Infusion product

Abstract

To provide an infusion product that houses, in one chamber of an infusion bag, a low-pH solution containing sugar in high concentrations, but yet suppresses the discoloration of the solution.SOLUTION: An infusion product has a multi-chamber infusion bag at least having mutually separated first and second chambers, a sugar-containing solution housed in the first chamber, and an amino acid-containing solution housed in the second chamber, where the sugar-containing solution contains 50 w / v% or more of sugar and has a pH of 4 or less. The sugar-containing solution is blended with citric acid and a conjugate base of citric acid, making it possible to suppress the coloring of the sugar-containing solution in the infusion product.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an infusion product, more specifically to an infusion product that contains a low-pH liquid medicine containing a high concentration of sugar in one chamber of an infusion bag, while suppressing discoloration of the liquid medicine. [Background technology]

[0002] Intravenous administration of nutrient-containing infusion preparations is widely used to maintain the life and nutrition of patients. In particular, glucose-added electrolyte infusions, which aim to replenish electrolytes, water, and calories, are highly useful as maintenance infusion preparations.

[0003] For example, Patent Document 1 discloses a glucose-added electrolyte infusion as a maintenance infusion formulation intended to actively replenish calories in addition to replenishing electrolytes and water, which contains 8.0 to 12.0 w / v% glucose and predetermined concentrations of sodium, potassium, calcium, magnesium, chloride, phosphorus, and acetate ions, and whose pH is adjusted to 4.0 to 6.0 with citric acid, and also discloses that this glucose-added electrolyte infusion is stable as a formulation.

[0004] Furthermore, in order to maintain the life and nutrition of patients, it is common to simultaneously administer not only sugars and electrolytes but also amino acids. To perform such administration, as described in Non-Patent Document 1, an infusion preparation containing a liquid agent containing sugars, amino acids, and electrolytes in an infusion bag is widely used.

[0005] Here, if reducing sugars and amino acids are allowed to coexist in a liquid preparation, they will be denatured by the Maillard reaction. Therefore, it is common to use an infusion bag having multiple storage chambers separated by partitions that can be connected when in use, and to store reducing sugars and amino acids in separate storage chambers.

[0006] For example, Patent Document 2 discloses a high-calorie infusion solution for patients with kidney disease, which is a container with two compartments formed by a separating means, the first compartment filled with an amino acid solution and the second compartment filled with a glucose and electrolyte solution, and which, after mixing, has a ratio (NPC / N) of non-protein energy (NPC: kcal) to nitrogen (N: g) of 600 to 300 and is free of phosphorus and potassium. It also describes that the glucose and electrolyte solution in this high-calorie infusion solution for patients with kidney disease contains L-lactic acid and has a pH of 4.0 to 5.0. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Japanese Patent Application Publication No. 6-172191 [Patent Document 2] Japanese Patent Application Laid-Open No. 2004-107213 [Non-patent literature]

[0008] [Non-Patent Document 1] Pharmacology and Therapy 24(10),2151(1996) Summary of the Invention [Problem to be solved by the invention]

[0009] In infusion products including infusion bags with multiple storage compartments, the compositions of the liquids contained in each storage compartment are designed so that the liquid mixture prepared immediately before use has a predetermined composition. For example, a sugar-containing liquid contained in a storage compartment is prepared at a higher concentration, taking into account that it will be diluted by mixing with liquids contained in other storage compartments when prepared immediately before use. The present inventors have encountered the problem of discoloration occurring after storage when a sugar-containing liquid is prepared to contain a high sugar concentration of 50 w / v% or more in a high-calorie infusion product including an infusion bag with multiple storage compartments. Generally, discoloration of liquids containing high sugar concentrations can be suppressed by lowering the pH. However, when the sugar concentration is high (50 w / v% or more), even when lactic acid or acetic acid, an organic acid similar to lactic acid, is used to adjust the pH to 4 or below, as described in Patent Document 2, discoloration after storage was not sufficiently suppressed.

[0010] Therefore, an object of the present invention is to provide an infusion product that contains a low pH liquid medicine containing a high concentration of sugar in one chamber of an infusion bag, while further suppressing discoloration of the liquid medicine. [Means for solving the problem]

[0011] As a result of extensive research, the present inventors have surprisingly found that citric acid and its conjugate base exhibit excellent discoloration suppression properties specific to the liquid preparation. The present invention was completed through further research based on this finding.

[0012] That is, the present invention provides the following aspects. Item 1. A multi-chamber infusion bag including at least a first chamber and a second chamber isolated from each other, a sugar-containing liquid agent contained in the first chamber, and an amino acid-containing liquid agent contained in the second chamber, The sugar-containing liquid preparation comprises 50 w / v % or more of sugar and a citrate buffer, and has a pH of 4 or less. Item 2. The infusion product according to Item 1, wherein the sugar-containing liquid preparation does not contain acetic acid and its conjugate base and / or lactic acid and its conjugate base. Item 3. The infusion product according to claim 1, wherein the sugar-containing liquid has a light transmittance of 94% or more at 445 nm after storage at 60°C for 4 weeks. Item 4. The infusion product according to any one of Items 1 to 3, wherein the titratable acidity of a mixture of all liquid medications contained in the multi-chamber infusion bag is 5 to 15. Item 5. The infusion product according to any one of Items 1 to 4, wherein the pH of the mixture of all liquid agents contained in the multi-chamber infusion bag is between 4 and 7. Item 6. The infusion product according to any one of Items 1 to 5, wherein the mixture of all liquid agents contained in the multi-chamber infusion bag does not contain phosphorus. Item 7. The infusion product according to any one of Items 1 to 6, wherein the mixture of all liquid medications contained in the multi-chamber infusion bag does not contain potassium. Item 8. The infusion product according to any one of Items 1 to 7, wherein the bacterial growth rate is within 2-fold 24 hours after the mixture of all liquid medications contained in the multi-chamber infusion bag is contaminated with bacteria. Item 9. The infusion product according to any one of Items 1 to 8, wherein the patient to be administered the product is a patient with renal failure. Item 10. An infusion product comprising a multi-chamber infusion bag including at least a first chamber and a second chamber isolated from each other, a sugar-containing liquid contained in the first chamber, and an amino acid-containing liquid contained in the second chamber, wherein the sugar-containing liquid contains 50 w / v % or more of sugar and has a pH of 4 or less, A method for inhibiting discoloration of a sugar-containing liquid preparation in an infusion product, comprising blending citric acid and a conjugate base of a citrate salt with the sugar-containing liquid preparation. [Effects of the Invention]

[0013] According to the infusion product of the present invention, discoloration of a low pH liquid containing a high concentration of sugar can be suppressed even when the liquid is contained in one chamber of an infusion bag. [Brief explanation of the drawings]

[0014] [Figure 1] 1 is a graph showing the effect of inhibiting the coloring of a sugar-containing liquid preparation (pH 3.8) in an infusion product, obtained in Test Example 1. [Figure 2] 1 is a graph showing the effect of inhibiting the coloring of a sugar-containing liquid preparation (pH 4.0) in an infusion product, obtained in Test Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0015] 1. Infusion products The infusion product of the present invention comprises a multi-chamber infusion bag including at least a first and a second compartment separated from each other, a sugar-containing liquid contained in the first compartment, and an amino acid-containing liquid contained in the second compartment, wherein the sugar-containing liquid contains 50 w / v % or more of sugar, citric acid, and a conjugate base of a citrate salt (hereinafter also referred to as "citrate buffer"), and has a pH of 4 or less. The infusion product of the present invention will be described in detail below.

