JP4622311B2 - Peripheral intravenous infusion - Google Patents

Description

  The present invention relates to an infusion solution for peripheral vein administration for nutritional supplement containing amino acids, sugars and electrolytes.

  There have been remarkable advances and improvements in nutritional fluids for patients who are unable or inadequate for oral and enteral feeding, and have made a great contribution to the medical field. Nutritional fluids include central venous fluids that supply large amounts of nutrients to large volumes of venous blood via central veins, and peripheral venous fluids that supply relatively small amounts of nutrients via peripheral veins. It is divided roughly into.

  Intravenous infusion for central venous administration is especially useful for preventing long-term malnutrition or severe invasion of muscle protein in the body, loss or insufficiency of visceral proteins, immune system breakdown, delayed wound healing, and organ failure. It is used when nutritional management for 2 weeks or more is required for the purpose of treatment. Generally, it is a high-calorie infusion consisting of carbohydrate, electrolyte, and amino acid solution, and is injected into a large volume of venous blood in the central vein.

  Peripheral intravenous fluids are used for relatively short periods of time using forearm veins and other peripheral indwelling needles for the purpose of maintaining and improving the nutritional status of non-invasive or mildly invasive patients with relatively good nutritional status. Administered for a while.

  In the case of infusion, it is most preferable to store all components in one container from the viewpoint of ease of use and prevention of mistakes during administration. However, when amino acid and glucose as a sugar component are mixed, they are altered by the Maillard reaction. In order to prevent this, a solution in which the pH of the mixed solution is acidified to about 5 has been developed. In the case of infusion for central venous administration infused into a large volume of venous blood, no major problem occurs even at such a low pH. However, in the case of infusion for peripheral intravenous administration, low pH often causes phlebitis and vascular pain. For this reason, in order to maintain the storage stability of the preparation and to maintain the pH of the infusion after mixing in the vicinity of the physiological pH of blood, the sugar solution is accommodated together with the electrolyte in one chamber of the two-chamber container, and in the other chamber. There is still a great demand for infusions for peripheral intravenous administration that separately contain amino acids and some electrolytes.

It is instructed to administer peripheral venous infusion solutions stored in separate chambers in which a sugar solution and an amino acid solution are separated by a septum, after the septum is opened and mixed well during use. However, in the medical field, there is a possibility that an operation error occurs in that the components in the lower chamber are administered first without opening the partition during use, and then the components in the upper chamber are administered. In that case, if the infusion component of one chamber contains potassium ions (K ⁺ ) at a high concentration, suppression of myocardial excitatory conduction, hypotension, ventricular fibrillation, and cardiac arrest may occur. In order to solve this problem, an improved Aminofried® ^(R) solution for peripheral intravenous administration containing dipotassium phosphate, a potassium source, divided into both the upper and lower chambers was issued on April 19, 2004. It has been approved by. This includes a sugar solution containing 14 mEq / L potassium ions in the lower chamber (side of intravenous administration), and 35 mEq / L potassium ions dispersed in the upper chamber, and only one of them is administered. Even if it is done, it avoids damage caused by high concentrations of potassium ions. Dipotassium hydrogen phosphate is used as a potassium ion source, and calcium gluconate is blended in the lower chamber together with the dipotassium hydrogen phosphate, so it is considered necessary to prevent calcium phosphate precipitation.

  An object of the present invention is to provide a solution for peripheral vein administration in a multi-chamber container containing a sugar solution in one chamber of a multi-chamber container and containing an amino acid in the other chamber even when the septum is not opened at the time of use. The aim is to supply a transfusion for peripheral vein administration in a multi-chamber container that has no risk of being administered at a high concentration, has good storage stability, and does not cause phlebitis or vascular pain at the time of administration.

  The present invention relates to an infusion for peripheral vein administration in which amino acids, sugars and electrolytes are housed in a multi-chamber container configured to communicate with each other, and (1) the first chamber (upper chamber) on the administration side to the vein Contains an amino acid solution that contains calcium ions and does not contain sugar, phosphate ions, and potassium ions. (2) The second chamber (lower chamber) away from the administration side contains phosphate ions and potassium ions. And a sugar solution not containing amino acids and calcium ions is contained, (3) the osmotic pressure ratio of the infusion solution after mixing both solutions to physiological saline is 3 or less, and (4) the infusion solution after mixing. It is an infusion for peripheral intravenous administration characterized by having a pH of 6.3 to 7.4.

  In this peripheral infusion solution, it is desirable that the concentration of potassium ion in the second chamber is 40 mEq / L or less, particularly 30 mEq / L or less, which does not cause vascular pain. Such a preparation can provide a highly safe infusion solution in which potassium ions do not exceed the administration rate of 20 mEq / hour. This infusion for peripheral vein administration preferably contains 10 mmol / L or more of phosphorus element. In this peripheral intravenous administration infusion, the volume ratio of the amino acid solution accommodated in the first chamber to the volume of the sugar solution in the second chamber is preferably from 1: 1.5 to 1: 3. In this infusion for peripheral vein administration, the second chamber is preferably provided with a mixed injection port for mixing other components immediately before administration. In this infusion for peripheral vein administration, it is preferable that the sugar solution contained in the second chamber does not contain sulfite ions.

