5% in the resulting fat emulsion.

In the present invention, the average particle size of the fat emulsion is preferably adjusted to 0.17 μm or less. By using this particle size, stability is improved as compared with the conventional fat emulsion (average particle size 0.2 to 0.3 μm), and phase separation of the fat emulsion due to the difference in specific gravity can be effectively suppressed. According to the study of the present inventors, a fat emulsion having an average particle size of 0.17 μm or less is easily obtained by adding and emulsifying at least one selected from the group consisting of glycerin and glucose during preparation of the fat emulsion. be able to. That is, the present inventor has found that glycerin and glucose have a specific action for promoting micronization. The average particle size of the fat emulsion can be measured according to a conventional measuring method such as a light scattering method.

One specific example of a method for producing a fat emulsion particularly suitable for the present invention is as follows. That is, adding fat and emulsifier to water and adding at least one selected from glycerin and glucose,
Thereafter, stirring is performed to prepare a crude emulsion, and then the crude emulsion is emulsified by a conventional method such as a high-pressure emulsification method. When employing the above-described high-pressure emulsification method, the method is carried out using an emulsifier such as a Manton gorin homogenizer, for example, about 2 to 50 times, preferably about 5 to 50 times under the condition of about ²⁰ to 700 kg / cm ^2. It can be carried out by passing through about 20 times. 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 a crude emulsion prepared using an oil and fat and an emulsifier to emulsify. Good. As for the amount of glycerin and / or glucose used, it is usually appropriate that the resulting fat emulsion contains about 30 to 70%, preferably about 40 to 60% of glycerin and / or glucose.

  Although it is not particularly necessary in the side effect inhibitor of the present invention, various additives known to be usually added and blended in fat emulsions can be further blended. Examples of the additive include an antioxidant, an antibacterial agent, a pH adjuster, and an isotonic agent. Antioxidants include sodium metabisulfite, sodium sulfite, sodium bisulfite, potassium metabisulfite, potassium sulfite, sodium thiosulfate and the like. Antibacterial agents include sodium caprylate, methyl benzoate, ethylenediaminetetraacetic acid (EDTA), sodium bisulfite and the like. The pH adjuster includes hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid, sodium hydroxide, potassium hydroxide and the like. Examples of tonicity agents include glycerin; sugars such as glucose, fructose and maltol; sugar alcohols such as xylitol and sorbitol. Among these, the oil-soluble material can be used by being mixed in advance with the oil component constituting the emulsion. The water-soluble material can be mixed with water for injection or added and incorporated into the aqueous phase of the resulting fat emulsion. These addition amounts are obvious to those skilled in the art, and may be the same as those addition amounts conventionally known.

(2) Infusion composition containing the side effect inhibitor of the present invention The infusion composition containing the side effect inhibitor of the present invention contains a sugar, an amino acid and an electrolyte.

  In the infusion composition, various sugars can be used as the sugar. Of these, reducing sugars are preferably used. Examples of reducing sugars include glucose, fructose, and maltose. These reducing sugars can be used alone or in combination of two or more. Furthermore, these reducing sugars can be used in combination with sorbitol, xylitol and the like.

As the amino acid, various amino acids (essential amino acids and non-essential amino acids) conventionally used for amino acid infusions for the purpose of nutritional supplementation to living bodies can be used. Specifically, for example, L-isoleucine, L-leucine, L-valine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, L-arginine, L-histidine, glycine, L- Examples include alanine, L-proline, L-aspartic acid, L-serine, L-tyrosine, L-glutamic acid, L-cysteine and the like. These amino acids do not necessarily need to be used in the form of free amino acids, inorganic acid salts (for example, L-lysine hydrochloride, etc.), organic acid salts (for example, L-lysine acetate, L-lysine malate, etc.) , Ester forms that can be hydrolyzed in vivo (for example, L-tyrosine methyl ester, L-methionine methyl ester, L-methionine ethyl ester, etc.), N-substituted products (for example, N-acetyl-L-tryptophan, N- Acetyl-L-cysteine, N-acetyl-L-proline, etc.), dipeptides with peptide bonds of the same or different amino acids (for example, L-tyrosyl-L-tyrosine, L-alanyl-L-tyrosine, L-arginyl) -L-tyrosine, L-tyrosyl-L-arginine, etc.).

