AU2015268572B2 - Infusion preparation - Google Patents

Abstract

-43 An object of the present invention is to provide an infusion preparation in which the Maillard reaction between an 5 amino acid and a reducing sugar does not occur during storage and the size of fat particles in the fat emulsion does not increase during storage, and in which various types of vitamins can be incorporated in a stable manner, in spite of the fact that it is a two-chamber infusion preparation. Furthermore, even if only one 10 of the infusions (of the infusion preparation) is administered, the patient is unlikely to develop hyperkalemia, vascular pain, or phlebitis. The present invention provides an infusion preparation containing two chambers separated by a partition that can be communicably opened, wherein a first chamber contains a 15 first-chamber infusion containing a sugar and a fat emulsion, a second chamber contains a second-chamber infusion containing an amino acid and an electrolyte, the first-chamber infusion is substantially free of potassium, and has a relative osmotic pressure of 2.0 to 3.0, the second-chamber infusion has a 20 potassium concentration of 40 mEq/L or less and a relative osmotic pressure of 2.5 to 3.5, and a mixture of the first- and second-chamber infusions has a potassium concentration of 16 mEq/L or more as measured upon communicably opening the partition.

Description

2015268572 08 Dec 2015 ρ/00/011 Regulation 3.2 Australia

Patents Act 1990

COMPLETE SPECIFICATION STANDARD PATENT

Invention Title:

Infusion preparation

The following statement is a full description of this invention, including the best method of performing it known to US: 1001299350 2015268572 08 Dec 2015 -1Α-

DESCRIPTION

Title of Invention؛ INFUSION PREPARATION Technical Field 5 [0.01]

The present invention relates to an Infusion preparation containing a sugar, a fat, an amino acid, and an electrolyte.

More specifically, the present invention provides an infusion preparation, which Is an Infusion preparation (a high-calorie 10 infusion preparation) contained in a two-chamber container, wherein a first chamber contains a sugar and a fat emulsion, and a second chamber contains an amino acid and an electrolyte. Background Art 15 [0002]

An Infusion preparation containing a sugar, an amino acid, and an electrolyte contained In an Infusion bag having two chambers is known and widely used for the nutritional management of patients (see Non-Patent Literature 1). 20 [0003]

Adding a reducing sugar and an amino acid to the same solution disadvantageous! causes the Maillard reaction and modifies the solution. Therefore. In the Infusion preparation. In order to prevent the Maillard reaction caused by a reducing sugar 25 and an amino acid, an infusion containing a reducing sugar Is placed in one chamber of an Infusion bag, and an infusion containing an amino- acid Is separately placed In the other chamber. At the time of use, the infusions are mixed by bringing the two chambers Into communication with each other and 30 subsequently administered to the patient. In order to facilitate the mixing procedure, the two chambers are generally separated by a partition wall (for exa٠le, an easily peelable seal) that can be communicably opened at the time of use. However, there Is a case where only one Infusion Is administered to the patient due 35 to the omission of the communication procedure. Such an error 2015268572 08 Dec 2015 -2- often occurs٠ Therefore, when such an infusion preparation in a two-chamber container Is used. It Is ve^ Important to ensure that the patient is prevented from being adversely affected even in the case where only one Infusion placed In one chamber is 5 administered due to the omission of the communication procedure before use.

[00.4]

For example, when the potassium concentration in one infusion Is relatively high, a patient may develop hyperkalemia 10 if this Infusion Is singly administered thereto. In order to eliminate such a problem, an Infusion preparation in which potassium Is separately placed into the two chambers and the potassium concentration In each infusion is adjusted to 40 mEq/L or less has been examined (Patent Literature 1). 15 [0005]

Further, particularly when an infusion Is administered Into a peripheral vein. If the osmotic pressure is too high. It may cause vascular pain or phlebitis. Therefore, It is considered to be desirable that an Infusion have an appropriate osmotic 20 pressure even before being mixed (Patent Literature 2).

[0006]

Further, when an Infusion preparation containing a sugar, an amino acid, and an electrolyte (a hlgh-calorle Infusion preparation) Is singly administered for a long period of time. It 25 may induce essential fatty acid deficiency, ae development of essential fatty acid deficiency can be prevented by the administration of a fat emulsion in combination with a high-calorie infusion preparation. Further, fat has a high calorific value per weight, and also has advantages such as the fact that, 30 unlike sugar, it does not cause osmotic diuresis. However, when a long time has elapsed after an electrolyte Infusion and a fat emulsion were mixed together, the size of fat droplets becomes large, leading to the risk of causing fat embolism when such a mixture Is administered. Therefore, an Infusion preparation In a 35 two-chamber container in which a fat emulsion and an electrolyte 2015268572 08 Dec 2015 -3- are placed In different chambers and mixed at the time of administration has been developed.

[0007)

Still further. It is knoi that acidosis may occur when a vitamin Bl deficiency occurs during the administration of a hlgh-calorie Infusion, and vitamin supplementation Is required to prevent such a risk when administering a hlgh-calorle Infusion.

In order to avoid such a problem, a high-calorle Infusion preparation comprising three liquids (liquids in large, medium, and small chambers) to which vitamins. In addition to a sugar, an amino acid, and an electrolyte, are added In advance has been developed (for example, the Fulcaliq infusion preparation). The hlgh-calorle Infusion preparation is prepared in a fonn that contains Infusions having different compositions In large, medium, and small chambers. In view of problems in the stability of vitamins (particularly fat-soluble vitamins). However, infusion preparations having three chambers require additional work during production and use, thus creating problems with production cost and use. Further, for example, the package insert for the Fulcaliq infusion preparation instructs the user not to mix a fat emulsion as a precaution during preparation.

[0008)

As described above, techniques that have been examined with respect to various problems are useful in solving the respective problems; however, an infusion preparation that has solved all of the problems was yet to be developed.

Citation List Patent Literature [0009) PTL 1؛ Japanese Unexamlned Patent Publication No. 2004-189677 PTL 2: Japanese Unexamined Patent Publication No. 2003-95937 Non-Patent Literature [0010] NPL 1؛ Japanese Phamnacolo^ & .erapeutics, 24(10), 2151 (1996) -3a- 2015268572 29 Aug 2017 [0010Α) tOOlOA)

Reference to any prior art in the specification is not, and 'Should not he taken as, an acknowledgment., or any form of suggestion, that this prior art forms part of the common, general knowledge in Australia or 'any other juri.sdiction or that this-P'rior art could reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in t'he art. [0010Β] AS used herein, except where th.e context requires o.therwise, t.he term "comprise" and vari.ations of the term, suc..'h as "comprising", "comprises''' and "'Comprised"., are no't intended to exclude O'ther additives, components,, intege'rs or Step'S. 1001919728 -4. 2015268572 29 Aug 2017

Technical Problems [0011]

An aspect of the present invention is to develop an infusion preparation that, can solve all of t,he above problems. 'Solution., to Problems [0013.]

The present inventors, surprisingly found that the following advantages can be :achieved, by using an infu'Sion preparation comprising two chamber-s separated by a 'partition that can be. communicably opened, wherein '.a firs.t chamber contains a first-chamber infus.ion comprising a. -sugar and a fat emulsion, a second chamber contains a second-chamber infusion comp-rising an .amino acid and an electrolyte, the first-chamber i'nfusion is substantially free of potassium and has a relative osmotic pressure of 3.. 0 to 3.0, the second-chamber infus'-ion, has a potassium concentration of 40 mEq/L or less .and a. relative osmotic pressure of 3.5 to 3.5, and a mixture .of the first- and second-chamber infusions, .has a potassium concentration of 1ج mEq/L· 0-r more as measured upon communicably opening the partition. In this- infusion preparation, the Maillard reaction be'tween an amino ac.id and a reducing .Su.gar does -not occur during storage, an-.d the si.ze of fat particl.e-s. i.n the fat emulsion does not incr-ease during storage. Even if only one of the infusions is administered, the patient is unlikely to develop hyperkalemia, vascul.ar- pain, or phlebiti.s. In -S'p.i'te of the fact that it is a two-ch'amber infusion preparation, 'V-arious types of vitamins can be inc.orporated in a stabl.e manner. Th.e present inventors made further improvements, and. fin-ally accomplished the present': 30 invention.

[0013]

More specifically,, the pres-ent invention includes the' infusion p.reparations itemized bel.ow.

Item 1. .An infusion prepara.tion comprising two chambers separated by a partition that can '.be communicably opened, wher-ein. 10019197.28 2015268572 08 Dec 2015 -5- a first chamber contains a first-chamber Infusicn ccmprising a sugar and a fat emulsion; a second Camber contains a second-chamber Infusion comprising an amino acid and an electrolyte; the first-chamber infusion Is substantially free of potassium, and has a relative osmotic pressure of 2.0 to 3..; the second-chamber infusion has a potassium concentration of 40 mEq/L or less and a relative osmotic pressure of 2.5 to 3.5; and a mixture of the first- and second-chamber infusions has a potassium concentration of 16 mEq/L or more as measured upon comnunicably opening the partition.