[0016] 1-1. Multi-chamber infusion bag A multi-chamber infusion bag includes at least a first chamber and a second chamber that are separated from each other. The first chamber and the second chamber may be separated by a partition that allows communication between them. Examples of such a partition include a partition formed with an easy-peel seal, a partition formed by clipping between the chambers, and a partition provided with an openable communication means. Among these partitions, from the viewpoints of industrial productivity of the infusion bag and ease of communication work, a partition formed with an easy-peel seal is preferred. The number of chambers (storage chambers) provided in the multi-chamber infusion bag may be two or more, for example, 2 to 4, preferably 2 to 3.

[0017] The multi-chamber infusion bag may be made of any of a variety of gas-permeable plastics commonly used for medical containers, including polyethylene, polypropylene, polyvinyl chloride, cross-linked ethylene-vinyl acetate copolymer, ethylene-α-olefin copolymer, and blends of these resins. The multi-chamber infusion bag may also be made of a laminate of multiple layers made of these resins.

[0018] 1-2. Sugar-containing liquid (Chamber 1) The first chamber of the multi-chamber infusion bag is filled with a sugar-containing liquid preparation. The sugar-containing liquid preparation contains 50 w / v% or more sugar and a citrate buffer, and is adjusted to a pH of 4 or less. Preferably, the sugar-containing liquid preparation further contains electrolytes and / or vitamins, and more preferably, further contains electrolytes and vitamins.

[0019] 1-2-1. Sugar The sugars to be incorporated into the sugar-containing liquid preparation can be any sugar used in sugar infusions intended to replenish nutrients to the living body, without any particular limitations. Specific sugars to be incorporated into the sugar-containing liquid preparation include reducing sugars such as glucose, fructose, and maltose, and non-reducing sugars such as xylitol, sorbitol, and glycerin. These sugars may be used alone or in combination of two or more. Among these sugars, reducing sugars are preferred, and glucose is more preferred, from the viewpoint of blood glucose level management.

[0020] The sugar content in the sugar-containing liquid is 50 w / v% or more. Even if sugar-containing liquids containing sugar at a high concentration of 50 w / v% or more are adjusted to a low pH of 4 or less by adding lactic acid or acetic acid, discoloration (yellowing) after storage cannot be sufficiently suppressed. However, in the infusion product of the present invention, discoloration after storage is effectively suppressed by adding a citrate buffer. Because the sugar-containing liquid in the infusion product of the present invention has excellent discoloration suppression effect after storage, effective discoloration suppression is possible even at higher sugar concentrations. From this perspective, examples of suitable sugar concentrations in sugar-containing liquids include 52.5 w / v% or more, preferably 55 w / v% or more, more preferably 57.5 w / v% or more, and even more preferably 58 w / v% or more. The upper limit of the sugar concentration in the sugar-containing liquid is not particularly limited, but from the perspective of obtaining excellent discoloration suppression effect after storage, examples include 62.5 w / v% or less, preferably 60 w / v% or less, and more preferably 59 w / v% or less.

[0021] Since the sugar-containing liquid preparation of the infusion product of the present invention is effectively inhibited from discoloring, the light transmittance at 445 nm of the sugar-containing liquid preparation after storage at 60°C for 4 weeks is evaluated to be 94% or more, preferably 95% or more, and the light transmittance is 100% or less, preferably 99% or less.

[0022] 1-2-2. Citrate buffer The sugar-containing liquid contains citric acid and a conjugate base of citric acid as a citrate buffer. The citrate buffer adjusts the pH of the sugar-containing liquid to 4 or less and prevents discoloration (yellowing) of the sugar-containing liquid after storage. As described above, sugar-containing liquids containing sugar at a high concentration of 50 w / v% or more cannot sufficiently prevent discoloration (yellowing) after storage even when the pH is adjusted to 4 or less by adding lactic acid or acetic acid. However, in the infusion product of the present invention, the addition of a citrate buffer to the sugar-containing liquid can sufficiently prevent discoloration of the sugar-containing liquid after storage.

[0023] Examples of the conjugate base of citric acid constituting the citrate buffer include metal salts of citric acid, such as potassium citrate (tripotassium citrate) and sodium citrate (trisodium citrate), and more preferably sodium citrate. The conjugate base of citric acid functions together with citric acid as a pH stabilizer for the sugar-containing liquid, and citric acid also functions as a pH adjuster. Either or both of the citric acid and the conjugate base of citric acid added to the sugar-containing liquid may be in the form of a hydrate.

[0024] The content of citrate buffer in the sugar-containing liquid preparation can be determined appropriately taking into consideration the effect of inhibiting discoloration of the sugar-containing liquid preparation after storage, assuming that the sugar-containing liquid preparation will be adjusted to the desired pH. However, from the viewpoint of obtaining a better effect of inhibiting discoloration of the sugar-containing liquid preparation after storage and from the viewpoint of avoiding a low pH of the mixed solution when all the liquid preparations contained in the multi-chamber infusion bag are mixed, even though the pH has been adjusted to a low pH of 4 or less, specific examples of citrate buffer in the sugar-containing liquid preparation include 0.5 to 1.5 g / L, preferably 0.6 to 1.3 g / L, more preferably 0.7 to 1 g / L, and even more preferably 0.8 to 0.9 g / L, in terms of the amount of sodium citrate.

[0025] In sugar-containing liquid preparations, the content ratio of sugar to citric acid buffer is determined according to the content of each of the above-mentioned components, but from the viewpoint of obtaining a better discoloration suppression effect after storage of the sugar-containing liquid preparation, the content ratio of citric acid buffer per 100 parts by weight of sugar, in terms of sodium citrate, is preferably 0.08 to 0.28 parts by weight, more preferably 0.1 to 0.2 parts by weight, and even more preferably 0.12 to 0.17 parts by weight.

[0026] 1-2-3. Electrolytes Electrolytes can be added to sugar-containing liquid preparations. Electrolytes used in the sugar-containing liquid preparations can be any electrolyte used in the field of infusion, without any particular restrictions. Specific examples of electrolytes include electrolytes contained in body fluids (e.g., blood, intracellular fluid) (body fluid electrolytes), and more specific examples include calcium, sodium, magnesium, zinc, chlorine, potassium, phosphorus, etc.

[0027] Among these, preferred electrolytes used in sugar-containing liquid preparations include calcium, sodium, magnesium, zinc, and chlorine. When the infusion product of the present invention is used for patients with renal failure, it is preferable that it does not contain at least one of potassium and phosphorus, and more preferably does not contain both potassium and phosphorus. Furthermore, from the viewpoint of obtaining a better coloration suppression effect after storage of the sugar-containing liquid preparation, the salt that is the electrolyte supply source preferably does not contain acetate ions and / or lactate ions as counter ions, and more preferably does not contain acetate ions and lactate ions.

[0028] Examples of calcium sources include calcium salts such as calcium gluconate, calcium chloride, calcium glycerophosphate, calcium lactate, calcium pantothenate, and calcium acetate, with calcium gluconate, calcium chloride, calcium glycerophosphate, calcium lactate, and calcium pantothenate being preferred, and calcium chloride being more preferred. These calcium sources may be used alone or in combination of two or more. These calcium sources may also be hydrates.