As the electrolyte, various water-soluble salts conventionally used for infusion can be used. The water-soluble salt includes, for example, various inorganic components (for example, sodium, potassium, calcium, magnesium, zinc, iron, copper, manganese, iodine, which are necessary for maintaining the function of the living body, the electrolyte balance of the body fluid, etc. , Phosphorus and the like). Specifically, for example, chloride, sulfate, acetate, gluconate, lactate and the like are included. These water-soluble salts may be hydrates.

In particular, it is preferable to use at least one phosphorus component selected from the group consisting of polyhydric alcohols or phosphate esters of sugars and salts thereof as a source of phosphorus, which is one of the electrolytes. Examples of the polyhydric alcohol phosphate include glycerophosphoric acid, mannitol-1-phosphate, and sorbitol-1-phosphate. Examples of sugar phosphates include glucose-6-phosphate, fructose-6-phosphate, mannose-6-phosphate, and the like. As salts of these phosphate esters, alkali metal salts such as sodium salts and potassium salts are preferably used. Preferable phosphoric acid ester salts include sodium salt or potassium salt of glycerophosphoric acid.

Preferred embodiments of the electrolyte component include the following compounds.
sodium:
Sodium chloride, sodium lactate, sodium acetate, sodium sulfate, sodium glycerophosphate, etc.
potassium:
Potassium chloride, potassium glycerophosphate, potassium sulfate, potassium acetate, potassium lactate, etc.
calcium:
Calcium gluconate, calcium chloride, calcium glycerophosphate, calcium lactate, calcium pantothenate, calcium acetate, etc.
magnesium:
Magnesium sulfate, magnesium chloride, magnesium glycerophosphate, magnesium acetate, magnesium lactate, etc.
Rin:
Potassium glycerophosphate, sodium glycerophosphate, magnesium glycerophosphate, calcium glycerophosphate,
zinc:
Zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, zinc acetate, etc.

The types, blending ratios and concentrations of sugars, amino acids, electrolytes and fat emulsions in the infusion composition containing the side effect inhibitor of the present invention depend on the intended use of the infusion solution, the degree of disease of the patient who administers it, the symptoms, etc. It can be determined as appropriate. A preferable blending ratio of each component is selected from the following range.
Oil 5-50g / L
Emulsifier 0.5-10g / L
50-50 g / L sugar
L-isoleucine 0.5-5g / L
L-Leucine 0.5-7g / L
L-Valine 0.5-5g / L
L-Lysine 0.5-7g / L
L-methionine 0.1-4g / L
L-Phenylalanine 0.3-5g / L
L-Threonine 0.3-5g / L
L-tryptophan 0.1-1g / L
L-Arginine 0.3-7g / L
L-Histidine 0.2-3g / L
Glycine 0.2-3g / L
L-Alanine 0.3-5g / L
L-proline 0.2-5g / L
L-Aspartic acid 0.03-2g / L
L-Serine 0.2-3g / L
L-tyrosine 0.03-0.5g / L
L-glutamic acid 0.03-2g / L
L-cysteine 0.03-1g / L
Sodium 15-60mEq / L
Potassium 10-50mEq / L
Calcium 3-15mEq / L
Magnesium 2-10mEq / L
Chlorine 0-80mEq / L
Phosphorus 1-15mEq / L
Zinc 0-30 μmol / L.

  The infusion composition containing the side effect inhibitor of the present invention can be prepared by dissolving and dispersing each of the above components in purified water (for example, water for injection). As a preferred preparation method, sugar infusion, amino acid infusion, electrolyte infusion and fat emulsion are prepared individually, sterilized by heat sterilization, etc., and then an appropriate amount of each infusion is aseptically so that each component has a desired concentration. It is possible to adopt a method of mixing with. A sugar infusion, an amino acid infusion, and an electrolyte infusion can be prepared according to a conventional method, and a fat emulsion can be prepared by the method described above.

The infusion solution thus prepared is filled in a glass container, a plastic (for example, polypropylene, polyethylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, etc.) container (for example, a bag or bottle), and then an inert gas (for example, nitrogen). Gas, helium gas, etc.) and sealed, and then subjected to a sterilization process to be sterilized into a product. Sterilization can be performed according to a conventional method. For example, it can be performed by a heat sterilization method such as high pressure steam sterilization, hot water immersion sterilization, hot water shower sterilization. When using a plastic container, it is preferable to sterilize in an atmosphere substantially free of oxygen.

In addition, the infusion prepared in accordance with the present invention has a solution containing a fat emulsion and sugar sealed in the first chamber of a sealed container having two chambers that are blocked by providing isolation means in the communication portion, and the amino acid in the second chamber It is also possible to make a product form that is heat-sterilized after enclosing a solution containing the electrolyte and the electrolyte. With this product, a desired infusion solution can be prepared by removing the isolation means at the time of use, allowing the first chamber and the second chamber to communicate with each other, and mixing the indoor fluids.

