JP2005220105A - Peripheral intraveneous nutrition infusion preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a peripheral intraveneous nutrition infusion preparation wherein a sugar, an amino acid and an electrolyte are compounded, which enables administration of sufficient nutrients through a peripheral vein and induces substantially no angialgia even in a patient who is relatively likely to develop angialgia caused by infusion. <P>SOLUTION: This peripheral intraveneous nutrition infusion preparation comprises the sugar, the amino acid and the electrolyte, contains no fat emulsion and has a pH of 6.8-7.6, an osmotic pressure ratio of 0.5-2 and a sugar concentration of 2-5w/v%. The peripheral intraveneous nutrition infusion preparation comprises two solutions, i.e. solution (A) containing the sugar and the electrolyte and solution (B) containing the amino acid, and shows the pH of 6.8-7.6, the osmotic pressure ratio of 0.5-2 and the sugar concentration of 2-5w/v% after mixing. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a peripheral parenteral nutrition infusion preparation containing a sugar, an amino acid and an electrolyte. More specifically, the present invention relates to a peripheral parenteral nutritional infusion preparation suitable for compensating for malnutrition and insufficient amino acid intake in postoperative patients with less occurrence of vascular pain.

  Parenteral nutrition and enteral nutrition have become widespread in patient nutrition management, and these therapies are already part of daily medicine. In particular, nutritional management for patients who have difficulty in providing nutrition through the oral route is performed by parenteral nutrition therapy. Parenteral nutrition therapy includes high calorie infusion (TPN) therapy using a central venous route and peripheral venous nutrition (PPN) therapy using a peripheral venous route. TPN therapy has the advantage that all the nutrients necessary for the human body can be administered parenterally over a long period of time, but TPN therapy has great merits and disadvantages. There is a movement to review the heavy use of therapy. For example, patients with bleeding tendency and coagulopathy, widespread burn patients, etc. have been conventionally contraindicated with TPN therapy. Other patients, for example, have good preoperative nutrition and relatively low invasiveness. For mild patients and patients whose oral ingestion period is not so long, TPN therapy is not performed as much as possible, and instead, nutritional infusions that can be administered from peripheral veins are performed in the same manner as general infusions. There is a tendency to try PPN therapy that is simple and has a low risk of medical accidents.

  However, when PPN therapy is performed, the occurrence of vascular pain is an unavoidable problem. For this reason, it is necessary to consider reducing the occurrence of vascular pain in the medical field where PPN therapy is performed. The cause of vascular pain is mainly in the infusion preparation itself, and its osmotic pressure, pH, titratable acidity, etc. are considered as one of the causes. In particular, in PPN therapy, the more energy is to be administered, the greater the osmotic pressure of the infusion preparation and the greater the tendency for vascular pain to occur.

Conventionally, in order to avoid the risk of the occurrence of vascular pain, a total infusion for peripheral venous administration using a fat emulsion as part of the energy source so that the required amount of energy can be administered without increasing the osmotic pressure as much as possible. Preparations have also been studied (for example, Patent Document 1 (JP-A-6-279290), Patent Document 2 (JP-A-6-31923)).
However, fat emulsions accumulate in the lungs when administered at a too high rate, and there is a risk of causing respiratory problems, and they may be taken into the reticuloendothelial system and cause a decrease in immune function. It should not be used in management. In diabetics, fat emulsions are prone to ketosis when blood sugar control is poor, and there are problems such as avoiding their use.
Therefore, development of peripheral parenteral nutritional infusion preparations that consist of sugar, amino acids, and electrolytes that do not contain fat emulsions, and that cause as little vascular pain as possible, and that are suitable for supplementing undernutrition and insufficient amino acid intake in postoperative patients Was desired.
JP-A-6-279290 JP-A-6-312923

The object of the present invention has been made in view of the above situation, and is applicable to a patient who can administer a sufficient nutrient source from a peripheral vein and is relatively likely to develop vascular pain caused by administration of an infusion solution. However, it is an object of the present invention to provide a peripheral parenteral nutritional infusion preparation containing a sugar, an amino acid and an electrolyte that are substantially free of vascular pain. The inventors of the present invention have made extensive studies for the above purpose, prepared various infusion preparation samples, reexamined the relationship between their properties and the occurrence of vascular pain, and as a result, obtained the following knowledge. It was.
(1) If the transfusion pH is set within a certain range, the occurrence of vascular pain can be reduced.
(2) When increasing the amount of calories to be administered, the occurrence of vascular pain can be suppressed by increasing the amount of water and keeping the osmotic pressure ratio at a certain limit.