[0029] Examples of sodium sources include sodium salts such as sodium chloride, sodium lactate, sodium acetate, sodium bisulfite, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium glycerophosphate, sodium citrate, and sodium lactate. Preferred examples include sodium chloride, sodium lactate, sodium bisulfite, sodium sulfate, sodium citrate, and sodium lactate, and more preferred examples include sodium chloride and sodium citrate. Sodium citrate is also used as a component of a citrate buffer. These sodium sources may be used alone or in combination of two or more. These sodium sources may also be hydrates.

[0030] Examples of magnesium sources include magnesium sulfate, magnesium chloride, magnesium acetate, etc., preferably magnesium sulfate and magnesium chloride, more preferably magnesium chloride. These magnesium sources may be used alone or in combination of two or more. These magnesium sources may also be hydrates.

[0031] Examples of zinc sources include zinc sulfate and zinc chloride, preferably zinc chloride. These zinc sources may be used alone or in combination of two or more. These zinc sources may also be hydrates.

[0032] Examples of chloride sources include sodium chloride, potassium chloride, magnesium chloride, calcium chloride, zinc chloride, thiamine chloride hydrochloride, and pyridoxine hydrochloride, and preferably sodium chloride, magnesium chloride, calcium chloride, zinc chloride, thiamine chloride hydrochloride, and pyridoxine hydrochloride. These chloride sources may be used alone or in combination of two or more. These chloride sources may also be hydrates.

[0033] Examples of potassium sources include potassium chloride, potassium acetate, potassium citrate, potassium glycerophosphate, potassium sulfate, and potassium lactate, preferably potassium chloride, potassium acetate, potassium citrate, potassium sulfate, and potassium lactate, and more preferably potassium chloride, potassium citrate, potassium sulfate, and potassium lactate. These potassium sources may be used alone or in combination of two or more. These potassium sources may also be hydrates.

[0034] Examples of phosphorus sources include sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium glycerophosphate, potassium glycerophosphate, etc. These phosphorus sources may be used alone or in combination of two or more.

[0035] The amount of electrolytes to be added to the sugar-containing liquid preparation is determined appropriately so that the electrolyte concentration of the mixture of all the liquid preparations contained in the multi-chamber infusion bag is within the range of electrolyte concentrations described in 1-5 below.

[0036] Vitamins Vitamins can be blended into sugar-containing liquid preparations. Vitamins used in the field of infusions can be used without any particular limitation as vitamins used in sugar-containing liquid preparations. Specific examples of vitamins include water-soluble vitamins such as B vitamins and vitamin C; and fat-soluble vitamins such as vitamin A, vitamin D, vitamin E, and vitamin K. Of these, B vitamins are preferably used in sugar-containing liquid preparations.

[0037] Examples of B vitamins include vitamin B1 (thiamine), vitamin B5 (pantothenic acid), vitamin B6, vitamin B12 (cyanocobalamin), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B7 (biotin), and vitamin B9 (folic acid). Of these, the B vitamins used in the sugar-containing liquid preparation are preferably vitamin B1 (thiamine), vitamin B5 (pantothenic acid), vitamin B6, and vitamin B12 (cyanocobalamin). Since the infusion product of the present invention inhibits discoloration (yellowing) of the sugar-containing liquid preparation after storage, it is preferable that the sugar-containing liquid preparation does not contain vitamin B2, which itself is yellow.

[0038] Examples of vitamin B1 include thiamine chloride hydrochloride, thiamine nitrate, prosultiamine, octotiamine, etc., with thiamine chloride hydrochloride being preferred. These vitamin B1 compounds may be used alone or in combination. Vitamin B1 is preferably not present together with sulfite to avoid decomposition of vitamin B1 itself. Therefore, in the infusion product of the present invention, vitamin B1 and sulfite are preferably separately formulated and isolated in different liquid preparations. Therefore, when vitamin B1 is formulated in a sugar-containing liquid, it is preferable not to formulate sulfite in the sugar-containing liquid. When vitamin B1 is formulated in a sugar-containing liquid, the amount of vitamin B1 in the sugar-containing liquid is, for example, 8 to 18 mg / L, preferably 10 to 16 mg / L, and more preferably 12 to 14 mg / L.

[0039] Examples of vitamin B5 (pantothenic acid) include pantothenic acid or its calcium salt, panthenol, etc., and preferably panthenol. These vitamin B5s may be used alone or in combination of two or more. When vitamin B5 is added to a sugar-containing liquid, the amount of vitamin B5 added to the sugar-containing liquid is, for example, 15 to 30 mg / L, preferably 20 to 25 mg / L, and more preferably 22 to 25 mg / L.

[0040] Examples of vitamin B6 include pyridoxine and pyridoxine salts such as pyridoxine hydrochloride, with pyridoxine hydrochloride being preferred. These vitamin B6s may be used alone or in combination. Vitamin B6 is preferably not converted to vitamin B2 to avoid instability due to light. Therefore, in the infusion product of the present invention, vitamin B6 and vitamin B2 are preferably separately formulated and isolated in different liquid preparations. Therefore, when vitamin B6 is formulated in a sugar-containing liquid, it is preferable not to formulate vitamin B2 in the sugar-containing liquid. When vitamin B6 is formulated in a sugar-containing liquid, the amount of vitamin B6 in the sugar-containing liquid is, for example, 8 to 18 mg / L, preferably 10 to 16 mg / L, and more preferably 12 to 14 mg / L.

[0041] Examples of vitamin B12 include cyanocobalamin, hydroxocobalamin acetate, and methylcobalamin, with cyanocobalamin being preferred. These vitamin B12 may be used alone or in combination of two or more. When vitamin B12 is added to a sugar-containing liquid, the amount of vitamin B12 added to the sugar-containing liquid is, for example, 3 to 15 μg / L, preferably 5 to 12 μg / L, and more preferably 7 to 10 μg / L.

[0042] The amount of vitamin to be added to the sugar-containing liquid preparation is determined appropriately so that the vitamin concentration of the mixture of all the liquid preparations contained in the multi-chamber infusion bag is within the vitamin concentration range described in 1-5 below.

[0043] 1-2-5. Other ingredients The sugar-containing liquid preparation may contain other components as appropriate. Examples of such other components include solvents, stabilizers, pH adjusters, etc. Typically, sugar-containing liquid preparations contain water as a solvent, preferably distilled water for injection. Furthermore, in order to obtain a better coloration suppression effect after storage of the sugar-containing liquid preparation, the sugar-containing liquid preparation preferably does not contain an acetate buffer (acetic acid and its conjugate base) and / or a lactic acid buffer (lactic acid and its conjugate base), and more preferably does not contain an acetate buffer (acetic acid and its conjugate base) or a lactic acid buffer (lactic acid and its conjugate base). Examples of the conjugate base of acetic acid that constitutes the acetate buffer include metal salts of acetic acid, such as potassium acetate and sodium acetate. Examples of the conjugate base of lactic acid that constitutes the lactic acid buffer include metal salts of L-lactic acid, such as potassium L-lactate and sodium L-lactate.