Item 2. The Infusion preparation according to Item 1 wherein the first-chafer Infusion has a pH of 4.5 to 6.5, and the second-chamber Infusion has a pH of 6.0 to 7.4.

Item 3. The infusion preparation according to Item 1 or 2, wherein the volume ratio of the first-chafer infusion to the second-chamber Infusion Is 3:2 to 35؛.

Item 4. The Infusion preparation according to any one of Items 1 to 3, wherein the first chamber further contains vitamin SI.

Item 5. The infusion preparation according to Item 4 wherein the first-chamber infusion further contains vitamin A, vitamin Β6, vitamin Β12, vitamin D, vitamin E, and vitamin K, and the second-chamber Infusion further contains vitamin c and vitamin Β2. Advantageous Effects of Invention [0.14]

The infusion preparation of the present invention solves all of the above problems. In the infusion preparation, the Maillard reaction between an amino acid and a reducing sugar does not occur during storage, and the size of fat particles in the fat emulsion does not increase during storage. Furthe^ore, even If only one of the Infusions is administered, the patient is unlikely to develop h^erkalemia, vascular pain, or phlebitis. ب vitamin Bl incorporated is expected to inhibit the onset of acidosis. Moreover, because the infusion preparation is 2015268572 08 Dec 2015 -6- contained in a two-chamber container in which other vitamins, such as llpld soluble vitamins, can be Incorporated, the time and labor required In the manufacturing process and use can be reduced. 5

Description of Embodiments [0015)

The present Invention Is described below In more detail.

[0016] 10 The present Invention provides an Infusion preparation comprising two chambers separated by a partition that can be co^unlcably opened, wherein a first chamber contains a first-chamber Infusion comprising a sugar and a fat emulsion, and a second chamber contains a second-chamber Infusion cojnprising an 15 amino acid and an electrolyte.

[0017]

First-Chamber Infusion

The first-chamber Infusion used In the present invention comprises a sugar and a fat emulsion. 20 [0018]

Examples of sugars that can be inco^orated in the first-chamber Infusion Include reducing sugars such as glucose, fructose, and maltose; non-reducing sugars such as ^litol, sorbitol and glycerol; etc. Among these sugars, reducing sugars 25 are preferable, and glucose Is particularly preferable, from the vie^oint of blood glucose level management, etc. Such sugars may be used singly or in a combination of two or more.

[0019]

The amount of sugar In the first-chamber infusion is 30 preferably in the range of 70 to 150 g/L. In the Infusion preparation of the present invention, the mixture of the first-and second-chamber Infusions may preferably have a sugar concentration of 50 to 100 g/L, and more preferably 50 to 75 g/L.

[0020] 35 To prevent the onset of acidosis during infusion 2015268572 08 Dec 2015 -7- therapy, vitamin Bl is preferably Incorporated in the first-chamber infusion. Examples of vitamin Bl that can be incorporated In the first-chamber Infusion Include thiamine chloride hydrochloride, thiamine mononitrate, prosultiamine, octotiamlne, and the like.

[0.21]

The amount of vitamin Bl In the first-chamber infusion may be, for example, in the range of 1.5 to 10 mg/L, and preferably 2 to 8 mg/L, based on thiamine. In the infusion preparation of the present invention, the mixture of the first-and second-chamber Infusions preferably has a vitamin Bl concentration of 1 to 6 mg/L, and more preferably 1.5 to 4 mg/L. [0022]

The fat emulsion Incorporated In the first-chamber Infusion Is an oil-in-water emulsion produced by dispersing an oil and/or fat In water using an emulsifying agent. The fat emulsion can be prodiiced according to a usual method. For example, after an oil and/or fat, and an emulsifying agent are added to water, the mixture is stirred to prepare a crude emulsion. Subsequently, the crude emulsion is emulsified by a conventional mettiod, such as a high-pressure emulsification method.

[0023]

Examples of oils and fats that can be preferably used Include edible oils. Specific examples thereof Include vegetable oils (e.g., soybean oil, olive oil, cottonseed oil, safflower oil, corn oil, coconut oil, and per Ilia oil),, fish oils (e.g., cod liver oil)؛ medium-chain fatty acid triglycerides (Cs-10 fatty acid triglycerides) (e.g., product name: PANACET (produced by N.F Coloration), ODO (produced by Nlsshin oil Mills, Ltd.), COCONARD (produced by Kao Coloration), Mlglyol (produced by Mitsuba Trading Co., Ltd.))؛ s^thetic triglycerides (e.g., 2-lln٠leoyl_ l,3-dioctanoyl glycerol (81,8), and 2-llnoleoyl-l,3-dldecanoyl-glycerol (101,10))؛ and the like. Such oils and fats may be used singly or In a combination of two or more.

[0024] 2015268572 08 Dec 2015 -8-

The emulsifying agent may be selected from, for example, various pharmaceutically acceptable emulsifying agents. Specific examples thereof Include egg yol^ phospholipid (egg yol^ lecithin), hydrogenated yolk phospholipid, soybean phospholipid (soybean lecithin), hydrogenated soybean phospholipid,, nonlonlc surfactants; and the like. Such emulsifiers may be used singly or In a combination of two or more. (0025]

Soybean oil is particularly preferable as an oil and/or fat. Egg-yolk phospholipid (egg yolk lecithin) Is particularly preferable as an emulsifying agent. Lecithin, such as egg yolk lecithin, is particularly preferable because it can also act as a phosphorus source, as described below.

[0026]

Insofar as an οΐΐ-in-water fat elision can be produced, the amounts of oil and/or fat and eilsifier used to prepare the fat emulsion are not particularly limited. The oil and/or fat Is typically used In such an amount as to achieve a concentration of about 0.5 to 6 w/v%, and preferably about 1 to 5 w/v%. In the obtained fat elision. Furthemore, the emulsifying agent Is typically used In such an amount as to achieve a concentration of about ..01 to 2 w/v%, and more preferably about 0.05 to 1 w/v%.

In the obtained fat emulsion. ΙΟΟΙΊλ

One example of a particularly preferable method for producing the fat emulsion according to the present invention Is described below. More specifically, an oil and/or fat and an emulsifying agent are added to water, and at least one member selected from glycerol and glucose Is also added thereto. The mixture is then stirred to prepare a crude emulsion. Subsequently, the crude emulsion Is emulsified by a conventional method, such as a high-pressure emulsification method. The high-pressure emulsification method may be carried out, for example, by passing the crude emulsion through an emulsifier, such as a Manton Gaulin homogenlzer, at a rate of 20 to 700 kg/cm2 about 2 to 50 times. 2015268572 08 Dec 2015 -9- and preferably 3 t. 2. times. In this method. Insofar as glycerol and/or glucose is present during the emulsification, the manner and timing of addition thereof are not limited. For example, glycerol and/or glucose may be added to the crude vision prepared by using an oil and/or fat and an emulsifying agent, and the resulting crude pulsion may be emulsified. The glycerol and/or glucose is typically used in such an amount as to achieve a concentration of about 30 to 70 w/v%, and preferably about 40 to 60 w/v%, in the obtained fat pulsion.

[0028]

If necessary, various additives that are known to be added to fat emulsions may be further Incorporated. Examples of such additives include pH adjusters. Specific examples of pH adjusters Include acids such as hydrochloric acid; alkalis such as sodium hydroxide and potassium hydroxide; and organic acids and amino acids. Examples of organic acids include acetic acid, lactic acid, citric acid, malic acid, succinic acid, and the like. Examples of amino acids include L-histidine, L-lysine, and the like. Among these, oil-soluble materials may be premixed Into an oily component of the emulsion. Water-soluble materials may be mixed into water for Injection, or added to an aqueous phase of the obtained fat emulsion. The amounts of additives to be used can be suitably determined, and may be the same as conventionally known amounts.

[0029]

The fat emulsion Is Incorporated in the first-chamber Infusion in an amount of 0.5 to 6 w/v%, preferably 1 to 5 w/v%, and more preferably 2 to 5 w/v%, based on oils and fats. In the Infusion preparation of the present invention, the mixture of the first- and second-chamber Infusions contains the fat emulsion In a concentration of 0.25 to 6 w/v%٠ preferably 0.5 to 3 w/v%, and more preferably 1 to 2.5 w/v%, based on oils and fats.