  As a result of intensive studies to achieve the above object, the present inventors have determined that the pH at the time of mixing the components is close to the pH of blood in the peripheral parenteral nutritional infusion formulation containing sugar, amino acid and electrolyte, and the osmotic pressure ratio is It has been found that a peripheral parenteral nutritional infusion preparation capable of suppressing the occurrence of vascular pain more reliably than before can be provided by appropriate adjustment. In addition, the solution containing sugar and electrolyte (A) in one chamber of the two-chamber container and the solution containing amino acid (B) in the other chamber are stored and mixed before use so that the pH is close to that of blood As a result, it was found that the peripheral parenteral nutrition infusion preparation was obtained, and the present invention was achieved.

That is, the present invention
(1) A peripheral parenteral nutritional infusion preparation comprising a sugar, an amino acid and an electrolyte and not containing a fat emulsion, wherein the peripheral parenteral nutrition infusion preparation has a pH of 6.8 to 7.6 and an osmotic pressure ratio of 0.5 to 2 and a peripheral parenteral nutritional infusion preparation having a sugar concentration of 2 to 5 w / v%.
(2) A peripheral parenteral nutritional infusion preparation comprising a solution (A) containing a sugar and an electrolyte and a solution (B) containing an amino acid and containing no fat emulsion, and having a pH of 6 when mixed. The peripheral parenteral nutrition infusion preparation according to (1) above, wherein the osmotic pressure ratio is 0.5 to 2 and the sugar concentration is 2 to 5 w / v%.
(3) A peripheral parenteral nutritional infusion preparation comprising a solution (A) containing a sugar and an electrolyte and a solution (B) containing an amino acid and not containing a fat emulsion, wherein the solution (A) is vitamin B1 The peripheral parenteral nutrition infusion preparation according to (2) above, which contains sulfite and does not contain sulfite and salts thereof.
(4) The solution (A) is stored in one chamber of a plastic container which is divided into two chambers by an isolation wall that can be used for business, and has a discharge port in one chamber, and the solution (B) is stored in the other chamber. The peripheral parenteral nutrition infusion preparation according to (2) or (3) above.
(5) The peripheral parenteral nutrition infusion preparation according to any one of (1) to (4) above, which does not contain a calcium salt.

  As described above, the peripheral parenteral nutrition infusion preparation of the present invention makes it difficult to cause vascular pain by setting the pH close to that of blood at the time of use and further making the osmotic pressure ratio close to 1.

Hereinafter, the peripheral parenteral nutrition infusion preparation of the present invention will be described in detail.
The solution (A) used in the present invention contains a sugar and an electrolyte.
The sugar used in the present invention may be conventionally used in various infusions, and examples thereof include monosaccharides such as glucose and fructose, and disaccharides such as maltose. Of these, reducing sugars such as glucose, fructose and maltose are particularly preferred. The solution (A) prepared in the present invention may contain a polyhydric alcohol such as glycerol or sugar alcohol. Examples of the sugar alcohol include sorbitol, xylitol, mannitol and the like. These sugars and polyhydric alcohols can be used alone or in combination of two or more. Among these, it is preferable to use glucose from the viewpoint of blood glucose management.

  The sugar concentration of the present invention is adjusted to 2-5 w / v%. When the sugar concentration is less than 2 w / v%, nutrition is insufficient, and when it exceeds 5 w / v%, the osmotic pressure ratio is increased and blood vessel pain is likely to occur.