[0044] 1-2-6. pH The sugar-containing liquid preparation is adjusted to a pH of 4 or less. In the present invention, pH is measured at 20°C. Even when sugar-containing liquid preparations containing sugar at a high concentration of 50 w / v% or more are prepared to a low pH of 4 or less by adding lactic acid or acetic acid, discoloration (yellowing) occurs after storage. However, the infusion product of the present invention effectively suppresses discoloration after storage by including a citrate buffer. In view of this excellent effect of suppressing discoloration after storage, a suitable pH for the sugar-containing liquid preparation is, for example, 3.9 or less, preferably less than 3.9. The lower limit of the pH is not particularly limited, but from the viewpoint of keeping the titratable acidity low when the infusion product of the present invention is administered to patients with renal failure, examples include 2.3 or more, preferably 3 or more, and more preferably 3.5 or more. The pH adjuster used to adjust the sugar-containing liquid preparation to the predetermined pH of 4 is not particularly limited, but preferably citric acid, which constitutes a citrate buffer, can be used.

[0045] 1-2-7. Capacity The amount of sugar-containing liquid to be contained, expressed as a ratio to the mixture of all liquids contained in the multi-chamber infusion bag, is, for example, 20 to 80% by volume, preferably 40 to 70% by volume, and more preferably 50 to 60% by volume.

[0046] 1-3. Amino acid-containing liquid (Chamber 2) The second chamber of the multi-chamber infusion bag is filled with an amino acid-containing liquid. The composition of the amino acid-containing liquid is not particularly limited as long as it contains amino acids. Preferably, the amino acid-containing liquid contains electrolytes and / or vitamins in addition to amino acids, and more preferably contains amino acids, electrolytes, and vitamins.

[0047] 1-3-1. Amino acids The amino acids used in the amino acid-containing liquid preparations can be any amino acid that is used in amino acid infusions intended for nutritional supplementation to the living body, without any particular limitations. The amino acids may be used in the form of free amino acids, or in the form of their pharmaceutically acceptable salts, esters, N-acyl derivatives, or dipeptides.

[0048] The free amino acids include essential amino acids and non-essential amino acids.The essential amino acids include L-leucine, L-isoleucine, L-valine, L-lysine, L-threonine, L-tryptophan, L-methionine, L-phenylalanine, and L-histidine.The non-essential amino acids include L-cysteine, L-tyrosine, L-arginine, L-alanine, L-proline, L-serine, L-aspartic acid, L-glutamic acid, and glycine, and preferably include L-cysteine, L-tyrosine, L-arginine, L-alanine, L-proline, L-serine, L-aspartic acid, and L-glutamic acid.

[0049] Examples of amino acid salts include inorganic acid salts such as L-arginine hydrochloride, L-cysteine ​​hydrochloride, L-glutamic acid hydrochloride, L-histidine hydrochloride, and L-lysine hydrochloride; and organic acid salts such as L-lysine acetate and L-lysine malate (preferably L-lysine acetate).

[0050] Examples of amino acid esters include L-tyrosine methyl ester, L-methionine methyl ester, and L-methionine ethyl ester. Examples of N-acyl amino acids include N-acetyl-L-cysteine, N-acetyl-L-tryptophan, and N-acetyl-L-proline, with N-acetyl-L-cysteine ​​being preferred from the viewpoint of stability. Examples of amino acid dipeptides include L-tyrosyl-L-tyrosine, L-alanyl-L-tyrosine, L-arginyl-L-tyrosine, and L-tyrosyl-L-arginine.

[0051] Although these amino acids may be used alone, from the viewpoint of nutritional supplementation, it is preferable to use two or more in combination, and it is more preferable to use at least all essential amino acids, their pharmaceutically acceptable salts, esters, N-acyl derivatives, and / or dipeptides. Furthermore, when the infusion product of the present invention is applied to patients with renal failure, it is even more preferable to use essential amino acids and non-essential amino acids in combination.

[0052] The amino acid may be one kind selected from free amino acids, pharmaceutically acceptable salts thereof, esters thereof, N-acyl derivatives thereof, and dipeptides, or two or more kinds may be used in combination.

[0053] The specific composition of the amino acid-containing liquid preparation can be appropriately determined by those skilled in the art from the viewpoint of providing nutrition to a living body, regardless of whether the infusion product of the present invention is for a patient with renal failure or not. Furthermore, when the infusion product of the present invention is for a patient with renal failure, the infusion product can be prepared so that the amount of branched-chain amino acids such as L-leucine, L-isoleucine, and L-valine is higher, the amount of L-methionine and L-phenylalanine is lower, and L-cysteine ​​is also included, compared to when the infusion product is for other patients.

[0054] When essential amino acids and non-essential amino acids are used in combination in an amino acid-containing liquid preparation, the ratio of the free amino acid equivalent weight of essential amino acids to the free amino acid equivalent weight of non-essential amino acids (essential amino acids / non-essential amino acids) is, for example, 1 to 5. From the viewpoint of appropriate amino acid supplementation for patients with renal failure, the ratio is preferably 2 to 4, and more preferably 2.4 to 3.8.

[0055] The amount of amino acids in the amino acid-containing liquid preparation is, specifically, for example, 10 to 120 g / L, preferably 50 to 100 g / L, more preferably 60 to 80 g / L, and even more preferably 70 to 75 g / L, in terms of the total amount of free amino acids.

[0056] Preferred examples of the combination and mixing ratio of amino acids to be incorporated into the amino acid-containing liquid preparation are as follows, calculated as free amino acids: L-leucine: 2.5 to 33 g / L, preferably 5 to 18 g / L, more preferably 13 to 15 g / L L-isoleucine: 0 to 23 g / L, preferably 3 to 12 g / L, more preferably 8 to 10 g / L L-valine: 0.9 to 27 g / L, preferably 3 to 13 g / L, more preferably 9 to 11 g / L L-lysine: 1.5 to 23 g / L, preferably 2 to 11 g / L, more preferably 2 to 8 g / L L-threonine: 1 to 13 g / L, preferably 1.2 to 6 g / L L-tryptophan: 0.5-5g / L L-methionine: 0.7 to 13 g / L, preferably 1 to 5 g / L, more preferably 2 to 4 g / L L-phenylalanine: 1 to 20 g, preferably 1.8 to 9 g / L, more preferably 4 to 6 g / L L-cysteine: 0.1 to 3 g / L, preferably 0.3 to 1.3 g / L L-tyrosine: 0.06-1.2g / L L-arginine: 1.5 to 23 g / L, preferably 2 to 11 g / L L-histidine: 1 to 13 g / L, preferably 1.2 to 6 g / L L-alanine: 1 to 23 g / L, preferably 1 to 8 g / L L-proline: 0.5 to 17 g / L, preferably 1.2 to 6 g / L L-serine: 0.5 to 10 g / L, preferably 1 to 5 g / L L-aspartic acid: 0.1 to 7 g / L, preferably 0.12 to 1.8 g / L L-glutamic acid: 0.1 to 10 g / L, preferably 0.12 to 1.8 g / L

[0057] 1-3-2. Electrolytes An electrolyte can be blended into the amino acid-containing liquid. The electrolyte used in the amino acid-containing liquid can be any electrolyte used in the field of infusion, without any particular limitation. Specific examples of the electrolyte include electrolytes contained in body fluids (e.g., blood, intracellular fluid) (body fluid electrolytes), more specifically, calcium, sodium, magnesium, zinc, chlorine, etc.

[0058] Among these, sodium is preferably used as an electrolyte in the amino acid-containing liquid preparation. When the infusion product of the present invention is used for patients with renal failure, it is preferable that it does not contain at least one of potassium and phosphorus, and more preferably does not contain both potassium and phosphorus.