[0030]

The first-chamber infusion has a pH in the range of 4.5 to 6.5, and preferably 5.0 to 6.5. When the pH Is within the 2015268572 08 Dec 2015 -1.- ab.ve-mentl.ned range, the fat emulsion and vitamin B in the first-chamber Infusion can be stabilized. The pH of the first-chamber Infusion can be adjusted by using a pH adjuster, such as hydrochloric acid, acetic acid, glacial acetic acid, lactic acid, malic acid, citric acid, sodium hydroxide, or potassium hydroxide. L-hlstldine may also be used as a pH adjuster. ل031.ء

In view of enhancing the stability of vitamin Bl, the first-chamber infusion preferably has a titratable acidity of 1 or less. The titratable acidity refers to an amount (mL) of a 0.1 mol/L sodium hydroxide aqueous solution retired to neutralize 100 ml of a solution to pH 7.4.

[0032؛

Distilled water for injection can be typically used as a solvent of the first-chamber Infusion.

[0033]

In the infusion preparation of the present invention, the fluid volume of the first-chamber infusion is suitably determined according to the total fluid volume of the infusion preparation and the fluid volume of the second-chamber infusion.

[0034]

The first-chamber Infusion Is substantially free of potassium. The phrase "substantially free of potassium" means that no potassium-containing compounds are added.

[0035]

The first-chamber infusion has a relative osmotic pressure of about 2.0 to 3.0. I relative osmotic pressure as used herein refers to a ratio relative to the osmotic pressure of physiological saline (i.e., a relative rat.i٠, with the osmotic pressure of physiological saline defined as 1). The relative osmotic pressure of the infusion refers to a ratio relative to the osmotic pressure of physiological saline, unless othe^lse specified.

[0036]

Second-Chamber Infusion 2015268572 08 Dec 2015 -11- *The second-chamber infusion used in the present Invention contains an amino acid and an electrolyte. ΙΠΛ

Any amino acid that can be lnco^orated In amino acid Infusions for the purpose of nutritional supplementation for the body may be used as an amino acid to be contained In the second-chamber Infusion. In the present invention, the amino acid is typically used In the fonn of a free amino acid. However, the amino acid may also be used In the fonn of a phannaceutlcally acceptable salt, an ester, a Ν-acyl derivative, or a dipeptide. Examples of free aml'no acids that can be Incorporated in the second-chamber Infusion Include L-leucine, L-isoleuclne, L-vallne, L-lyslne, 1.-threonine, L-tryptophan, L-methionine, L-phenylalanine, L-cysteine, L-tyroslne, !.-arginine, L-hlstidlne, L-alanine, L-proline, L-serine, glycine, !,-aspartic acid, L-glutamlc acid, and the like. Examples of amino acid salts Include Inorganic acid salts such as L-arglnlne hydrochloride, L-cysteine hydrochloride, L-glutamlc acid hydrochloride, L-histidlne hydrochloride, and L-lysine hydrochloride; organic acid salts such as L-lysine acetate and L-lyslne malate; etc. Examples of amino acid esters include !.-tyrosine methyl ester, L-methionine methyl ester, L-methionine ethyl ester, and the like. Examples of Ν-acyl amino acids include N-acetyl-L-cysteine, Ν-acetyl-L-t^tophan, N-acetyl-L-proline, and the like. Examples of amino acid dipeptldes include L-tyrosyl-L-tyrosine, L-alanyl-L-t۴osine, L-arginyl-L-tyrosine, L-tyrosyl-L-arglnlne, and the like. In particular, L-cysteine Is preferably Incorporated in the form of acetylcysteine In view of stability. Such amino acids may be used singly, but are preferably used In a combination of two or more, from the viewpoint of nutritional supplementation. For example. It is preferable to incorporate at least all of the essential amino acids (1.e., 9 types of amino acids: L-leucine, L-isoleuclne, L-vallne, L-lysine, !.-threonine, L-t^ptophan, L-methionine, L-phenylalanlne, and L-histidine).

[0038] 2015268572 08 Dec 2015 -1,-

The amount of amino acids In the second-chamber Infusion may be, for .example, preferably 40 to 120 g/L, and more preferably 50 to 100 g/L, based on the total amount of free amino acids. In the infusion preparation of the present Invention, the mixture of the first- and second-chamber Infusions preferably has an amino acid concentration of 10 to 50 g/L, and more preferably 20 to 30 g/L, based on the total amount of free amino acids. 10039] A preferable combination of amino acids to be Incorporated In the second-chamber infusion, and proportions thereof are, for example, as follows. In terms of free amino acids؛ L-leucine: 5 to 15 g/L; L-isoleucine: 3 to 9 g/L; L-valine: 3 to 9 g/L; L-lyslne3 ؛ to 12 g/L; L-threonine: 1.2 to 6 g/L; L-tr^tophan: 0.3 to 3 g/L; L-methionine: 0.6 to 4.8 g/L; L-phenylalanine: 1.8 to 9 g/L; L٩steine: 0.1 to 1.8 g/L; L-tyrosine: 0.06 to 1.2 g/L; !,-arginine: 3 to 12 g/L; L-hlstidine: 1.2 to 6 g/L; L-alanine: 3 to 9 g/L; L-proline: 1.2 to 6 g/L; L-serine: 0.6 to 4.2 g/L; glycine: 1.2 to 6 g/L; L-aspartic acid: 0.12 to 1.8 g/L; and L-glutamic acid: 0.12 to 1.8 g/L.

[0040]

In the Infusion preparation of the present Invention, the mixture of the first- and second-chamber infusions preferably contains amino acids In the following concentrations, In terms of free amino acids: L-leucine: 3 to 9 g/L; L-isoleucine: 1.5 to 4.5 g/L; L-vallne: 1.5 to 4.5 g/L; L-lyslne: 1.5 to 5 g/L; L-threonine: 0.6 to 3 g/L; L-t^tophan: 0.15 to 1.5 g/L; L-methionine: 0.3 to 2.4 g/L; L-phenylalanine: 0.85 to 4.5 g/L; L-cysteine: 0.03 to 0.9 g/L; L-tyrosine: 0.03 to 0.6 g/L; L-arginine: 1.5 to 5 g/L; L-histidine: 0.6 to 3 g/L; L-alanine: 1.5 to 4.5 g/L; L-proline: 0.6 to 3 g/L; L-serine: 0.3 to 2.1 g/L; glycine: 0.6 to 3 g/L; L-aspartlc acid: 0.06 to 0.9 g/L; and L-glutamic acid: 0.06 to 0.9 g/L.

[0041]

The electrolyte to be incorporated in the second-chamber Infusion Is an electrolyte that is used in the Infusion 2015268572 08 Dec 2015 -13 field. More specifically, it Is an electrolyte contained in a body fluid (body fluid electrolyte) (e.g., blood and intracellular fluid), which can be said to be a physiologically Important electrolyte. Specific examples of such electrolytes Include potassium, calcium, sodium, magnesium, phosphors, zinc, chlorine, and the like. In the Infusion preparation of the present invention. It Is preferable that such an electrolyte not be Incorporated in the first-chamber Infusion. In particular, although potassium Is usually incorporated In both infusions of a two-chamber Infusion preparation In order to avoid the risk of administering a high concentration of potassium, potassium is incorporated only In the second-chamber infusion according to the Infusion preparation of the present Invention.

[0042)

Examples of potassium sources Include potassium chloride, potassium acetate, potassium citrate, potassium glycerophosphate, potassium sulfate, potassium lactate, and the like. Among these, potassium glycerophosphate is preferable becaiise It also acts as a phosphorus source. Such potassium sources may be in the form of a hydrate. Potassium Is Incorporated in such an amount as to achieve a concentration of 40 mEq/L or less (preferably 25 to 40 mEq/L) In the second-chamber infusion. In the infusion preparation of the Invention, the mixture of the first- and second-chamber infusions has a potassium concentration of 16 mEq/L or more (preferably 16 to 25 mEq/L), and more preferably 16 to 20 mEq/L.