As the electrolyte used in the present invention, the same compounds as those used in general electrolyte infusion can be used, and sodium, potassium, magnesium, calcium, chloro, phosphorus, zinc, iron, copper, manganese, which are electrolytes essential for living organisms. Water-soluble salts of inorganic components such as Specifically, sodium bicarbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium lactate, sodium citrate, sodium chloride, sodium sulfate, potassium chloride, potassium iodide, diphosphate Potassium hydrogen, dipotassium hydrogen phosphate, potassium lactate, potassium citrate, potassium acetate, calcium lactate, sodium glycerophosphate, potassium glycerophosphate, calcium glycerophosphate, calcium gluconate, calcium chloride, calcium citrate, magnesium chloride, magnesium sulfate, Magnesium acetate, zinc chloride, zinc sulfate, iron sulfate, ferrous chloride, ferric chloride, iron gluconate, copper sulfate, manganese sulfate and the like can be used, and these may be hydrates.
In addition, when blending calcium salt and phosphate electrolytes, if the pH of the solution is high, specifically, if it exceeds pH 7.0, precipitation may occur due to both salts. Preferably, for example, when calcium salt is added to the sugar solution, phosphate is added to the amino acid solution, and when phosphate is added to the sugar solution, calcium salt is preferably added to the amino acid solution. . When the pH of the liquid is as high as 7.0 or more and precipitation due to the calcium salt occurs, it is preferable not to include the calcium salt. Moreover, since a magnesium salt may also precipitate with a phosphate, it is preferable to mix it with the calcium salt.

  The vitamin B1 used in the present invention may be any of those conventionally used, such as thiamine, fursultiamine, thiamine disulfide, cocarboxylase, prosultiamine, chicotiamine, thiamine monophosphate disulfide, bisbench. Examples include amines, benfotiamine and the like, and salts thereof. Of these, thiamine and its salt are preferred.

The solution (B) used in the present invention contains an amino acid.
The amino acid used in the present invention is not particularly limited as long as it is an amino acid used in the technical field of infusion agents, and includes essential amino acids, non-essential amino acids and / or salts, esters or N-acyl derivatives of these amino acids. is there. Specifically, L-leucine, L-isoleucine, L-valine, L-lysine, L-threonine, L-tryptophan, L-methionine, L-phenylalanine, L-cysteine, L-tyrosine, L-arginine, L -Histidine, L-alanine, L-proline, L-serine, glycine, L-aspartic acid, L-glutamic acid and the like. These amino acids include not only free amino acids but also various salts such as metals with sodium and potassium. It may be a salt, acetic acid, organic acid salt with malic acid, hydrochloric acid, mineral acid salt with sulfuric acid or the like, and some amino acids may be L-tyrosine methyl ester, L-methionone. Esters such as methyl ester, N-acetyl-L-cysteine, N-acetyl-L-tryptophan, N-acetyl-L-proline Of N- substituted derivatives, L- tyrosyl -L- tyrosine, L- alanyl -L- tyrosine, L- Argyle -L- tyrosine, it may be a peptide such as L- tyrosyl -L- arginine.

  The pH of the solutions (A) and (B) can be adjusted as necessary, and the pH adjuster used in the present invention is not limited as long as it can be used as a pharmaceutical additive. For example, citric acid, acetic acid, tartaric acid, carbonic acid, lactic acid, fumaric acid, propionic acid, boric acid, phosphoric acid, sulfuric acid and their compounds, adipic acid, hydrochloric acid, gluconic acid, succinic acid, potassium hydroxide, calcium hydroxide, One or more selected from sodium hydroxide, magnesium hydroxide, sodium bicarbonate, maleic acid, malic acid and the like can be mixed.

  Moreover, sulfites, such as sodium hydrogen sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, can be added to the solution (B) as a stabilizer.

  As described above, the drug solution of the peripheral parenteral nutrition infusion preparation of the present invention has been described. However, the present invention is not limited to these, and for the purpose of combining with other preparations as needed, it is not limited to vitamins. Water-soluble vitamins other than B1, fat-soluble vitamins, saccharides, amino acids, electrolyte components, additives and the like may be added.

  The solution (A) and the solution (B) thus prepared may be mixed in advance, or may be used after being divided into two chambers and mixed when used. Further, as described above, the preparation according to the present invention may be adjusted at a time according to a conventional method without adjusting the solutions (A) and (B) in advance.