[0059] The sodium source may be the sodium salt used in the sugar-containing liquid preparations, but the sodium source used in the amino acid-containing liquid preparations may be sodium lactate, which is also used as a metabolic acidosis corrector.

[0060] The amount of electrolyte to be added to the amino acid-containing liquid preparation is determined appropriately so that the electrolyte concentration of the mixture of all the liquid preparations contained in the multi-chamber infusion bag is within the range of electrolyte concentrations described in 1-5 below.

[0061] Vitamins Vitamins can be blended into the amino acid-containing liquid preparation. Vitamins used in the amino acid-containing liquid preparation can be any vitamin used in the field of infusion, without any particular limitation. Specific examples of vitamins include water-soluble vitamins such as B vitamins and vitamin C; and fat-soluble vitamins such as vitamin A, vitamin D, vitamin E, and vitamin K. Of these, B vitamins are preferably used in the amino acid-containing liquid preparation.

[0062] Examples of B vitamins include vitamin B1 (thiamine), vitamin B5 (pantothenic acid), vitamin B6, vitamin B12 (cyanocobalamin), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B7 (biotin), vitamin B9 (folic acid), etc. Among these, preferred examples of B vitamins used in amino acid-containing liquid preparations include vitamin B3 (niacin) and vitamin B9 (folic acid).

[0063] Examples of vitamin B3 (niacin) include nicotinamide. When vitamin B3 is added to an amino acid-containing liquid, the amount of vitamin B3 added to the amino acid-containing liquid is, for example, 70 to 100 mg / L, preferably 80 to 95 mg / L, and more preferably 85 to 90 mg / L.

[0064] To avoid instability of vitamin B9 itself, it is preferable that vitamin B9 (folic acid) not be present together with vitamin B2. Therefore, in the infusion product of the present invention, vitamin B9 and vitamin B2 are preferably separately formulated and isolated in different liquid preparations. Therefore, when vitamin B9 is formulated in an amino acid-containing liquid, it is preferable not to formulate vitamin B2 in the amino acid-containing liquid. When vitamin B9 is formulated in an amino acid-containing liquid, the amount of vitamin B9 in the amino acid-containing liquid is, for example, 1 to 1.7 mg / L, preferably 1.2 to 1.5 mg / L.

[0065] The amount of vitamin to be added to the amino acid-containing liquid preparation is determined so that the vitamin concentration in the mixture of all the liquid preparations contained in the multi-chamber infusion bag is within the range of vitamin concentrations described in 1-5 below.

[0066] 1-3-4. Other ingredients The amino acid-containing liquid preparation may contain other components as appropriate. Examples of other components include solvents, stabilizers, buffers, pH adjusters, etc. The amino acid-containing liquid preparation usually contains water as a solvent, and the preferred water is distilled water for injection.

[0067] The amino acid-containing liquid preparation may contain a stabilizer. Examples of stabilizers include sulfites such as sodium bisulfite. In particular, when the amino acid-containing liquid preparation does not contain vitamin B1 as a vitamin, it is preferable to add sulfites, since there is no risk of sulfites causing decomposition of vitamin B1.

[0068] 1-3-5. pH The pH of the amino acid-containing liquid is not particularly limited as long as it is adjusted to be higher than the pH of the sugar-containing liquid so that the mixture of all liquids contained in the multi-chamber infusion bag is adjusted to the desired pH. For example, the pH of the amino acid-containing liquid may be 5 to 8, preferably 6 to 7.5, and more preferably 6.5 to 7.5. The pH adjuster used in the amino acid-containing liquid is not particularly limited, but preferably acetic acid (which may be in the form of glacial acetic acid) can be used.

[0069] 1-3-6. Capacity The amount of the amino acid-containing liquid to be contained, expressed as a ratio to the mixture of all liquids contained in the multi-chamber infusion bag, is, for example, 20 to 70% by volume, preferably 30 to 50% by volume, and more preferably 40 to 50% by volume.

[0070] 1-4. Vitamin-containing liquid (Room 3) As described above, in the infusion product of the present invention, the multi-chamber infusion bag may have a storage chamber other than the first and second chambers. When the multi-chamber infusion bag of the infusion product of the present invention has a third chamber as another storage chamber, the third chamber can be filled with a vitamin-containing liquid. The third chamber may be housed inside the first or second chamber.

[0071] Vitamins The vitamins used in the vitamin-containing liquid preparation can be any vitamin used in the field of infusions, without any particular limitation. Specific examples of vitamins include water-soluble vitamins such as B vitamins and vitamin C; and fat-soluble vitamins such as vitamin A, vitamin D, vitamin E, and vitamin K. Of these, it is preferable that the vitamins used in the vitamin-containing liquid preparation contain at least fat-soluble vitamins. Furthermore, the vitamins used in the vitamin-containing liquid can include water-soluble vitamins such as B vitamins and / or vitamin C, and preferably B vitamins and vitamin C. When the vitamin-containing liquid preparation contains B vitamins, the B vitamins are preferably vitamin B2 and vitamin B7 (biotin).

[0072] Examples of vitamin B2 include riboflavin, riboflavin sodium phosphate, and flavin mononucleotide, with riboflavin sodium phosphate being preferred. These vitamin B2 compounds may be used singly or in combination. Vitamin B2 is preferably not coexistent with vitamin B9 (folic acid) to avoid destabilizing vitamin B9 (folic acid). Therefore, in the infusion product of the present invention, vitamin B9 and vitamin B2 are preferably separately formulated and isolated in different liquid preparations. Therefore, when vitamin B2 is formulated in a vitamin-containing liquid, it is preferable not to formulate vitamin B9 in the vitamin-containing liquid. When vitamin B2 is formulated in a vitamin-containing liquid, the amount of vitamin B2 in the vitamin-containing liquid is, for example, 0.3 to 0.9 mg / mL, preferably 0.45 to 0.65 mg / mL.

[0073] When vitamin B7 (biotin) is added to a vitamin-containing liquid, the amount of vitamin B7 (biotin) added to the vitamin-containing liquid is, for example, 6 to 9 μg / mL, and preferably 7 to 8 μg / mL.

[0074] When vitamin C (ascorbic acid) is added to the vitamin-containing liquid, the amount of vitamin C added to the vitamin-containing liquid is, for example, 10 to 40 mg / mL, and preferably 20 to 30 mg / mL.

[0075] Examples of vitamin A include retinol and its esters, as well as their oil solutions (vitamin A oils). Examples of retinol esters include retinol palmitate and retinol acetate. When vitamin A is added to a vitamin-containing liquid, the amount of vitamin A added is, for example, 200 to 600 IU / mL, preferably 350 to 450 IU / mL. IU stands for International Unit, also known as Vitamin A Unit.

[0076] Examples of vitamin D include vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol), and their active forms, with vitamin D3 being preferred. These vitamin Ds may be used alone or in combination of two or more. When vitamin D is added to a vitamin-containing liquid, the amount of vitamin D added to the vitamin-containing liquid is, for example, 0.2 to 1 μg / mL, preferably 0.4 to 0.8 μg / mL.

[0077] Examples of vitamin E include tocopherol acetate and tocopherol succinate, preferably tocopherol acetate. These vitamin E compounds may be used alone or in combination of two or more. When vitamin E is added to a vitamin-containing liquid, the amount of vitamin E added to the vitamin-containing liquid is, for example, 0.5 to 2 mg / mL, preferably 1 to 1.5 mg / mL.