[0043)

Examples of calcium sources Include calcium salts such as calcium gluconate, calcium chloride, calcium glycerophosphate, calcium lactate, calcium pantothenate, and calcium acetate. Calcium salts may be in the form of a hydrate (e.g., calcium gluconate hydrate). Calcium is Inco^orated In such an amount as to achieve a concentration of 15 mEq/L or less (preferably 6 to 12 mEq/L) in the second-chamber Infusion. In the Infusion preparation of the Invention, the mixture of first- and second- 2015268572 08 Dec 2015 -14- chamber infusions has a calcium concentration of 9 mEq/L or less (preferably 3 to 6 mEq/L). (0.44)

Examples of sodium sources Include sodium salts such as 5 sodium chloride, sodium lactate, sodium acetate, sodium sulfate, sodium glycerophosphate, sodium citrate, and sodium lactate. ' ien phosphors, and calcium and/or magnesium are Incorporated In the infusion preparation of the present Invention, sodium citrate Is preferably used as a sodium source in order to prevent 10 precipitation of these elements. Sodium sources may be In the form of a hydrate. Sodium is incorporated In the second-chamber infusion In a concentration of 50 to 100 mEq/L, and preferably 40 to 80 mEq/L In the second-chamber infusion. In the infusion preparation of the present Invention, the mixture of the first-15 and second-chamber Infusions preferably has a sodium concent'ratlon of 25 to 50 mEq/L, and preferably 30 to 40 mEq/L. (0045)

Examples of magnesium sources Include magnesium sulfate, magnesium chloride, magnesium acetate, and the like. .Magnesium 20 sources may be In the form of a hydrate. The am.ount of magnesium in the second-chamber infusion may be, for example, 1 to 20 mEq/L, and preferably 5 to 15 mEq/L, in the second-chamber infusion. In the infusion preparation of the present invention, the mixture of the first- and second-chamber infusions preferably has a 25 magnesium concentration of 0.5 to 10 mEq/L, and preferably 2 to 6' mEq/L. (0046)

When an inorganic salt Is used as a phosphorus source, calcium phosphate and magnesium phosphate may precipitate. 30 Accordingly, an organic salt, such as sodium glyceropliosphate or potassium glycerophosphate, is preferably used. Wien lecithin is used as an emulsifying agent In the first chamber, the lecithin also acts as a phosphorus source, ien the phosphorus derived from lecithin can provide a sufficient amount of phosphorus. It 35 Is unnecessa^ to incorporate phosphors In the second chamber. 2015268572 08 Dec 2015 -15- and no precipitation of calcium phosphate, etc., occurs, which is preferable. The amount of phosphorus in the second-chamber Infusion may be, for example, 0 to 20 iol/L. In the Infusion preparation of the invention, the mixture of the first- and second-chamber infusions preferably has a phosphorus concentration of 1 to 20 mmol/L, and more preferably 5 to 10 iol/L.

[0047]

Examples of zinc sources include zinc sulfate, zinc chloride, and the like. Zinc sources may be in the fonn of a hydrate. The amount of zinc In the second-chamber Infusion is 2.5 to 15 μπίθΙ/L. In the Infusion preparation of the Invention, the mixture of the first- and second-chamber infusions preferably has a zinc concentration of 1.5 to 9 Jjmol/L.

[0048]

Examples of chlorine sources Include sodium chloride, potassium chloride, magnesium chloride, calcium chloride, and the like. The amount of chlorine in the second-camber infusion may be, for example, 50 to 100 mEq/L, and preferably 40 to 80 mEq/L. In the infusion preparation of the present Invention, the mixture of the first- and second-chamber infusions preferably has a chlorine concentration of 25 to 60 mEq/L, and more preferably 30 to 40 mEq/L.

[0049]

The pH of the second-chamber infusion is preferably adjusted to 6.0 to 7.4, and preferably 6.5 to 7.2, by using a pH adjuster. If necessa^. Examples of pH adjusters that can be used may be the same as mentioned above for the first-chamber infusion In particular, the use of citric acid is preferable because it can inhibit the precipitation of calcium phosphate, len the second-chamber infusion has a pH within the above-mentioned range amino acids that are prone to undergo chemical changes, such as L-cysteine and L-glutamic acid, can be stabilized. Furthemnore, the pH of the mixture of the second-chamber infusion with the first-chamber Infusion can be maintained In the- optimum range as 2015268572 08 Dec 2015 -16- described belcw.

[0.50]

As a sclvent in the second-chamber infusion, distilled water for Injection can be typically used. 5 [0051]

In the infusion preparation of the present invention, the second-chamber infusion has a relative osmotic pressure of about 2.5 to 3.5.

[0052] 10 If necessary, the infusion preparation of the present invention may contain a stabilizer. Examples of stabilizers that can be incorporated in the infusion preparation of the present invention include sulfites such as sodium bisulfite. To avoid the decomposition of vitamin Bl contained In the first-chamber 15 infusion, sulfite is incorporated In the second-chamber Infusion. The amount of sulfite in the second-chamber infusion may be, for example, 20 to 50 mg/L.

[0053]

In addition to vitamin Bl, various other types of 20 vitamins can be added to the Infusion preparation of the present invention. Various types of vitamins can be stably added to the infusion preparation in the two-chamber container without the need to place the infusion preparation in a three- or four-chamber container. Is Is one of the features of the infusion 25 preparation of the present Invention. Vitamins are classified Into water-soluble vitamins and fat-soluble vitamins. In the Infusion preparation of the present invention, a fat-soluble vitamin Is added to the first-chamber Infusion. Further, a water-soluble vitamin may be added to either the first- or second-30 chamber Infusion. However, as described above, vitamin Bl Is added to the first-chamber infusion.

[0054]

Examples of water-soluble vitamins added to the Infusion preparation of the present Invention Include B-complex 35 vitamins and vitamin c. In addition to vitamin Bl (thiamine). 2015268572 08 Dec 2015 -17- examples ٠f B-complex vitamins include vitamin Β2 (riboflavin), vitamin Β3 (niacin), vitamin Β5 (pantothenic acid). vitamin Βδ. vitamin Β7 (biotin), vitamin Β9 (folic acid), and vitamin Β12 (^anocobalamin). Further, examples of fat-soluble vitamins 5 Include vitamin A, vitamin D (in particular, cholecalciferol). vitamin E. and vitamin K. (.055)

When vitamin c (ascorbic acid) Is added, it can be added to either or both of the first- and second-chamber 10 Infusions. However, it is preferably added to the second-chamber Infusion, ien vitamin c is added to the second-chamber Infusion, the amount of vitamin c In the second-chamber infusion is. for example. 50 to 500 mg/L, and preferably 100 to 400 mg/L٠ Further, In the infusion preparation of the present invention, the vitamin 15 c concentration in the mixture of the first- and second-chamber Infusions is preferably set to satisfy the following ranges: generally 25 to 250 mg/L٠ preferably 50 to 200 mg/L, and more preferably 40 to 100 mg/L. (0056) 20 As vitamin Β2, riboflavin, riboflavin sodium phosphate, flavin mononucleotide, and the like can be used, ien vit٠in Β2 Is added, it can be added to either or both of the first- and second-chamber Infusions. However, vitamin Β2 and folic acid are preferably placed in different chambers In order to prevent the 25 destabilization of folic acid caused by a reaction between vitamin Β2 and folic acid. For example, when folic acid Is added to the first-chamber Infusion, vitamin Β2 is preferably added to the second-chamber Infusion, ien vitamin Β2 Is added to the second-chamber Infusion, the amount of vitamin Β2 In the second-30 chamber infusion is, for example, generally 2.5 to 15 mg/L, and preferably 4 to 8 mg/L, in terns of riboflavin. Further, In the Infusion preparation of the present Invention, the vitamin Β2 concentration in the mixture of the first- and second-chamber Infusions Is preferably set to satisfy the following ranges: 2015268572 08 Dec 2015 -18- generally 0.5 to 10 mg/L, and preferably 0.5 to 3 mg/L٠ In tems of riboflavin.

[0057]

As vitamin Β6, pyrldoxine, salts of pyrldoxine such as pyridoxine hydrochloride, and the like can be used. Mien vitamin Β6 is added. It can be added to either or both of the first- and second-chamber Infusions. However, vitamin Β6 becomes ve^ unstable to light when it coexists with vitamin Β2. Therefore, vitamin Β6 Is preferably added to the infusion to which vitamin Β2 Is not added. Wien vitamin Β6 is added to the first-chamber Infusion, the amount of vitamin Β6 in the first-chamber infusion Is, for example, generally 2 to 10 mg/L, and preferably 2.5 to 5 mg/L, in terns of pyrldoxine. Further, In the infusion preparation of the present Invention, the vitamin Β6 concentration In the mixture of the first- and second-chamber infusions Is preferably set to satisfy the following ranges ؛ generally 1 to 10 mg/L, and preferably 1.5 to 3.5 mg/L, In terns of pyrldoxine.

[0058] len folic acid Is added, it can be added to either or both of the first- and second-chamber Infusions; however, it is preferably added to the first-chamber Infusion. When folic acid is added to the first-chamber infusion, the amount of folic acid In the first-chamber infusion is, for example, generally.0.1 to 0.8 mg/L, and preferably 0.2 to 0.5 mg/L. Further, in the Infusion preparation of the present Invention, the folic acid concentration In the mixture of the first- and second-chamber Infusions Is preferably set to satisfy the following ranges: generally 0.1 to 0.7 mg/L, and preferably 0.2 to 0.4 mg/L.