  The peripheral parenteral nutrition infusion preparation of the present invention has a pH adjusted to 6.8 to 7.6 when administered. In the form of being separated and accommodated in two chambers, the pH when all the liquids are mixed is 6.8 to 7.6, preferably pH 7.0 to 7.5, and more preferably pH 7.3 to 7.5. Is done. If the pH of the mixed solution is less than 6.8 or exceeds 7.6, vascular pain is likely to occur.

Moreover, the osmotic pressure ratio when all the liquids are mixed is adjusted to 0.5-2. When the osmotic pressure ratio of the mixed solution is less than 0.5 or exceeds 2, vascular pain is likely to occur.
Here, the osmotic pressure ratio of the present invention is defined as the ratio of the osmolarity of the sample solution to the osmolarity (286 mOsm) given by the physiological saline.

  The peripheral parenteral nutrition infusion preparation thus obtained provides a peripheral parenteral nutrition infusion preparation that has a pH close to that of blood at the time of use, and can hardly cause vascular pain by making the osmotic pressure ratio close to 1. be able to.

  In the present invention, a method for preparing a peripheral parenteral nutritional infusion preparation follows a conventional method.

  Although it does not specifically limit as a container which accommodates the peripheral parenteral nutrition infusion formulation of this invention, It is a container which has one chamber (FIG. 1) or two chambers (FIG. 2), Comprising: The isolation wall between the two is a plastic container that can be opened for business use. For example, as the material of the container, gas permeable plastics used for medical containers, such as polyethylene, polypropylene, polyvinyl chloride, crosslinked ethylene / vinyl acetate copolymer, ethylene / α-olefin copolymer, these An infusion container made of a soft synthetic resin material such as a blend or a laminate of each of the polymers, wherein the isolation wall between the chambers is opened by pressure from outside, or all or a part of the isolation wall is opened. There is a container that can communicate with the room. The isolation wall is formed by a band-shaped weak seal or the like that bisects a container formed by using a heat seal device or the like between opposing surfaces of a pair of synthetic resin sheets forming a soft container (see FIG. 2). Grid). This weak seal should be adjusted so that the seal conditions such as seal temperature, pressure, time, etc. are weaker than the usual seal that completely fuses (strong seal: hatched portion in FIGS. 1 and 2). Can be formed. It is an infusion container in which a solution (A) containing sugar and electrolyte or vitamin B1 is contained in one chamber of such a container, and a solution (B) containing an amino acid is contained in the other chamber. Each of the containers according to FIG. 1 and FIG. 2 is formed by folding a tubular sheet manufactured by inflation molding into two and applying strong seals at both ends of the container to form a container.

The container can be filled and accommodated according to a conventional method. For example, each liquid is filled in an inert gas atmosphere, plugged, and heat sterilized.
The heat sterilization method can be performed by a known method such as high-pressure steam sterilization, hot water sterilization, hot water shower sterilization, etc., and a peripheral parenteral nutrition infusion preparation can be obtained. Also, the operating conditions of the sterilization method, such as sterilization time and sterilization temperature, can be the same as the normal sterilization operating conditions of this type. Furthermore, the heat sterilization can be performed in an inert gas atmosphere such as nitrogen as necessary.

Furthermore, in order to reliably prevent alteration such as oxidation of the peripheral parenteral nutrition infusion preparation of the present invention, the container can be packaged with an oxygen-absorbing agent in an outer container that does not substantially transmit oxygen.
Various known oxygen scavengers can be used. For example, what uses iron compounds, such as iron hydroxide, iron oxide, and iron carbide, as an active ingredient can be utilized. Commercially available products include AGELESS (Mitsubishi Gas Chemical Co., Ltd.), Modulan (Nippon Kayaku Co., Ltd.) and Secur (Nippon Soda Co., Ltd.).