[0078] Examples of vitamin K include vitamin K1 (phytonadione), vitamin K2 (menatetrenone), and vitamin K3 (menadione), with vitamin K1 being preferred. These vitamin Ks may be used alone or in combination of two or more. When vitamin K is added to a vitamin-containing liquid, the amount of vitamin K added to the vitamin-containing liquid is, for example, 0.01 to 0.025 mg / mL, preferably 0.015 to 0.02 mg / mL.

[0079] The amount of vitamin to be added to the vitamin-containing liquid preparation is determined appropriately so that the vitamin concentration in the mixture of all the liquid preparations contained in the multi-chamber infusion bag is within the vitamin concentration range described in 1-5 below.

[0080] 1-4-2.Other ingredients Vitamin-containing liquid preparations may contain other ingredients besides vitamins as appropriate. These other ingredients include solvents, stabilizers, buffers, pH adjusters, etc. Vitamin-containing liquid preparations usually contain water as a solvent, preferably distilled water for injection.

[0081] Vitamin-containing liquids preferably contain a solubilizer to stably solubilize fat-soluble vitamins. Examples of solubilizers include nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters and polyoxyethylene hydrogenated castor oil, and polyethylene glycols, with polyoxyethylene sorbitan fatty acid esters and polyethylene glycols being preferred. Examples of polyoxyethylene sorbitan fatty acid esters include polysorbate 80 and polysorbate 20. When polysorbate 80 is added to a vitamin-containing liquid, the amount of polysorbate 80 added to the vitamin-containing liquid is, for example, 3 to 15 mg / mL, preferably 5 to 8 mg / mL. When polysorbate 20 is added to a vitamin-containing liquid, the amount of polysorbate 20 added to the vitamin-containing liquid is, for example, 0.1 to 82 mg / mL, preferably 0.5 to 31.5 mg / mL. Examples of polyethylene glycols include macrogol 200, macrogol 300, macrogol 400, and macrogol 600, with macrogol 400 being preferred. When macrogol 400 is added to a vitamin-containing liquid, the amount of macrogol 400 added to the vitamin-containing liquid may be, for example, 1 to 20 mg / mL, and preferably 5 to 15 mg / mL.

[0082] The pH of the vitamin-containing liquid is preferably adjusted using a pH adjuster. The pH adjuster is not particularly limited, but examples thereof include bases such as potassium hydroxide and sodium hydroxide, preferably sodium hydroxide. The preferred pH of the vitamin-containing liquid is, for example, 4 to 10, preferably 6 to 8.

[0083] 1-4-3. Capacity The amount of the vitamin-containing liquid agent contained in the multi-chamber infusion bag is, for example, 0.3 to 1.5% by volume, preferably 0.5 to 1.0% by volume, relative to the mixture of all liquid agents contained in the multi-chamber infusion bag.

[0084] 1-5. Mixed solution (administered infusion) When the infusion product of the present invention is used, all of the liquid preparations contained in the multi-chamber infusion bag are mixed together, and the prepared mixture is used as the infusion solution to be administered.

[0085] 1-5-1. pH In the present invention, when all the liquid preparations contained in the multi-chamber infusion bag are mixed, the resulting mixture can be controlled to a pH close to that of the amino acid-containing liquid preparation, and the pH of the mixture can be 4 to 7, preferably 5 to 7, and more preferably 5.6 to 6.2.

[0086] Thus, the mixed solution obtained by the infusion product of the present invention has a pH close to neutral. Usually, an infusion solution adjusted to a pH close to neutral has poor resistance to bacterial growth. However, the mixed solution obtained by the infusion product of the present invention has excellent resistance to bacterial growth, even though it is adjusted to a pH close to neutral.

[0087] The bacterial growth resistance of the mixed solution obtained by the infusion product of the present invention is such that the bacterial growth rate 24 hours after the mixed solution of all liquid preparations contained in a multi-chamber infusion bag is contaminated with bacteria is within 2-fold, preferably within 1.9-fold, and most preferably within 1.8-fold. The bacteria in question are selected from the group consisting of Candida (e.g., Candida albicans ATCC2091), Staphylococcus epidermidis (e.g., Staphylococcus epidermidis ATCC12228), Bacillus cereus (e.g., Bacillus cereus ATCC11778), and Serratia marcescens (e.g., Serratia marcescens ATCC13880), which are known to contaminate TPN infusion products and are the main cause of catheter infections. The number of bacteria grown can be measured by adding the bacteria to the mixed solution and measuring the number of viable bacteria by the plate surface smear method after 24 hours.

[0088] 1-5-2. Osmotic pressure ratio The mixed solution obtained by the infusion product of the present invention has an osmotic pressure ratio of, for example, 7 to 9.6, preferably 7.4 to 9.4, and more preferably 7.6 to 9.2. Here, the osmotic pressure ratio refers to the ratio to the osmotic pressure of saline (i.e., the relative ratio when the osmotic pressure of saline is set to 1).

[0089] 1-5-3.Titratable acidity The mixed solution obtained by the infusion product of the present invention has a titratable acidity of, for example, 5-15, preferably 6-12, and more preferably 7-9.

[0090] 1-5-4.Calorific value The calorific value of the mixed solution obtained from the infusion product of the present invention is determined depending on the content of ingredients such as sugars and amino acids, but is, for example, 1200 to 1700 kcal / L, preferably 1300 to 1600 kcal / L.

[0091] 1-5-5. Other ingredients When administering the mixed solution obtained from the infusion product of the present invention to a patient with renal failure, it is preferable that the mixed solution does not contain at least one of potassium and phosphorus, and it is more preferable that the mixed solution does not contain both potassium and phosphorus.

[0092] 1-5-6. Composition example The composition of the mixed solution obtained by the infusion product of the present invention is as follows: glucose 50-450g / L; Preferably, 100 to 400 g / L, More preferably, 300 to 350 g / L Total amino acids (free amino acid equivalent) 10-60g / L, Preferably, 15 to 45 g / L, More preferably, 20 to 40 g / L, More preferably, 25 to 35 g / L Sodium ion 10-160mEq / L, Preferably 40 to 70 mEq / L, More preferably, 45 to 65 mEq / L, More preferably, 40 to 60 mEq / L Magnesium ion 1-40mEq / L, Preferably, 2 to 20 mEq / L, More preferably, 2 to 10 mEq / L Calcium ion 1-40mEq / L, Preferably, 2 to 20 mEq / L, More preferably, 2 to 10 mEq / L Chloride ions 20-60mEq / L, Preferably, 25 to 55 mEq / L, More preferably, 30 to 50 mEq / L Lactate ions 1-30mEq / L, Preferably, 5 to 25 mEq / L, More preferably, 10 to 20 mEq / L Acetate ion 1-70mEq / L, Preferably, 5 to 55 mEq / L, More preferably, 10 to 30 mEq / L Citrate ion 1-25mEq / L, Preferably, 5 to 15 mEq / L, Zinc 2-200 μmol / L, Preferably, 10 to 50 μmol / L, More preferably, 15 to 30 μmol / L Vitamin B1 0.4-30mg / L Preferably 1 to 10 mg / L Vitamin B2 0.5-15mg / L Preferably 1 to 10 mg / L Vitamin B6 0.5-20mg / L Preferably 1 to 10 mg / L Vitamin B12 0.5-50μg / L, Preferably 1 to 10 μg / L Nicotinic acids 5-80mg / L Preferably 10 to 60 mg / L Folic acid 0.05~1mg / L Preferably 0.1 to 0.8 mg / L Vitamin C 12-400mg / L Preferably 20 to 300 mg / L Vitamin A 400-6500IU / L Preferably 800 to 4000 IU / L Vitamin D 0.5-10 μg / L, Preferably 1 to 6 μg / L Vitamin E 1-30 mg / L, Preferably 2.5 to 15 mg / L Vitamin K 0.01 to 10 mg / L, Preferably 0.03 to 5 mg / L, more preferably 0.05 to 1 mg / L Biotin 5~150μg / L, Preferably 10 to 70 μg / L