More specifically, FIG. 1 is a schematic view of the product. In the figure, a container 1 is made of a plastic material or the like, and has a first chamber 2 and a second chamber 3 for storing an infusion solution. Room 1 and 2
The chamber 3 can communicate with the communication part 4. That is, the first chamber 2 and the second chamber 3 are isolated by an isolation means such as a weak seal provided in the communication portion 4. This product starts with port 5
A liquid containing a fat emulsion and a sugar is injected into the first chamber 2 via the port, and a liquid containing an amino acid and an electrolyte is injected into the second chamber 3 via the port 6. The liquids are preferably injected into the first chamber 2 and the second chamber 3 under an inert gas (for example, nitrogen gas, argon gas). Next, after injecting each liquid into the first chamber 2 and the second chamber 3, the ports 5 and 6 are sealed, and the container 1 is heat sterilized according to a conventional method to obtain a product. Each sterilized solution can be stored in that state. In this product, a desired infusion solution can be prepared by removing the isolation means at the time of use, allowing the first chamber 2 and the second chamber 3 to communicate with each other, and mixing the liquids contained in each of them. The infusion solution thus obtained can be aseptically removed from the port 7 via a tube (not shown) and administered to a living body.

In the above product, the preparation of the liquid containing the fat emulsion and sugar contained in the first chamber 2 can be performed by various methods. For example, it can be prepared by adding sugar to the fat emulsion prepared by the method described above. Also, a liquid containing a fat emulsion and sugar can be prepared by adding sugar in advance when preparing the fat emulsion. The liquid containing the fat emulsion and sugar is the concentration of the liquid stored in the second chamber 3 (i.e., the liquid containing amino acids and electrolytes), the concentration of each liquid injected into the first chamber 2 and the second chamber 3. The composition can be appropriately adjusted depending on the volume ratio. The liquid containing the fat emulsion and sugar is about 0.1 to 30% fat, preferably about 1 to 20%, more preferably about 2 to 10%, about 0.01 to 10% emulsifier, preferably about 0.05 to 5%. More preferably, the composition contains about 0.1 to 1%, about 5 to 60% of sugar, preferably about 7 to 40%, more preferably about 10 to 30%.

Further, the liquid containing the amino acid and the electrolyte accommodated in the second chamber 3 can be prepared by various methods. The liquid can be prepared by dissolving various amino acids and an electrolyte in purified water such as water for injection. The liquid containing the amino acid and the electrolyte is the first.
The composition is appropriately adjusted according to the concentration of the liquid contained in the chamber 2 (that is, the infusion solution containing the fat emulsion and sugar), the volume ratio of each liquid injected into the first chamber 2 and the second chamber 3, etc. be able to. In general, the liquid has a total amino acid content of about 1 to 15%, preferably about 2 to 13%, more preferably about 3 to 12%. As an electrolyte, sodium is about 50 to 180 mEq / L, potassium is about 40 to 135 mEq / L, calcium. The composition contains about 10 to 50 mEq / L, about 5 to 30 mEq / L of magnesium, about 0 to 225 mEq / L of chlorine, about 3 to 40 mEq / L of phosphorus, and about 0 to 100 μmol / L of zinc.

The liquid property of the infusion product prepared as described above is not particularly limited, but considering the safety to the living body, it is appropriate that the pH is adjusted to 5.0 to 8.0, preferably 5.5 to 7.5. is there. In particular, when a polyhydric alcohol or a sugar phosphate ester and a salt thereof are used as a phosphorus supply source, there is an advantage that precipitation can be effectively suppressed even at a relatively high pH. The pH adjuster used for adjusting the pH of the infusion solution is not particularly limited as long as it is physiologically acceptable. Usually, various acids are used as the pH adjuster. In particular, use of an organic acid is preferable. Examples of the organic acid include citric acid, gluconic acid, lactic acid, malic acid, maleic acid, malonic acid and the like. Among these, an organic acid having a chelating power for divalent metal ions is particularly preferable. The most preferred organic acid is citric acid. The pH adjuster can be added to each solution constituting the infusion solution at an appropriate time. For example, in the product shown in FIG. 1, a pH adjusting agent can be added to the liquid in the first chamber, the liquid in the second chamber, or both, respectively, so that each liquid can be adjusted to a pH within the above range.