[0059]

As vitamin Β12, cyanocobalamin, hydroxocobalamin acetate, methylcobalamln, and the like can be used. When vitamin Β12 Is added. It can be added to either or both of the first- and second-chamber infusions; however, it Is preferably added to the first-chamber Infusion. Mien vitamin Β12 Is added to the first- 2015268572 08 Dec 2015 ع 19 ا٠ chamber infusion, the amount of vitamin Β12 In the first-chamber infusion Is, for exa٠le, 2 to 1. pg/L, and preferably 2.5 to 5 pg/L٠ Further. In the Infusion preparation of the present Invention, the vitamin Β12 concentration in the mixture of the first- and second-chamber infusions is preferably set to satisfy the following ranges: generally 0.5 to 10 mg/L, and preferably 0.5 to 3 mg/L٠ (0060؛

As niacin, for example, nicotinamide can be preferably used, ien niacin is added, it can be added to either or both of the first- and second-chamber infusions; however, it is preferably added to the second-chamber Infusion. Wien niacin is added to the second-chamber Infusion, the amount of niacin In the second-chamber Infusion Is, for example, 10 to 100 mg/L, and preferably 20 to 50 mg/L. Further, in the infusion preparation of the present Invention, the niacin concentration in the mixture of the first- and second-chamber Infusions is preferably set to satisfy the following ranges: generally 5 to 50 mg/L, and preferably 5 to 20 mg/L. \11٠؟أ

As pantothenic, acid, panthenol can be preferably used. ٠en pantothenic acid Is added, it can be added to either or both of the first- and second-chamber Infusions; however. It is preferably added to the second-chamber Infusion. Wien pantothenic acid Is added to the second-chamber infusion, the amount of pantothenic acid In the second-chamber Infusion Is, for example, 5 to 30 mg/L, and preferably 10 to 20 mg/L, In the case of panthenol. Further, In the infusion preparation of the present invention, the panthenol concentration In the mixture of the first- and second-chamber infusions is preferably set to satisfy the following ranges: generally 2.5 to 15 mg/L, and preferably 5 to 10 mg/L. (0062؛

Wien biotin Is added, it can be added to either or both ٠f the first- and second-chamber infusions; however, it is 2015268572 08 Dec 2015 -20- preferably added t. the second-chamber Infusi.n. When blotln Is added to the second-chamber Infusion, the amount of blotln In the second-chamber infusion is, for example, 10 to 100 pg/L, and preferably 20 to 80 pg/L. Further, in the infusion preparation of the present Invention, the blotln concentration in the mixture of the first- and second-chamber Infusions is preferably set to satisfy the following ranges: generally 1 to 50 pg/L, and preferably 10 to 40 pg/L٠ [00633

As vitamin A, retinol palmitate can be preferably used. Further, vitamin A oil formed by dissolving retinol palmltate In oil can also be used. Vitamin A is fat-soluble, and is added to the first-chamber infusion. The amount of vitamin A In the first-chamber Infusion is, for example, 1,000 to 5,000 IU/L, and preferably 2,000 to 4,000 IU/L٠ Further, in the infusion preparation of the present Invention, the vitamin A concentration in the mixture of the first- and second-chamber Infusions Is preferably set to satisfy the following ranges: generally 500 to 2,500 IU/L, and preferably 1,000 to 2,000 IU/L. IU stands for International Unit. It is also called vitamin A unit.

[00643

As vitamin D, cholecalciferol (vitamin D3) can be preferably used. Vitamin ٠ is fat-soluble, and is added to the first-chamber Infusion. The amount of vitamin D in the first-chamber Infusion Is, for example, 2 to 10 pg/L, and preferably 2.5 to 5 pg/L. Further, in the Infusion preparation of the present invention, the vitamin D concentration In the mixture of the first- and second-chamber infusions Is preferably set to satisfy the following ranges: generally 0.5 to 10 pg/L, and preferably 0.5 to 3 pg/L٠ [00653

As vitamin E, tocopherol acetate can be preferably used. Vitamin E is fat-soluble, and is added to the first-chamber Infusion. I amount of vitamin E In the first-chamber Infusion is, for example, 2 to 50 mg/L, and preferably 5 to 20 mg/L. 2015268572 08 Dec 2015 35 -21-

Further, in the infusi.n preparatien ٠f the present Invention, the vitamin D concentration In the mixture of the first- and second-chamber infusions is preferably set to satisfy the following ranges؛ generally 1 to 25 mg/L٠ and preferably 2.5 to 10 mg/L.

[00661

As vitamin K, phytonadlone (vitamin Ki) can be preferably used. Vitamin K is fat-soluble, and is added to the first-chamber Infusion. The amount of vitamin K in the first-chamber infusion Is, for example, 50 to 2,500 ^ig/L٠ and preferably 80 to 2,000 pg/L. Further, In the infusion preparation of the present invention, the vitamin K concentration In the mixture of the first- and second-chamber Infusions is preferably set to satisfy the following ranges: generally 20 to 1,200 pg/L, and preferably 30 to 1,000 pg/L٠ [00671 A preferable example of the first- and second-chamber infusion compositions is shown below.

[00681

First-Chamber Infusion Purified soybean oil: 10-50 g/L Glucose: 70-150 g/L

Thiamine chloride hydrochloride: 3-10 mg/L

Pyridoxine hydrochloride: 3-7 mg/L

Cyanocobalamin: 2.5-5 pg/L

Folic acid: 0.2-0.5 mg/L

Vitamin A oil: 2,000-4,000 IU/L

Cholecalclferol: 2.5-5 pg/L

Tocopherol acetate: 5-20 mg/L

Phytonadlone: 80-2,000 pg/L

[00691

Second-Chamber Infusion

L-leucine: 5-15 g/L 2015268572 08 Dec 2015 -22-

L-lsoleucine: 3-9 g/L L-valine: 3-9 g/L L-lysine hydrochloride: 3.5-15 g/L L-threonlne: 1.2-6 g/L L-t^ptophan3-3.. ؛ g/L L-methlonine: 0.6-4.8 g/L Acetylcysteine: 0.13-2.4 g/L L-phenyHanine: 1.8-9 g/L L-t^os!ne: 0.06-1.2 g/L L-arginine: 3-12 g/L L-hlstldine: 1.2-6 g/L L-alanine: 3-9 g/L L-proline6-1.2 ؛ g/L L-serine: 0.6-4.2 g/L Glycine: 1.2-6 g/L L-asparatic acid: 0.12-1.8 g/L L-glutamic acid: 0.12-1.8 g/L Sodium: 40-80 mEq/L Potassium: 25-40 mEq/L Calcium: 6-12 mEq/L Magnesium: 5-15 mEq/L Chlorine: 40-80 mEq/L Phosphoms: 0-20 ioL/L Zinc: ,2.5-15 pmol/L

Riboflavin Sodium Phosphate: 5-10 mg/L Ascorbic acid: 0.1-0.4 g/L Blotln: 20-80 μg/L Nicotinamide: 20-50 mg/L Panthenol: 9-19 mg/L

Both of the first- and second chamber infusions can be produced by a knoi method for producing Infusions. For example, the. first- and second chamber Infusions can be produced by dissolving each of the above-described infusion components In distilled water for injection. Fat-soluble components are 2015268572 08 Dec 2015 -23- preferably used, f.r example, after being emulsified as described abcve. (007.3

Mixture of the First- and Second-Chamber Infusions

The Infusion preparation of the present invention Is used by mixing the first-chamber infusion and the second-chamber Infusion at the time of use. In order to improve the safety by suppressing the occurrence of vascular pain and phlebitis, it Is desirable that the mixture of the first- and second-chamber Infusions have a pH of 6 to 7.4, and preferably 6.5 to 7.0, a tltratable acidity of 1 to 10, and a relative osmotic pressure of 2 to 3.

[0071]

Further, In the infusion preparation of the present Invention, the volume ratio between the first-chamber Infusion and the second-chamber infusion Is suitably detennined according to the above-described amount of the first- and second-chamber infusions and the like. In view of the stability of each component contained and the osmotic pressure setting In each chamber, the volume ratio (first-chamber infusion:second-chamber Infusion] Is, for example, 3:2-3:5.

[0072]

Further, the calorific value of the mixture is preferably 450 to 750 kcal/L, more preferably 500 to 650 kcal/L. In this calorific value, the percentage of fat is preferably 40% or less, and more preferably 20 to 40%. Further, in this calorific value, the percentages of sugar, fat, and amino acid are preferably as follows: 40 to 60% of s-ugarj 20 to 40% of fat; and 10 to 30% of amino acid, and more preferably, 45 to 55% of sugar; 25 to 35% of fat; and 15 to 25% of amino acid.