[0093] 1-6. Manufacturing method of infusion products The method for producing the infusion product of the present invention is conventional and can be appropriately selected by those skilled in the art. For example, a method can be used in which a liquid formulation is placed (filled) into each chamber, including the first and second chambers, of a multi-chamber infusion bag under an inert gas (e.g., carbon dioxide or nitrogen) atmosphere, and the bag is then stoppered and sterilized by heating. Examples of heat sterilization methods include high-pressure steam sterilization and hot water shower sterilization. Heat sterilization can also be performed in an inert gas (e.g., carbon dioxide or nitrogen) atmosphere, if necessary.

[0094] Furthermore, in order to reliably prevent deterioration, oxidation, etc., the infusion product of the present invention is preferably packaged in an oxygen-barrier outer bag together with a deoxidizer as a multi-chamber infusion bag. In particular, when an infusion bag having a partition wall formed with an easily peelable seal is used as the multi-chamber infusion bag, the infusion product of the present invention is preferably packaged in the outer bag in a folded state at the easily peelable seal portion, for example, in a state folded in half at the easily peelable seal portion, so that the partition wall does not open due to external pressure. In addition, an inert gas may be filled into the outer bag packaging the infusion product of the present invention.

[0095] 1-7. Usage and administration The infusion product of the present invention can be used for nutritional management purposes for patients who have difficulty with oral intake and are in a hypoproteinemic or malnutrition state, or for patients before and after surgery or during an invasive phase. Because the infusion product of the present invention prepares a high-concentration, high-calorie mixed solution (administered infusion), it is preferably used for patients who are unable to take oral intake for a long period of time, specifically, for patients who are unable to take oral intake for more than one week, and particularly for more than 10 days. Furthermore, if the mixed solution obtained by the infusion product of the present invention does not contain at least one of potassium and phosphorus, preferably both potassium and phosphorus, it can be suitably used for patients with renal failure. Renal failure as referred to here includes both acute and chronic renal failure.

[0096] The infusion product of the present invention allows the prepared mixed solution (administered infusion solution) to be administered into the central vein by the so-called high-calorie infusion method. That is, the infusion product of the present invention is a total parenteral nutrition (TPN) infusion product. Because the central vein close to the heart is thick and has a large blood flow, even if a highly concentrated high-calorie infusion solution is administered, it is instantly diluted by a large amount of blood, thereby reducing the impact on blood vessels and blood cells.

[0097] The dosage for an adult is 500 to 1800 mL, preferably 800 to 1300 mL per day. The dosage may be increased or decreased as appropriate by those skilled in the art depending on age, symptoms, and body weight. The administration rate is preferably such that the above-mentioned daily dosage is administered continuously over 24 hours.

[0098] 2. Method for preventing discoloration of sugar-containing liquids in infusion products Furthermore, the present invention provides a method for suppressing discoloration of sugar-containing liquid preparations in infusion products. Discoloration suppression refers to the reduction in the degree of discoloration (yellowing) in a sugar-containing liquid preparation containing 50 wt% or more sugar and having a pH of 4 or less when a citrate buffer is included, compared to when a citrate buffer is not included (preferably when an acetate buffer and / or a lactate buffer is included). Discoloration suppression can be evaluated, for example, by examining the light transmittance at 445 nm after storing the sugar-containing liquid preparation at 60°C for 4 weeks. The higher the light transmittance after storage, the more suppressed the discoloration can be evaluated. The light transmittance after storage is preferably 94% or more, more preferably 95% or more. Furthermore, the higher the light transmittance, the better, but the upper limit can be, for example, 100% or less, or 99% or less.

[0099] Specifically, the method for inhibiting discoloration of a sugar-containing liquid in an infusion product of the present invention comprises a multi-chamber infusion bag including at least a first and a second compartment separated from each other, a sugar-containing liquid contained in the first compartment, and an amino acid-containing liquid contained in the second compartment, wherein the sugar-containing liquid contains 50 w / v% or more of sugar and has a pH of 4 or less, and is characterized in that citric acid and a conjugate base of citric acid are blended into the sugar-containing liquid. The configuration of the multi-chamber infusion bag used in the method for inhibiting discoloration of a sugar-containing liquid in an infusion product of the present invention, the types and amounts of liquid components, and the method for using the infusion product are as described in the section "1. Infusion Product" above. [Example]

[0100] The present invention will be explained in more detail below by showing examples, but the present invention is not limited to these examples.

[0101] Test Example 1 A sugar-containing liquid preparation [citrate buffer] (Preparation Example 1), a sugar-containing liquid preparation [acetate buffer] (Comparative Preparation Example 1), and a sugar-containing liquid preparation [lactic acid buffer] (Comparative Preparation Example 2) were prepared with the compositions shown in Table 1 and a pH of 3.8 or 4.0 (pH at 20°C. In the following, the pH measurement temperature is 20°C). The sugar content in each of the sugar-containing liquids was 58.4 w / v%.

[0102] [Table 1]

[0103] The amino acid-containing liquid preparations shown in Table 2 were prepared. The pH of the amino acid-containing liquid preparations was adjusted to 6.9.

[0104] [Table 2]

[0105] The vitamin-containing liquid preparations shown in Table 3 were prepared. The pH of the vitamin-containing liquid preparations was adjusted to 6.5.

[0106] [Table 3]

[0107] The preparations of Preparation Example 1 shown in Table 1, the amino acid-containing liquid preparations shown in Table 2, and the vitamin-containing liquid preparations shown in Table 3 were filled into each chamber of a multi-chamber infusion bag having three storage chambers separated from each other by partitions formed by easily peelable seals under a nitrogen atmosphere, sealed, and then subjected to moist heat sterilization according to a conventional method. The container was then folded at the easily peelable seals and enclosed in an outer packaging bag made of a light-shielding barrier film together with a deoxidizer to produce the infusion product of Example 1. Similarly, the sugar-containing liquid preparations of Comparative Preparation Example 1 or Comparative Preparation Example 2, the amino acid-containing liquid preparations shown in Table 2, and the vitamin-containing liquid preparations shown in Table 3 were filled into each chamber of a multi-chamber infusion bag having three storage chambers separated from each other by partitions formed by easily peelable seals under a nitrogen atmosphere, sealed, and then subjected to moist heat sterilization according to a conventional method. The container was then folded at the easily peelable seals and enclosed in an outer packaging bag made of a light-shielding barrier film together with a deoxidizer to produce the infusion product of Comparative Example 1 or Comparative Example 2, respectively.