In addition, an anti-coloring agent (for example, sodium bisulfite, thioglycerol, dithiothreitol, etc.) may be added to the infusion product in order to prevent the product from being colored during sterilization and storage. The addition amount of the coloring inhibitor is usually about 1% or less. For example, in the product shown in FIG. 1, the anti-coloring agent can be added to the first indoor fluid, the second indoor fluid, or both.

Furthermore, vitamins (for example, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, etc.) can be appropriately added to the infusion product as necessary. These vitamins can also be added to the first indoor fluid, the second indoor fluid, or both, for example, in the product shown in FIG. In addition, a buffer such as L-histidine and tris (hydroxymethyl) aminomethane may be added to the liquid stored in the first chamber. The amount of buffer added is usually about 1% or less.

  Thus, according to the present invention, the decrease in the activity of the drug metabolizing enzyme in the liver, which has good storage stability, has good storage stability without causing precipitation, phase separation, alteration, coloring, etc., was suppressed. Infusion products can be provided. This product is intravenously administered to a patient as it is or diluted with water, alone or mixed with other drugs as necessary. Furthermore, it can also be used for administration in dosage forms such as oral and enteral.

It is the schematic which shows one embodiment of the product which accommodated the infusion solution which mix | blended the activity fall side effect inhibitor of the drug-metabolizing enzyme based on this invention.

  Examples are given below to illustrate the present invention in more detail.

Test for decreased activity of drug metabolizing enzyme P450 in the liver.This example shows the expression of drug metabolizing enzyme (P450) at the mRNA level under energy overdosage by sugar (glucose) loading using a TPN model of young rats. The effects and the effects of fat administration were examined, and were performed as follows.
<Test method>
(1) Test animals The test animals were Masahiro Ohshita, Mari Yamaguchi, Kazuhisa Doi, Nobuhiko Ueda, Isao Hiraoka, Hiroo Tsukahara, Seiji Tashiro (The 18th Annual Meeting of the Japan Society for Parenteral and Enteral Nutrition) (Abstract Collection), Vol.18 Special Issue, 91 (2003)), a young rat TPN model (3 weeks old male SD rat, weight 60-70 g) was used.

(2) Test infusion solution (TPN solution) containing the side effect inhibitor of the present invention
As a test infusion solution (TPN solution) containing the side effect inhibitor of the present invention, a sugar-containing fat emulsion prepared by emulsifying soybean oil with egg yolk lecithin, and an infusion solution containing an amino acid and an electrolyte were used. Their compositions and preparation methods are as follows.

Dissolve 300 mL of glucose in 500 mL of sugar-containing fat emulsion water, add 39.6 g of purified soybean oil and 5.702 g of egg yolk phospholipid (purified egg yolk lecithin), coarsely emulsify the mixture with a homomixer, add water to make a total volume of 600 mL A crude emulsion was obtained. The obtained crude emulsion was emulsified with a Menton Gorin homogenizer (manufactured by Gorin, 15M-8TA type) until the average particle size became 0.17 μm or less to obtain an emulsion. Water and 0.06 g of L-histidine as an additive were added to 300 mL of the obtained emulsion to make a total volume of 600 mL. The final solution pH was adjusted to 4.9 to 6.1 with hydrochloric acid.

Each of the following amino acids and electrolytes shown below was added and dissolved in water for injection heated to about 80 ° C. containing an amino acid and an electrolyte under a nitrogen stream to a predetermined concentration. After adding 15 mg of sodium hydrogen sulfite, the pH of the solution was adjusted to 6.2 with citric acid to prepare an amino acid / electrolyte infusion solution.

Amino acid / electrolyte infusion composition (in 300 mL)
L-Leucine 4.200g
L-isoleucine 2.400g
L-valine 2.400g
L-Lysine 2.4g
L-methionine 1.200g
L-Phenylalanine 2.400g
L-threonine 1.800g
L-tryptophan 0.360g
L-Arginine 3.150g
L-Histidine 1.500g
Glycine 1.590g
L-alanine 2.550g
L-Proline 1.800g
L-aspartic acid 0.450 g
L-serine 0.900g
L-tyrosine 0.150g
L-glutamic acid 0.450 g
L-cysteine 0.223g
Sodium chloride 0.585g
Potassium chloride 1.050g
Calcium gluconate 1.906g
Magnesium sulfate 0.616g
Potassium glycerophosphate 50% solution 3.206g
Anhydrous sodium acetate 2.051g
Zinc sulfate 2.876mg
Sodium sulfite 15mg.