An approximate calorific value of each component can be detennined by multiplying the amount (g) by 4 for sugar, by 9 for fat, and by 4 for amino acid. Specifically, the calorific value of sugar Is about 4 kcal/g, the calorific value of fat Is about 9 2015268572 08 Dec 2015 -24- kcal/g, and the calorific value of amino acid Is about 4 kcal/g. An approximate calorific value can be deteimlned based on this inf oration. The calorific value of the mixture described above. Is based on a value calculated by the above fonnula. 5 [0074} A preferable example of the composition of each component in the mixture Is shown below.

[0.75} Table 1

Components Amount (1,000 mL) Electrolytes Na 35 mEq K 20 mEq Mg 5 mEq Ca 5 mEq Cl 35 mEq p 10 mol Zn 5 pmol Sugar Glucose 75 g Fat Purified soybean oil 20 g Amino acid Amino acid 30 g Vitamins diamine chloride hydrochloride 1.9 mg Riboflavin sodium phosphate 2.3 mg Pyridoxine hydrochloride 2.45 mg Cyanocobalamin 2.5 pg Nicotinamide 20 mg Panthenol 7 mg Folic acid 0.2 mg Biotin 30 pg Ascorbic acid 50 mg Vitamin A oil 1,650 IU Cholecalciferol 2.5 pg Tocopherol acetate 5 mg Phytonadione 1 mg 10 [0076}

Infusion Preparation Usage Form

The Infusion preparation of the present Invention is used in order to manage the nutrition of a perioperative patient when the patient has mild hypoprotelnemia or mild malnutrition 15 due to inade٠ate oral intake or when the patient Is In the invasive phase. In particular, the infusion preparation is suitably used to manage the nutrition of a patient having 2015268572 08 Dec 2015 -25- difficulty receiving cral nutritional support in the postoperative period or due to a digestive disorder and the like (preferably, a patient who has undergone gastric resection surgeiy). The Infusion preparation of the present invention is administered to a patient for 1 to 14 days after surges, and preferably lto3 days after surges. Thereby, the nutritional status of the patient can be maintained in a healthy state. The dose and the dosing rate can be suitably dete^ined in view of each patient's s„tms٠ age, and the like. In particular, when the Infusion preparation of the present Invention is used, the infusion preparation can maintain, by itself, the nutritional status of the patient in a healthy state for the duration of administration. ιο.τη

The infusion preparation of the present Invention Is preferably administered into a peripheral vein. In other words, the Infusion preparation of the present Invention Is preferably an Infusion preparation for peripheral intravenous administration. Usually, when an Infusion Is administered Into a peripheral vein, if the osmotic pressure of the infusion is too high, it may cause vascular pain or phlebitis. However, there Is no such risk when the infusion preparation of the present Invention Is used. Therefore, the effect of the infusion preparation of the present invention is preferably demonstrated when the Infusion preparation is administered into a peripheral vein.

Infusion Container

The container In which the first-chamber infusion and the second-chamber Infusion are placed is not particularly limited insofar as the container has two chambers that are intercommunicable. Examples Include two-chamber containers (Infusion bags) in which the chambers are separated by a partition wall that can be communicably opened, such as ones in which a partition wall Is formed by an easily peelable seal (Japanese Unexamined Patent Publication No. Η2-4671, Japanese 2015268572 08 Dec 2015 -26-

Unexamined utility Model Publication No. Η5-5138, and the like); ones in which a partition wall Is formed by clipping the space between the chambers (Japanese Unexamlned Patent Publication No. S63-309263, and the like); and ones In which various communicating means that can open the partition wall Is provided to the partition wall (Japanese Examined Patent Publication No. S63-20550, and the like). ٠f these, an Infusion bag In which the partition wall Is formed by an easily peelable seal Is preferable because it Is suitable for mass production and the chambers can be easily brought into communication. Further, various gas-pe^eable plastics commonly used for medical containers are used as materials of the above container. Examples include flexible plastics, such as polyethylen'e, polypropylene, pol٣inyl chloride, crossllnked ethylene-vlnyl acetate copolymer, ethylene-a-olefln copolymer, blends of such polders, and laminates comprising such polymers.

[0078)

The first- and second-chamber Infusions can be placed and contained In the container by a conventional method. For example, the chambers are filled with the respective Infusions under an Inert gas atmosphere, sealed, and sterilized by heat.

Heat sterilization can be performed by a known method, such as high-pressure steam sterilization or hot water shower sterilization. If necessa^, the heat sterilization can be carried out in an inert gas atmosphere such as carbon dioxide or nitrogen.

[0075]

Further, the first- and second-chamber Infusions contained In the container are preferably packaged together with an .؟gen absorber In an oxygen barrier exterior bag. In order to reliably prevent degeneration and oxidation. Particularly when an Infusion bag in which the partition wall Is formed by an easily peelable seal is used as a container, the infusion bag is preferably packaged in such a manner that the infusion bag Is folded, for example, in half, at the easily peelable seal portion 2015268572 08 Dec 2015 25 30 -27- so that the partition wall will not be coranunlcably opened by external pressure. Further, for example, the package may be filled with an inert gas If necessa^.

[.080] 5 Commonly widely used films, sheets, and the like formed from various materials can be used as materials of the oxygen barrier exterior bag, which are suitable for the packag'e.

Specific examples Include ethylene vinylalcohol copol^ner, pol٣lnylldene chloride, polyac^lonitrile, pol٣inyl alcohol, 10 polyamide, and polyester. Examples also Include films and sheets formed from materials comprising at least one of the above-mentioned materials.

[0081]

Further, as the .xygen absorber, various kno™ types 15 can be used. For example, ones comprising, as an active ingredient, an iron compound such as ferric hydroxide, ferric oxide, or iron carbide, and ones comprising low-molecular-weight phenol and activated carbon, can be used. Trade names of typical commercial products Include "Ageless" (produced by Mitsubishi Gas 20 Chemical), "Moduran" (produced by Nippon Kayaku), "Secur" (produced by Nippon Soda), "Tamotsu" (produced by Oji Kako), and "Keepit” (produced by Drency).

Examples [0082]

The present invention Is described In further detail below in reference to Examples, but Is not limited thereto.

[0083]

Example 1 Fomulation of Infusion Preparation 1. FoOTiulation of First-Chamber Infusion

Purified soybean oil, purified egg yolk lecithin, and glucose in the amounts shown In Table 2 were added to water. The mixture was subjected to crude emulsification using a homomlxer. The result was subjected to fine emulsification using a high-pressure emulsifier (Manton-Gaulin), and water was further added 2015268572 08 Dec 2015 -28- thereto to make the total amount 250 mL. I pH was adjusted to about 6.0 using a pH adjuster (L-histidine and hydrochloric acid). The first-chamber infusion thus obtained had a relative osmotic pressure of 3.0, and a titratable acidity of 0.5. 5 [0084)

Table 2

Components of First-Chamber Infusion

Purified soybean oil 10 g Glucose 37.5 g Purified egg yolk, lecithin 1.2 g Ii-hlstldine 0.04 g [0085] 10 2. Fomiulation o.f Second-Chamber Infusion

Amino acids, electrolytes, and a stabilizer (sodium hydrogen sulfite) In the amounts shown In Table 3 were dissolved in distilled water for injection to prepare an amino acid electrolyte solution. The pH of the solution was adjusted to 6.7 15 with glacial acetic acid, and the total amount was adjusted to 250 mL, giving the second-chamber Infusion. The second-chamber Infusion thus prepared had a relative osmotic pressure of 3.0 and potassium concentration of 40 mEq/L.

[0086] 20 30 2015268572 08 Dec 2015 -29-

Table 3 Components of Second-Camber Infusion L-leuclne 2.100 g L-isoleucine 1.200 g L-vallne 1.200 g L-lysine hydrochloride 1.965 g L-threonlne 0.855 g L-tryptophan 0.300 g L-methionine 0.585 g Acetylcysteine 0.202 g L-phenylalanine 1.050 g L-tyrosine 0.075 g L-arglnine 1.575 g !.-histidine 0.750 g L-alanine 1.200 g L-proline 0.750 g L-serine 0.450 g Glycine 0.885 g L-asparatic acid 0.150 g L-glutamlc acid 0.150 g Sodium chloride 0.220 g Potassium chloride 0.220 g Sodium citrate 0.310 g Sodium acetate 0.403 g Sodium lactate (72% solution] 1.167 g Potassium glycerophosphate (50% solution) 1.750 g Calcium gluconate hydrate 0.561 g Ma^esium sulfate hydrate 0.309 g Zinc sulfate hydrate 0.70 mg Sodium hydrogen sulfite 12.5 mg 10087] 5 3. Filling and Packaging 250 mL of the first-chamber Infusion and 250 mL of the second-chamber infusion obtained above were each placed In each chamber of the two-chamber polyethylene container wherein the chambers were partitioned by an easily peelable seal. The 10 atmosphere In the vacant space of each chamber was replaced with nitrogen gas. After sealing, the container was subjected to high-pressure steam sterilization according to a conventional method. Thereafter, the container was folded at the easily peelable seal portion, and enclosed in an exterior bag (.؟gen-barrler exterior 15 bag] foraied from a multllayered-barrler film (Product name: 2015268572 08 Dec 2015 -3.-