[0108] Each infusion product was stored at 60°C. Light transmittance at 445 nm (10 mm solution thickness) was measured before storage, and after 1 week, 2 weeks, and 4 weeks of storage to evaluate the coloration of the sugar-containing solution (n=3). Light transmittance at 445 nm can be used to evaluate yellow coloration. It was confirmed that no insoluble matter was generated at any stage. Figure 1 shows the change in light transmittance (%T) of the sugar-containing solution with a pH adjusted to 3.8, and Figure 2 shows the light transmittance (%T) of the sugar-containing solution with a pH adjusted to 4.0.

[0109] As shown in Figures 1 and 2, the decrease in light transmittance after 4 weeks at 60°C was clearly suppressed in the sugar-containing liquid preparation [citrate buffer] of Preparation Example 1 in the infusion product of Example 1 compared to the sugar-containing liquid preparation [acetate buffer] of Comparative Preparation Example 1 in the infusion product of Comparative Example 1 and the sugar-containing liquid preparation [lactic acid buffer] of Comparative Preparation Example 2 in the infusion product of Comparative Example 2.

[0110] Specifically, the light transmittance of sugar-containing liquid preparations whose pH was adjusted to 3.8 after 4 weeks at 60°C was 92.3% for the sugar-containing liquid preparation [acetate buffer] (pH 3.8) of Comparative Preparation Example 1 in the infusion product of Comparative Example 1, 93.2% for the sugar-containing liquid preparation [lactic acid buffer] (pH 3.8) of Comparative Preparation Example 2 in the infusion product of Comparative Example 2, and 96.3% for the sugar-containing liquid preparation [citrate buffer] (pH 3.8) of Preparation Example 1 in the infusion product of Example 1. Furthermore, the light transmittance of the sugar-containing liquid preparations adjusted to pH 4.0 after 4 weeks at 60°C was 87.4% for the sugar-containing liquid preparation [acetate buffer] (pH 4.0) of Comparative Preparation Example 1 in the infusion product of Comparative Example 1, and 89.2% for the sugar-containing liquid preparation [lactic acid buffer] (pH 4.0) of Comparative Preparation Example 2 in the infusion product of Comparative Example 2, while it was 89.2% for Preparation Example 1 in the infusion product of Example 1 and 95.4% for the sugar-containing liquid preparation [citrate buffer] (pH 4.0) in the infusion product of Example 1.

[0111] Therefore, it was shown that discoloration after storage can be suppressed by adding a citrate buffer to a sugar-containing liquid preparation containing 50 w / v % or more of sugar and having a pH of 4 or less.

[0112] Test Example 2 The infusion product of Example 1 was prepared in the same manner as in Test Example 1. In the infusion product of Example 1, one chamber of the multi-chamber infusion bag was pressed to open the partition, thereby mixing the sugar-containing liquid, amino acid-containing liquid, and vitamin-containing liquid of Preparation Example 1 to obtain a mixed solution. The composition, pH, and osmotic pressure ratio of the obtained mixed solution are shown in Table 4.

[0113] [Table 4]

[0114] The main causative bacteria of catheter infections, Staphylococcus epidermidis (ATCC12228), Staphylococcus aureus (ATCC6538), Candida albicans (ATCC2091), Bacillus cereus (ATCC11778), and Serratia marcescens (ATCC13880), were used to investigate the resistance of bacteria to growth when the mixed solution was contaminated with bacteria. Specifically, each bacterium was added to the mixture, and the viable cell count (CFU / mL) was measured 24 hours later using the plate surface smear method. The growth rate 24 hours after the addition of each bacterium (the ratio of the viable cell count immediately after the addition of each bacterium to 100%) is shown in Table 5.

[0115] [Table 5]

[0116] As shown in Table 5, no bacterial growth of more than two times was observed in the mixed solution. It was unexpected that the infusion product of the present invention has excellent resistance to bacterial growth, despite being a highly concentrated, high-calorie TPN infusion product.

Claims

1. A multi-chamber infusion bag including at least a first chamber and a second chamber isolated from each other, a sugar-containing liquid medicine contained in the first chamber, and an amino acid-containing liquid medicine (excluding those containing vitamin C) contained in the second chamber, The sugar-containing liquid preparation comprises 50 w / v % or more of sugar, citric acid and a conjugate base of citric acid, and has a pH of 4 or less.

2. A multi-chamber infusion bag including at least a first chamber and a second chamber isolated from each other, a sugar-containing liquid medicine contained in the first chamber, and an amino acid-containing liquid medicine contained in the second chamber, the sugar-containing liquid preparation contains 50 w / v % or more of glucose, citric acid, and a conjugate base of citric acid, and has a pH of 4 or less; An infusion product, wherein the mixed solution of all liquid medications contained in the multi-chamber infusion bag contains acetate ions and lactate ions, and also contains the glucose at a concentration of 300 to 350 g / L.

3. 3. The infusion product according to claim 1, wherein the sugar-containing liquid preparation does not contain acetic acid and its conjugate base and / or lactic acid and its conjugate base.

4. 4. The infusion product according to claim 1, wherein the sugar-containing liquid has a light transmittance of 94% or more at 445 nm after storage at 60° C. for 4 weeks.

5. 5. The infusion product according to claim 1, wherein the titratable acidity of a mixture of all liquid medications contained in the multi-chamber infusion bag is 5 to 15.

6. The infusion product according to any one of claims 1 to 5, wherein the pH of the mixture of all liquid agents contained in the multi-chamber infusion bag is between 4 and 7.

7. The infusion product according to any one of claims 1 to 6, wherein the sugar-containing liquid preparation and the amino acid-containing liquid preparation do not contain phosphorus.

8. The infusion product according to any one of claims 1 to 7, wherein the mixture of all liquid medications contained in the multi-chamber infusion bag does not contain potassium.

9. The infusion product according to any one of claims 1 to 8, wherein the number of bacteria growing in the mixed solution of all liquid medications contained in the multi-chamber infusion bag 24 hours after the mixed solution is contaminated with bacteria is within two times the normal number.

10. The infusion product according to any one of claims 1 to 9, wherein the patient to be administered the product is a patient with renal failure.

11. The infusion product according to any one of claims 1 to 10, wherein the sugar content in the sugar-containing liquid preparation is 57.5 w / v % or more.

12. An infusion product comprising: a multi-chamber infusion bag including at least a first chamber and a second chamber isolated from each other; a sugar-containing liquid agent contained in the first chamber; and an amino acid-containing liquid agent (excluding those containing vitamin C) contained in the second chamber, wherein the sugar-containing liquid agent contains 50 w / v % or more of sugar and has a pH of 4 or less; A method for inhibiting discoloration of a sugar-containing liquid preparation in an infusion product, comprising blending citric acid and a conjugate base of citric acid with the sugar-containing liquid preparation.

13. An infusion product comprising a multi-chamber infusion bag including at least a first chamber and a second chamber isolated from each other, a sugar-containing liquid contained in the first chamber, and an amino acid-containing liquid contained in the second chamber, wherein the sugar-containing liquid contains 50 w / v % or more of glucose and has a pH of 4 or less, and a mixture of all the liquids contained in the multi-chamber infusion bag contains acetate ions and lactate ions, and the glucose is contained at a concentration of 300 to 350 g / L. A method for inhibiting discoloration of a sugar-containing liquid preparation in an infusion product, comprising blending citric acid and a conjugate base of citric acid with the sugar-containing liquid preparation.

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