Preparation of test infusion solution (TPN solution) The above sugar-containing fat emulsion was mixed with an infusion solution containing an amino acid and an electrolyte, and 0.9 mL of a comprehensive vitamin preparation (trade name: “Otsuka MV Injection”) was added to the present invention. A test infusion solution (TPN solution) containing a side effect inhibitor was prepared.

  In addition, for comparison, a comparative infusion solution (TPN solution) in which glucose was increased so that the same amount of heat as that of the fat component of the present invention side effect inhibitor was obtained instead of blending the present side effect inhibitor. Was prepared as follows. That is, the following components (amount relative to the total amount of 900 mL) were added to water, and 0.9 mL of a multivitamin (trade name: “Otsuka MV Note”) was further added.

Glucose 194.6g
L-Leucine 4.2g
L-isoleucine 2.4g
L-Valine 2.4g
L-lysine acetate 4.44g
L-threonine 1.71g
L-tryptophan 0.6g
L-methionine 1.17g
L-Phenylalanine 2.1g
L-cysteine 0.3g
L-tyrosine 0.15g
L-Arginine 3.15g
L-Histidine 1.5g
L-alanine 2.4g
L-proline 1.5g
L-serine 0.9g
Aminoacetic acid 1.77g
L-aspartic acid 0.3g
L-glutamic acid 0.3g
Potassium acetate 1.08g
Calcium gluconate 1.87g
Magnesium sulfate 0.62 g
Potassium dihydrogen phosphate 0.55g
Zinc sulfate 3.0g
Sodium chloride 1.99g
Potassium chloride 0.89g
The composition of each infusion thus obtained is summarized in the following table.

(3) Experimental method
Three-week-old SD male rats (body weight 60-70 g) were divided into 3 groups of 5 animals, 5 animals and 4 animals. One of them
Each group of rats (invention group, 5 animals) and 2 groups (comparison group, 4 animals) was placed with a central venous catheter under ether anesthesia and administered the following TPN over 4 days. As the TPN solution, a test infusion solution containing the side effect inhibitor of the present invention prepared in the above (2) was used in Group 1. Two groups used comparative infusions. In addition, each rat of group 3 (control group, 5 animals) was allowed to freely take CRF-1 (Oriental Yeast Co., Ltd., fat content of about 15%) and water as food. The experimental animals to be administered TPN were fasted overnight from the day before the administration start date.

The dose calorie in the TPN administration group (Group 1 and Group 2) is 900 kcal / L. The administration rate of the TPN solution started at 3 mL / kg / hr, and increased to 10, 20, and 30 mL / kg / hr every second half of the day, and 40 mL / kg / hr after the third day.

(4) Preparation of total RNA
At the end of the 4 day experimental period, livers were collected from each group of rats. About 10 mg was collected from the same part of the liver of each rat, and Total RNA was extracted from the liver piece as follows using QIAshredder (Qiagen) and Rneasy Mini Kit (Qiagen). All extraction operations were performed at room temperature.

That is, RLT solution containing β-mercaptoethanol (Sigma Chemical Co.) (RLT solution (supplied as RNeasy Mini Kit (50)): β-mercaptoethanol = 100: 1) was put into a test tube in 1 mL portions, About 10 mg of collected liver was added and homogenized. 400 of the resulting homogenate
μL was added to a QIAshredder column (Qiagen Co., Ltd.) and centrifuged at 15,000 rpm for 2 minutes. 350 μL of the eluate was collected, and an equal amount of 70% ethanol solution was added thereto. After stirring using a test tube mixer three times for 10 seconds, the entire amount was added to an RNeasy Mini spin column (Qiagen Co., Ltd.), centrifuged at 12,000 rpm for 30 seconds, and the eluate in the collection tube was removed by suction. 700 μL of RW1 solution (supplied as RNeasy Mini Kit (50)) was added to the RNeasy Mini spin column, centrifuged at 12,000 rpm for 30 seconds, and the collection tube was replaced. 500 μL of RPE solution (supplied as RNeasy Mini Kit (50)) was added to the RNeasy Mini spin column, centrifuged at 12,000 rpm for 30 seconds, and the eluate in the collection tube was removed by suction. Add 500 μL of RPE solution to the RNeasy Mini spin column, centrifuge at 15,000 rpm for 2 minutes, and then add 1.5 mL of Collection
Replace the tube with 50 μL of RNeasy Mini spin column (RNeasy Mini Kit
(Supplied as (50)) was added and centrifuged at 10,000 rpm for 1 minute to elute the total RNA.