Bovlon, produced by NSR (Nippon Synthetic Chemical Industry Co.. Ltd.) together with a deoxidant (Product name؛ Ageless, produced by Mitsubishi Gas Chemical Company, Inc.), obtaining an Infusion preparation. Note that the mixture (the components are shown In 5 Table 4) of the first-chamber infusion and the second-chamber Infusion of the Infusion preparation had a pH of 6.7, a titratable acidity of 7, and a potassium concentration of 20 mEq/L. During storage for 3 days from the time of mixing, the mixed Infusion exhibited a volume ratio of coarse particles 10 having a particle size of 0.5 pm or more of 0.05% or less, which was lower than the requirements of the United States Phaimacopeia (USP), indicating that the fat particles thereof were stable. The particle size was measured using AccuSizer 780 (produced by Pertlcle sizing System). 15 [0088] 2015268572 08 Dec 2015 -31-

Table 4 Components of Mixed Infusion Components Amount (500 mL) Sugar Glucose 37.5 g Fat Soybean oil 10 g Amino acids L-leucine 2.100 g L-isoleucine 1.200 g L-valine 1.200 g L-lysine hydrochloride 1.965 g L-threonine .0.855 g L-tryptophan 0.300 g L-methionine 0.585 g Acetylcysteine 0.202 g L-phenylalanine 1.050 g L-tyroslne 0.075 g L-arginine 1.575 g L-histldlne 0.790 g L-alanine 1.200 g L-prollne 0.750 g L-serlne 0.450 g Glycine 0.885 g L-asparatic acid 0.150 g L-glutamic acid 0.150 g Electrolytes Na 17.5 mEq K 10 mEq Mg 2.5 mEq Ca 2.5 mEq Cl 17.5 mEq p 5 mmol Zn 2.5 pmol [0089]

Example 2 Foimulatlon of Infusion Preparation 10 1. Fomulation of First-Chamber Infusion 250 mLofa fluid comprising 0.96 mg of thiamine chloride hydrochloride In addition to the components shown in Table 2 was prepared in the same manner as in Example 1 to obtain a first-chamber Infusion. The pH of the first-chamber Infusion 15 was adjusted to about 6.0. The first-chamber Infusion had a relative osmotic pressure of 3 and a titratable acidity of 0.5. 2. Fomulation of Second-Chamber Infusion 2015268572 08 Dec 2015 -32- A second-chamber infusion was prepared in the same manner as in Example 1. 3. Filling and Packaging 25. mL of the first-chamber infusion and 25. mL of the second-chamber infusion obtained above were each placed in each chamber of the two-chamber polyethylene container wherein the chambers were partitioned by an easily peelable seal. The atmosphere In the vacant space of each chamber was replaced with nitrogen gas. After sealing, the container was subjected to high-pressure steam sterilization according to a conventional method. Thereafter, the container was folded at the easily peelable seal portion, and enclosed In an exterior bag (o^gen-barrier exterior bag) formed from a multilayered-barrier film (Product name: Bovlon, produced by NSR) together with a deoxidant (Product name: Ageless, produced by Mitsubishi Gas Chemical Company, Inc.), obtaining an infusion preparation. Note that the mixture (the components are shown in Table 5) of the first-chamber infusion and the second-chamber infusion of the infusion preparation had a pH of 6.7, a tltratable acidity of 7, and a potassium concentration of 20 mEq/L. Dring storage for 3 days from the time of mixing, the mixed infusion exhibited a volume ratio of coarse particles having a particle size of 0.5 pm or more of 0.05% or less. Indicating that the fat particles thereof were stable. (0090) 2015268572 08 Dec 2015 -33-

Table 5 Components of Mixed Infusion Components Amount (50. mL) Sugar Glucose 37.5 g Fat Soybean oil 10 g Amino acids L-leuclne 2.100 g L-lsoleucine 1.200 g L-vallne 1.200 g L-lysine hydrochloride 1.965 g L-threonlne 0.855 g L-t^tophan 0.300 g L-methionlne 0.585 g Acetylcysteine 0.202 g L-phenylalanine 1.050 g L-tyroslne 0.075 g L-arginlne 1.575 g L-hlstldine 0.790 g L-alanlne 1.200 g L-prollne 0.750 g L-serine 0.450 g Glycine 0.885 g L-asparatic acid 0.150 g L-glutamlc acid 0.150 g Electrolytes Na 17.5 mEq K 10 mEq Mg 2.5 mEq Ca 2.5 mEq Cl 17.5 mEq p 5 mol Zn 2.5 pmol Vitamins Thiamine chloride hydrochloride 0.96 mg [0091] 5 Example 3 - of Infusion Preparation 1. Foimulatlon of First-Camber Infusion 250 mL of fluid comprising 2.75 mg of vitamin A oil (825 IU), 1.25 pg of cholecalciferol. 2.5 mg of tocopherol acetate, 1 mg of phytonadlone, 0.96 mg of thiamine chloride 10 hydrochloride, 1.23 mg of pyridoxine hydrochloride, 1.25 pg of , and 0.1 mg of folic acid In addition to the components shown In Table 2 was prepared In the same manner as in Example 1 to obtain a first-chamber Infusion. The vitamin A oil. 2015268572 08 Dec 2015 -34- cholecalciferol, tocopherol acetate, and phytonadlone were dissolved In the purified soybean oil beforehand. The pH of the first-chamber infusion was adjusted to about 6... The first-chamber infusion had a relative osmotic pressure of 3.0 and a titratable acidity of 0.5. 2. FoCTulation of Second-Chamber Infusion 250 mL of fluid comprising 25 mg of ascorbic acid, 15 pg of biotin, 10 mg of nicotinamide, 3.5 mg of panthenol, and 1.15 mg of riboflavin sodium phosphate in addition to the components shown In Table 3 was prepared in the same manner as In Example 1 to obtain a second-chamber Infusion. The second-chamber infusion had a relative osmotic pressure of 3 and a potassium concentration of 40 mEq/L. The pH of the second-chamber infusion was adjusted to 6.7. 3. Filling and Packaging 250 mL of the first-chamber infusion and 250 mL of the second-chamber Infusion obtained above were each placed in each chamber of the two-chamber polyethylene container wherein the chambers were partitioned by an easily peelable seal. The atmosphere in the vacant space of each chamber was replaced with nitrogen gas. After sealing, the container was subjected to high-pressure steam sterilization according to a conventional method. Thereafter, the container was folded at the easily peelable seal portion, and enclosed in an exterior bag (o^gen-barrier exterior bag) formed from a multilayered-barrier film (Product name:

Bovlon, produced by NSR) together with a deoxidant (Product name: Ageless, produced by Mitsubishi Gas Chemical Company, Inc.), obtaining an infusion preparation. Note that the mixture (the components are shown in Table 6) of the first-chamber infusion and the second-chamber Infusion of the Infusion preparation had a pH of 6.7, a titratable acidity of 7, and a potassium concentration of 20 mEq/L. During storage for 3 days from the time of mixing, the mixed infusion exhibited a volume ratio of 2015268572 08 Dec 2015 -35- coarse particles having a particle size of 0,5 سا or more of ...5% or less. Indicating that the fat particles thereof were stable.

[.092] 2015268572 08 Dec 2015 -36-

Table 6 Components of Mixed Infusion Components Amount (5.. ml) Sugar Glucose 37.5 g Fat Soybean oil 10 g Amino acids L-leucine 2.100 g L-lsoleuclne 1.200 g L-valine 1.200 g L-lysine hydrochloride 1.965 g L-threonine 0.855 g L-tryptophan 0.300 g !.-methionine 0.585 g Acetylcysteine 0.202 g L-phenylalanine 1.050 g !.-tyrosine 0.075 g !.-arginine 1.575 g L-histidine 0.790 g L-alanine 1.200 g L-proline 0.750 g L-serine 0.450 g Glycine 0.885 g !.-asparatic acid 0.150 g L-glutamic acid 0.150 g Electrolytes Na 17.5 mEq K 10 mEq Mg 2.5 mEq Ca 2.5 mEq Cl 17.5 mEq p 5 mmol Zn 2.5 pmol Vitamins Thiamine chloride hydrochloride 0.96 mg Riboflavin sodium phosphate 1.15 mg Pyridoxine hydrochloride 1.23 mg Cyanocobalamin 1.25 pg Nicotinamide 10 mg Panthenol 3.5 mg Folic acid 0.10 mg Biotin 15 pg Ascorbic acid 25 mg Vitamin A oil 825 IU Cholecalclferol 1.25 pg Tocopherol acetate 2.5 mg Phytonadlone 1 mg

The infusion preparation (before mixing the first 2015268572 08 Dec 2015 -37- chamber Infusion and the second-chamber Infusion) was stored at room temperature for 6 months. Thereafter, the amount of each vitamin component contained In the first-chamber infusion or the second-chamber Infusion was measured using HPLC. Table 7 shows the results. As Is clear from the results, each of the vitamin components can be stably present in the Infusion preparation even after 6 months storage.