  As the material of the outer container that does not substantially transmit oxygen suitable for packaging, film sheets of various materials that are generally used can be used. For example, polyethylene terephthalate (PET), polyethylene naphthalate (PEN), ethylene-vinyl alcohol copolymer (EVOH), polyvinylidene chloride (PVDC), polyacrylonitrile, polyvinyl alcohol, polyamide, polyester, and at least one of these Wrapping materials composed of film sheets that contain, packaging materials in which gas barrier materials such as silicon oxide, aluminum oxide, and aluminum are vapor-deposited on these materials, and packaging materials made from a multilayer film that combines these materials Etc.

EXAMPLES Next, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these.
(Example 1)
Glucose 18.75 g, L-leucine 1.4 g, L-isoleucine 0.8 g, L-valine 0.8 g, L-lysine hydrochloride 1.31 g, L-threonine 0.57 g, L-tryptophan 0.2 g, L- Methionine 0.39, L-phenylalanine 0.7 g, L-cysteine 0.1 g, L-tyrosine 0.05 g, L-arginine 1.05 g, L-histidine 0.5 g, L-alanine 0.8 g, L-proline 0.5 g, L-serine 0.3 g, glycine 0.59 g, L-aspartic acid 0.1 g, L-glutamic acid 0.1 g, sodium chloride 0.20 g, sodium lactate 0.573 g, calcium gluconate 0.28 g, Magnesium sulfate 0.156 g, zinc sulfate 0.35 mg and dipotassium phosphate 0.58 g are dissolved in distilled water for injection to make 500 mL, Of glacial acetic acid small amount as pH7.0 using as H modifier was prepared infusion.
The infusion solution (500 mL) was filled in a polyethylene container and sealed, followed by high-pressure steam sterilization. A conceptual diagram of this state is shown in FIG. Furthermore, the container is sealed in a gas-impermeable outer packaging material (aluminum vapor-deposited film, manufactured by Dai Nippon Printing Co., Ltd.) together with one oxygen scavenger (ageless, manufactured by Mitsubishi Gas Chemical Co., Ltd.), and peripheral parenteral nutrition infusion preparation 1 was obtained.
The pH of the peripheral parenteral nutrition infusion preparation 1 was 7.0, and the osmotic pressure ratio was 1.7.

(Example 2)
30 g of glucose, 0.32 g of sodium chloride, 0.916 g of sodium lactate, 0.249 g of magnesium sulfate and 0.56 mg of zinc sulfate were dissolved in distilled water for injection to 700 mL, and a pH of 5. using a small amount of glacial acetic acid as a pH regulator. As 0, a sugar / electrolyte solution was prepared. Meanwhile, L-leucine 2.8 g, L-isoleucine 1.6 g, L-valine 1.6 g, L-lysine hydrochloride 2.62 g, L-threonine 1.14 g, L-tryptophan 0.4 g, L-methionine 0.8 g. 78 g, L-phenylalanine 1.4 g, L-cysteine 0.2 g, L-tyrosine 0.1 g, L-arginine 2.1 g, L-histidine 1 g, L-alanine 1.6 g, L-proline 1 g, L-serine 0.6 g, 1.18 g of glycine, 0.2 g of L-aspartic acid, 0.2 g of L-glutamic acid, 1.16 g of dipotassium hydrogen phosphate and 60 mg of sodium hydrogen sulfite are dissolved in distilled water for injection to make 300 mL, pH adjustment An amino acid solution was prepared at pH 7.8 using a small amount of glacial acetic acid as an agent. 350 mL of the sugar solution and 150 mL of the amino acid solution prepared as described above were filled in each chamber of the two-chamber container made of polyethylene and sealed, and then nitrogen gas was introduced to perform high-pressure steam sterilization. A conceptual diagram of this state is shown in FIG. Furthermore, the container is sealed in a gas-impermeable outer packaging material (aluminum vapor-deposited film, manufactured by Dai Nippon Printing Co., Ltd.) together with two oxygen scavengers (ageless, manufactured by Mitsubishi Gas Chemical Co., Ltd.), and a peripheral parenteral nutrition infusion preparation 2 was obtained.
The pH of the liquid after mixing the sugar / electrolyte solution and amino acid solution of peripheral parenteral nutrition infusion preparation 2 was 7.5, and the osmotic pressure ratio was 1.5.