  The total RNA concentration thus obtained was calculated from the OD260 measurement result. In subsequent experiments, total RNA having a purity obtained from OD260 / OD280 of 1.6-1.7 was used.

The total RNA was diluted with a 50 μg / mL Yeast tRNA solution to adjust its concentration to 5 μg / mL. In addition, 50 μg / mL Yeast tRNA solution was prepared by adding Yeast tRNA (GIBCO BRL) to Distilled water (
Wako Pure Chemical Industries, Ltd.).

(5) Measurement of mRNA Using the ABI PRISMTM7700 Sequence Detection System, mRNA of housekeeping gene (β-actin) and drug metabolizing enzyme (P450) was quantified for the total RNA sample prepared in (4). Quantification was performed by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR).

The following molecular species were selected as mRNA of the drug metabolizing enzyme (P450).
CYP1A2, CYP2A2, CYP2B2, CYP2C11, CYP2D1, CYP2D2, CYP2E1, CYP3A1, CYP3A2, and CYP4A1
RT-PCR was performed in a 50 μL / tube system using TaqMan One-Step RT-PCR Master Mix Reagents Kit (Applied Biosystems) containing 300 nM Forward Primer, 900 nM Reverse Primer and 200 nM TaqMan Probe. The temperature was maintained at 48 ° C. for 30 minutes, and then kept at 95 ° C. for 10 minutes, followed by 40 cycles of 95 ° C. for 15 seconds and 60 ° C. for 1 minute, and the fluorescence intensity was measured for each cycle.

  The reaction solution was Micro Amp Optical 96-well Plate (Applied Biosystems), the cover was Optical Adhesive Covers (Applied Biosystem), and the pad placed on the cover was Optica; Cover Compression Pads (Applied Biosystem). Using.

Table 2 below shows the base sequences of primers and probes used for quantification of each mRNA, the GeneBank accession number of each molecular species, and the position from the start codon according thereto. Each primer and probe were synthesized using an automatic synthesizer according to a conventional method.

(6) Calculation method and statistical processing Table 3 below shows the result of calculating the quantitative value of mRNA of each P450 molecular species according to the ΔCt method using β-actin mRNA as an endogenous control, as an average value ± standard deviation.

(7) Results and Discussion From the results shown in Table 3, the following is clear. That is, the mRNA expression level of CYP1A2 in the comparison group decreased to 1% or less (0.76%) with reference to the control group (100%), whereas the mRNA expression level of CYP1A2 was maintained at about 40% in the present invention group. Has been. Although there is a degree of difference in other molecular species of P450, the comparison group decreased from about 1.3% to 31% compared to the control group,
In the group of the present invention, about 32% to 84% is maintained. From this, it is clear that the present invention group can significantly suppress the decrease in the activity of P450, which is a drug metabolizing enzyme, based on the use of the fat emulsion.

Test for reducing activity of β-oxidase and its related enzymes involved in fatty acid oxidation in the liver This test was conducted in the same manner as in Example 1, using a test infusion containing the side effect inhibitor of the present invention,
Β-under-energy overdose with glucose (glucose) load using a TPN model of young rats
The effects on the expression of oxidase and related enzymes at the mRNA level and the effects of administration of fat were examined and were carried out as follows.

(1) Experimental method
Three-week-old SD male rats (body weight 60-70 g) were divided into three groups of 8, 6 and 7. One of them
Each group of rats (invention group, 7 animals) and 2 groups (comparative group, 6 animals) was placed with a central venous catheter under ether anesthesia and administered with the following TPN over 4 days. As a TPN solution, a test infusion solution containing the side effect inhibitor of the present invention having the composition shown in Table 1 prepared in the same manner as in Example 1 (2) was used as a TPN solution. In group 2, comparative infusions shown in Table 1 were used. In addition, each group of 3 rats (control group, 8 rats) was allowed to freely ingest CRF-1 (Oriental Yeast Co., Ltd., fat content of about 15%) and water as food. The experimental animals to be administered TPN were fasted overnight from the day before the administration start date.

The dose calorie in the TPN administration group (Group 1 and Group 2) is 900 kcal / L. The administration rate of the TPN solution was started at 3 mL / kg / hr, then increased to 10, 20, and 30 mL / kg / hr every half day, and 40 mL / kg / hr after the third day.