Table 7

Remaining rate after 6 months storage (%) Riboflavin sodium phosphate 100.1 Ascorbic acid 99.9 Blotln 97.8 Nicotinamide 99.6 Panthenol 100.4 Thiamine chloride hydrochloride 98.7 Pyridoxine hydrochloride 99.3 Cyanocobalamin 103.2 Folic acid 100.0 Cholecalciferol 100.5 Tocopherol acetate 99.0 Phytonadione 101.5 Vitamin A oil 102.2 [.093)

Example 4 Fomulation of Infusion Preparation 1. Foimulation of First-Chamber Infusion 300 mL of fluid comprising 2.75 mg of vitamin A oil (825 IU). 1.25 pg of cholecalciferol, 2.5 mg of tocopherol acetate. 37.55 pg of phytonadione. 1.92 mg of thiamine chloride hydrochloride. 1.82 mg of pyridoxine hydrochloride. 1.25 pg of and 0.15 mg of folic acid In addition to the components shown in Table 2 was prepared in the same manner as In Example 3 to obtain a first-chamber Infusion. The pH of the first-chamber infusion was adjusted to about 6.0. The first-chamber infusion had a relative osjnotic pressure of 2.5 and a titratable acidity of 0.5. 2015268572 08 Dec 2015 -38- 2. Formulation of Second-Chamber Infusion 25. mL of fluid ccmprlslng 5. mg of vitamin c (ascorbic acid). 15 pg of biotin, 10 mg of nicotinamide, 3.5 mg of , and 1.15 mg of vitamin Β2 (riboflavin sodium phosphate) was prepared In the same manner as in Example 3 to obtain a second-chamber infusion. The pH of the second-chamber Infusion was adjusted to 6.7. The second-chamber Infusion had a relative osmotic pressure of 3.0 and a potassium concentration of 40 mEq/L. 3. Filling and Packaging 300 mL of the first-chamber infusion and 250 mL of the second-chamber Infusion obtained above were each placed in each chamber of the two-chamber polyethylene container herein the chambers were partitioned by an easily peelable seal. The atmosphere in the vacant space of each chamber was replaced with nitrogen gas. After sealing, the container was subjected to high-pressure steam sterilization according to a conventional method. Thereafter, the container was folded at the easily peelable seal portion, and enclosed in an exterior bag (o^gen-barrier exterior bag) formed from a multilayered-barrier film (Product name: Bovlon, produced by NSR) together with a deoxldant (Product name: Ageless, produced by Mitsubishi Gas Chemical Company, Inc.), obtaining an Infusion preparation. Note that the mixture (the components are shorai In Table 8) of the first-chamber infusion and the second-chamber infusion of the Infusion preparation had a pH of 6.7, a titratable acidity of 6, and a potassium concentration of 18.2 mEq/L. During storage for 3 days from the time of mixing, the mixed Infusion exhibited a volume ratio of coarse particles having a particle size of 0.5 pm or more of 0.05% or less. Indicating that the fat particles thereof were stable. (0094) 2015268572 08 Dec 2015 -39-

Table 8 Components of Mixed Infusion Components Amount (550 mL) Sugar Glucose 37.5 g Fat Soybean oil 10 g Amino acids L-leucine 2.100 g L-isoleucine 1.200 g L-valine 1.200 g L-lysine hydrochloride 1.965 g L-threonine 0.855 g L-t^ptophan 0.300 g L-methlonine 0.585 g Acetylcysteine 0.202 g L-phenylalanlne 1.050 g L-tyrosine 0.075 g L-arglnine 1.575 g L-histidine 0.790 g L-alanlne 1.200 g L-proline 0.750 g L-serine 0.450 g Glycine 0.885 g L-asparatlc acid 0.150 g L-glutamic acid 0.150 g Electrolytes Na 17.5 mEq K 10 mEq Mg 2.5 mEq Ca 2.5 mEq Cl 17.5 mEq p 5 mmol Zn 2.5 pmol Vitamins Thiamine chloride hydrochloride 1.92 mg Riboflavin sodium phosphate 1.15 mg Pyridoxine hydrochloride 1.82 mg Cyanocobalamin 1.25 pg Nicotinamide 10 mg Panthenol 3.5 mg Folic acid 0.15 mg Biotin 15 pg Ascorbic acid 50 mg Vitamin A oil 825 IU Cholecalciferol 1.25 pg Tocopherol acetate 2.5 mg Phytonadione 37.5 pg [0095] 2015268572 08 Dec 2015 -40-

Comparative Example 1 Formulation of Infusion Preparation 1. Foraiulatlon of First-Chamber Infusion

Purified soybean oil, purified egg yolk lecithin, and glucose in the amounts shown in Table 2 were added to water. The 5 mixture was subjected to crude emulsification using a homomlxer. The result was subjected to fine emulsification using a high-pressure emulsifier (Manton-Gaulin), and water was added thereto to make the total amount 350 mL. The pH was adjusted to about 6.0 using a pH adjuster (L-histidine and hydrochloric acid). The 10 first-chamber infusion thus obtained had a relative osmotic pressure of 2.1, and a titratable acidity of 0.5. 2. Fo^ulation of Second-Chamber Infusion 150 mL of fluid comprising the components shown In 15 Table 3 was prepared in the same manner as in Example 1 to obtain a second-chamber Infusion, ^e pH of the second-chamber infusion was adjusted to 6.7. The second-chamber infusion had a relative osmotic pressure of 5 and a potassium concentration of 67 mEq/L. 20 3. Filling and Packaging 350 mL of the first-chamber infusion and 150 mL of the second-chamber infusion obtained above were each placed in each chamber of the two-chamber polyethylene container wherein the chambers were partitioned by an easily peelable seal. The 25 atmosphere In the vacant space of each chamber was replaced with nitrogen gas. After sealing, the container was subjected to high-pressure steam sterilization according to a conventional method. Thereafter, the container was folded at the easily peelable seal portion, and enclosed in an exterior bag (oxygen-barrier exterior 30 bag) formed from a multilayered-barrier film (Product name:

Bovlon, produced by NSR) together with a deoxldant (Product name: Ageless, produ'ced by Mitsubishi Gas Chemical Company, Inc.), obtaining an infusion preparation. The mixed Infusion of the first-chamber infusion and the second-chamber infusion of the 35 infusion preparation, comprised the same components at the same 2015268572 08 Dec 2015 -41- pr٠p٠rt!٠ns as that In Example 1. However, In the foraulation of Comparative Example 1, the second-chamber Infusion had .a high potassium concentration of 67 mEq/L; therefore. If the Infusion preparation were used before opening the partition, a high 5 concentration of potassium would undesirably be administered into the body, thus making it extremely dangerous. Furthennore, the relative osmotic pressure In the second chamber was very high at 5 and adverse effects such as phlebitis caused thereby cannot be neglected.

Claims (5)

1. CLAIMS [Claim 1] An infusion preparation comprising two chambers separated by a partition that can be communicably opened, wherein a first chamber contains a first-chamber infusion comprising a sugar and a fat emulsion; a second chamber contains a second-chamber infusion comprising an amino acid and an electrolyte; the first-chamber infusion is substantially free of potassium, and has a relative osmotic pressure of 2.0 to 3.0; the second-chamber infusion has a potassium concentration of 40 mEq/L or less and a relative osmotic pressure of 2.5 to 3.5; and a mixture of the first- and second-chamber infusions has a potassium concentration of 16 mEq/L or more as measured upon communicably opening the partition. [Claim
2. 2] The infusion preparation according to claim 1 wherein the first-chamber infusion has a pH of 4.5 to 6.5, and the second-chamber infusion has a pH of 6.0 to 7.4. [Claim
3. 3] The infusion preparation according to claim 1 or 2, wherein the volume ratio of the first-chamber infusion to the second-chamber infusion is 3:2 to 3:5. [Claim
4. 4] The infusion preparation according to any one of claims 1 to 3, wherein the first chamber further contains vitamin Bl. [Claim
5. 5] The infusion preparation according to claim 4, wherein the first-chamber infusion further contains vitamin A, vitamin B6, vitamin B12, vitamin D, vitamin E, and vitamin K, and the second-chamber infusion further contains vitamin C and vitamin B2.