(Example 3)
Under a nitrogen stream, 37.5 g glucose, 0.4 g sodium chloride, 1.145 g sodium lactate, 0.312 g magnesium sulfate, 0.7 mg zinc sulfate and 1.0 mg thiamine hydrochloride were dissolved in distilled water for injection to adjust the pH. A sugar solution was prepared at pH 5.0 using a small amount of glacial acetic acid. On the other hand, under nitrogen flow, L-leucine 2.8 g, L-isoleucine 1.6 g, L-valine 1.6 g, L-lysine hydrochloride 2.62 g, L-threonine 1.14 g, L-tryptophan 0.4 g, L -0.78 g of methionine, 1.4 g of L-phenylalanine, 0.2 g of L-cysteine, 0.1 g of L-thyrosin, 2.1 g of L-arginine, 1 g of L-histidine, 1.6 g of L-alanine, 1 g of L-proline L-serine 0.6 g, glycine 1.18 g, L-aspartic acid 0.2 g, L-glutamic acid 0.2 g, dipotassium hydrogen phosphate 1.16 g and sodium hydrogen sulfite 60 mg were dissolved in distilled water for injection, 300 mL And an amino acid solution was prepared at pH 7.8 using a small amount of glacial acetic acid as a pH regulator. 350 mL of the sugar solution and 150 mL of the amino acid solution prepared as described above were filled in each chamber of the two-chamber container made of polyethylene and sealed, and then nitrogen gas was introduced to perform high-pressure steam sterilization. A conceptual diagram of this state is shown in FIG. Furthermore, the container is sealed in a gas-impermeable outer packaging material (aluminum vapor-deposited film, manufactured by Dai Nippon Printing Co., Ltd.) together with two oxygen scavengers (ageless, manufactured by Mitsubishi Gas Chemical Co., Ltd.), and a peripheral parenteral nutrition infusion preparation 3 was obtained.
The pH of the liquid after mixing the sugar / electrolyte solution and amino acid solution of peripheral parenteral nutrition infusion preparation 3 was 7.5, and the osmotic pressure ratio was 1.7.

  The present invention is capable of administering a nutrient source from a peripheral vein and is substantially free of vascular pain even in patients who are said to be relatively susceptible to vascular pain resulting from infusion administration. In addition, the present invention relates to a peripheral parenteral nutritional infusion preparation suitable for supplementing malnutrition and insufficient amino acid intake in postoperative patients by combining an electrolyte, and can be used industrially.

It is a conceptual diagram which shows the container by which the peripheral parenteral nutrition infusion preparation concerning Example 1 was filled and sterilized. It is a conceptual diagram which shows the container by which the peripheral parenteral nutrition infusion preparation concerning Example 2 or 3 was filled and sterilized.

Claims (5)

A peripheral parenteral nutritional infusion preparation comprising a sugar, an amino acid and an electrolyte and not containing a fat emulsion, wherein the peripheral parenteral nutrition infusion preparation has a pH of 6.8 to 7.6, an osmotic pressure ratio of 0.5 to 2 and a sugar A peripheral parenteral nutrition infusion preparation, characterized in that the concentration is 2 to 5 w / v%. A peripheral parenteral nutritional infusion preparation comprising a solution (A) containing a sugar and an electrolyte and a solution (B) containing an amino acid and not containing a fat emulsion, the pH at the time of mixing being 6.8-7 The peripheral parenteral nutrition infusion preparation according to claim 1, having an osmotic pressure ratio of 0.5 to 2 and a sugar concentration of 2 to 5 w / v%. A solution containing a sugar and an electrolyte (A) and an amino acid-containing solution (B), which is a peripheral parenteral nutrition infusion preparation containing no fat emulsion, and the solution (A) contains vitamins B1 The peripheral parenteral nutrition infusion preparation according to claim 2, which does not contain sulfurous acid and salts thereof. The solution (A) is stored in one chamber of a plastic container having a discharge port in one chamber, and the solution (B) is stored in the other chamber. The peripheral parenteral nutrition infusion preparation according to claim 2 or 3. The peripheral parenteral nutrition infusion preparation according to any one of claims 1 to 4, which does not contain a calcium salt.

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