(2) Preparation of total RNA
At the end of the 4 day experimental period, livers were collected from each group of rats. About 10 mg was collected from the same part of the liver of each rat, and QIAshredder (Qiagen Co., Ltd.) and Rneasy M
TotalRNA was extracted as follows using ini Kit (Qiagen). All extraction operations were performed at room temperature.

That is, RLT solution containing β-mercaptoethanol (Sigma Chemical Co.) (RLT solution (supplied as RNeasy Mini Kit (50)): β-mercaptoethanol = 100: 1) was put into a test tube in 1 mL portions, About 10 mg of collected liver was added and homogenized. 400 of the resulting homogenate
μL was added to a QIAshredder column (Qiagen Co., Ltd.) and centrifuged at 15,000 rpm for 2 minutes. 350 μL of the eluate was collected, and an equal amount of 70% ethanol solution was added thereto. After stirring using a test tube mixer three times for 10 seconds, the entire amount was added to an RNeasy Mini spin column (Qiagen Co., Ltd.), centrifuged at 12,000 rpm for 30 seconds, and the eluate in the collection tube was removed by suction. 700 μL of RW1 solution (supplied as RNeasy Mini Kit (50)) was added to the RNeasy Mini spin column, centrifuged at 12,000 rpm for 30 seconds, and the collection tube was replaced. 500 μL of RPE solution (supplied as RNeasy Mini Kit (50)) was added to the RNeasy Mini spin column, centrifuged at 12,000 rpm for 30 seconds, and the eluate in the collection tube was removed by suction. Add 500 μL of RPE solution into the RNeasy Mini spin column, centrifuge at 15,000 rpm for 2 minutes, replace with 1.5 mL collection tube, and add 50 μL of Rnase free water (RNeasy Mini Kit in the RNeasy Mini spin column.
(Supplied as (50)) was added and centrifuged at 10,000 rpm for 1 minute to elute the total RNA.

  The total RNA concentration thus obtained was calculated from the OD260 measurement result. In subsequent experiments, total RNA having a purity obtained from OD260 / OD280 of 1.6-1.7 was used.

The total RNA was diluted with a 50 μg / mL Yeast tRNA solution to adjust its concentration to 5 μg / mL. In addition, 50 μg / mL Yeast tRNA solution was prepared by adding Yeast tRNA (GIBCO BRL) to Distilled water (
Wako Pure Chemical Industries, Ltd.).

(3) Measurement of mRNA Using the ABI PRISMTM7700 Sequence Detection System, the housekeeping gene (β-actin) and the following fatty acid β-oxidase and related to the total RNA sample prepared in (4) above Enzyme mRNA was quantified. Quantification was performed by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR).
<Fatase of fatty acid>
SCAD (Short-chain acyl-Coenzyme A dehydrogenase),
MCAD (Medium-chain acyl-Coenzyme A dehydrogenase),
LCAD (Long-chain acyl-Coenzyme A dehydrogenase),
VLCAD (Very long-chain acyl-Coenzyme A dehydrogenase),
ECH (Enoyl-Coenzyme A hydratase),
HAD (3-Hydroxyacyl coenzyme A dehydrogenase) or HADHSC (L-3-Hydroxyacyl-Coenzyme A dehydrogenase, short chain),
HADHB (Hydroxyacyl-Coenzyme A dehydrogenase), and
ACAA2 (Acetyl-Coenzyme acyltransferase 2, also known as: 3-Oxoacyl Coenzyme thiolase).
<Enzymes related to β-oxidation of fatty acids>
LC-ACS (Long-chain acyl-Coenzyme A synthetase, aka Fatty acid Coenzyme A ligase, long chain 2 (Facl2)),
CPTI (Carnitine palmitoyltransferase I), and
CPTII (Carnitine palmitoyltransferase II).

RT-PCR was performed in a 50 μL / tube system using TaqMan One-Step RT-PCR Master Mix Reagents Kit (Applied Biosystems) containing 300 nM Forward Primer, 900 nM Reverse Primer and 200 nM TaqMan Probe. The temperature was maintained at 48 ° C. for 30 minutes, and then kept at 95 ° C. for 10 minutes, followed by 40 cycles of 95 ° C. for 15 seconds and 60 ° C. for 1 minute, and the fluorescence intensity was measured for each cycle.

  The reaction solution was Micro Amp Optical 96-well Plate (Applied Biosystems), the cover was Optical Adhesive Covers (Applied Biosystem), and the pad placed on the cover was Optica; Cover Compression Pads (Applied Biosystem). Using.

Table 4 below shows the base sequences of primers and probes used for quantification of each mRNA, the GeneBank accession number of each molecular species, and the position from the start codon according thereto. Each primer and probe were synthesized using an automatic synthesizer according to a conventional method.

(4) Calculation method and statistical processing Table 5 below shows the result of calculating the quantitative value of mRNA of each enzyme according to the ΔCt method using β-actin mRNA as an endogenous control, as an average value ± standard deviation.

(5) Results and Discussion From the results shown in Table 5, the following is clear. That is, the expression level of LC-ACS mRNA in the comparison group was reduced to 29% with the control group as a reference (100%), whereas it was maintained at about 124% in the present invention group. Other enzymes include CPTI, CPTII, SCAD, MCAD, VLCAD, ECH, HAD, Hadhb
And ACAA2 expression levels were 55, 72, 42, 18, 51, 52 in the comparison group compared to the control group, respectively.
, 42, 17, 67, 232%, while in the present invention group, it is maintained at 74, 134, 138, 73, 103, 131, 97, 126, 160, 96%, respectively. From this, it is clear that the present invention group can significantly suppress the decrease in the activity of fatty acid β-oxidase and related enzymes based on the use of the fat emulsion.

Test for overexpression of ABC transporter In this example, in the same manner as in Example 2, a test transfusion containing the side effect inhibitor of the present invention was used, and a TPN model of young rats was used to determine the sugar (glucose) load. Using the ABI PRISMTM7700 Sequence Detection System, the following effects on the expression of ABC transporters at the mRNA level and the fat content of total RNA samples prepared from test rats that received TPN administration under energy overdose The effect of the administration of this was investigated, and was performed using the following real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR).
<ABC Transporter>
ABCB1 (MDR1 / Pgp1),
ABCC1 (MRP1), and
ABCC5a (MRP5).

Table 6 below shows the base sequences of primers and probes used for quantification of each mRNA, the GeneBank accession number of each molecular species, and the position from the start codon according thereto. Each primer and probe were synthesized using an automatic synthesizer according to a conventional method.

  Table 7 below shows the results of calculating the quantitative values of mRNA of each enzyme according to the ΔCt method using β-actin mRNA as an endogenous control.

From the results shown in Table 7, the following is clear. That is, the ABCB1 mRNA expression level in the comparison group increased to 1582% relative to the control group (100%), whereas the expression level in the present invention group was about 61%, and the increase (overexpression) was not observed. I couldn't. The expression levels of ABCC1 and ABCC5a were also increased to 144% and 201% in the comparison group compared to the control group, respectively, whereas they were maintained at 91% and 97% in the present invention group. There wasn't.

From this, it is clear that the present invention group can significantly suppress overexpression of ABC transporter based on the use of fat emulsion.

1 container
2 Room 1
3 Room 2
4 Communication part
5,6,7 ports

Other information content:
SEQ ID NO: 1, 2, 4, 5, 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, 28, 29, 31, 32, 34, 35 , 37, 38, 40, 41, 43, 44, 46, 47, 49, 50, 52, 53, 55, 56, 58, 59, 61, 62, 64, 65, 67, 68, 70, 71, 73 And 74 are primer sequences, and SEQ ID NOs: 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60 , 63,
66, 69, 72 and 75 are probe sequences.

Claims (6)

Drug-metabolizing enzyme activity characterized by comprising a fat emulsion blended in the infusion composition in order to suppress the decrease in the activity of the drug-metabolizing enzyme in the liver caused by administration of the infusion composition containing sugar, amino acid and electrolyte Reduction inhibitor. 2. The drug metabolic enzyme activity decrease inhibitor according to claim 1, wherein the fat emulsion is obtained by emulsifying soybean oil using egg yolk lecithin as an emulsifier. The drug metabolic enzyme activity decrease inhibitor according to claim 1 or 2, wherein the fat emulsion has an average particle size of 0.17 µm or less. The drug-metabolizing enzyme activity decrease inhibitor according to any one of claims 1 to 3, wherein the drug-metabolizing enzyme is cytochrome P450. The infusion composition further comprises at least one phosphorus component selected from the group consisting of a polyhydric alcohol or a sugar phosphate ester and a salt thereof, and the drug metabolizing enzyme activity reduction according to any one of claims 1 to 4 Inhibitor. The drug-metabolizing enzyme according to any one of claims 1 to 5, wherein the infusion composition further contains at least one color-preventing agent selected from the group consisting of sodium bisulfite, thioglycerol and dithiothreitol. Activity decrease inhibitor.

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