This infusion for peripheral vein administration preferably further contains vitamins. These vitamins were selected from vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, vitamin A, vitamin D, vitamin E, vitamin K, vitamin H, folic acid, pantothenic acids and nicotinic acids It is preferable. Among vitamins, it is particularly desirable to include vitamin B _1.

  The vitamins may be contained in the sugar solution in the second chamber, or are contained in a chamber other than the first chamber and the second chamber that are isolated so as to communicate with the first chamber and / or the second chamber. It may be.

The characteristics of the infusion for peripheral vein administration of the present invention are listed below.
(1) Since the sugar solution and the amino acid solution are housed in separate chambers in which the sugar solution and the amino acid solution can communicate with each other, both can be kept stable even if the pH is not particularly lowered. There is no worry of phlebitis because it is close to pH.
(2) The first chamber on the side of intravenous administration does not contain potassium ions, and potassium ions are contained in the sugar solution side accommodated in the second chamber with a large volume so that the concentration of potassium ions is kept low. As a result, even if the first chamber amino acid solution was first injected without first communicating the septum between the first chamber and the second chamber at the time of administration, a high concentration of potassium was also injected. Disorders such as hyperkalemia caused by ions do not occur.
(3) Since calcium ions and phosphate ions are contained in separate chambers, there is no need to lower the pH in order to prevent calcium phosphate precipitation, so the pH of the infusion after mixing is close to the pH of blood There is no worry of phlebitis.
(4) Since the sugar concentration is controlled so that the osmotic pressure ratio of the infusion solution to the physiological saline after mixing both solutions is 3 or less, blood vessels that occur when a high-concentration sugar solution is administered to the peripheral vein There is no pain.
(5) It is easy to prepare a preparation mixed with vitamins and other drug components.

  According to the present invention, the storage stability of the components is good, and even in an unexpected situation where the sugar solution and the amino acid solution are not mixed before administration, high concentration potassium ions are not injected, phlebitis due to low pH, sugar or It is possible to provide an excellent infusion solution for peripheral intravenous administration that does not cause the risk of vascular pain due to a high concentration of potassium ions.

  In the infusion for intravenous administration of the present invention, the sugar that can be used is not particularly limited as long as it is a sugar that is usually used for infusion. For example, reducing sugars include glucose, fructose, and maltose, and non-reducing sugars include trehalose, xylitol, Examples include sorbitol and glycerin. Of the various sugars, glucose is preferably added from the viewpoint of nutritional effect.

  In the infusion solution for intravenous administration of the present invention, the amino acid that can be used is not particularly limited as long as it is an amino acid that is usually used in infusion solutions. Specifically, L-isoleucine, L-leucine, L-valine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, L-alanine, L-arginine, L-aspartic acid, L-cysteine, L-glutamic acid, L-histidine, L-proline, L-serine, L -Tyrosine and glycine can be mentioned. These amino acids can be used singly or in combination, but are preferably combined from the viewpoint of use in protein synthesis. Among them, L-isoleucine, L-leucine, L-valine, L-lysine are preferred. , L-methionine, L-phenylalanine, L-threonine, L-tryptophan, and L-histidine are preferably used, more preferably 9 essential amino acids and non-essential amino acids are used in combination It is preferable to do. The composition of these amino acids may be appropriately adjusted depending on the type and condition of the patient's disease, but an amino acid composition suitable for a postoperative patient described in JP-A-60-123413 can be preferably used. Each amino acid is not necessarily used as a free amino acid, and may be used in the form of an inorganic acid salt, an organic acid salt, an ester that can be hydrolyzed in vivo, or the like. Further, it may be used in the form of dipeptides in which the same or different amino acids are peptide-bonded.

  The electrolyte used in the present invention is not particularly limited as long as it is a commonly used electrolyte, and specific examples include inorganic and organic salts of sodium, potassium, calcium, magnesium, chlorine and phosphorus. About each inorganic and organic salt, the same thing as the active ingredient mix | blended with the infusion solution and enteral nutrient already marketed can be used. The electrolyte is necessary for maintaining the function of the living body and the electrolyte balance of the body fluid. Trace elements can also be added as an electrolyte. Here, the trace element is a metal element that is indispensable for a living body although it is in a trace amount. Trace element supplementation is necessary not only to prevent deficiency, but also to promote protein synthesis, promote wound healing, and increase the activity of enzymes in the mitochondria. Specific examples include inorganic and organic salts of zinc, iron, manganese, copper, chromium, molybdenum, selenium, fluorine and iodine. In this case, you may mix | blend the trace element formulation marketed for high-calorie infusions. Each trace element may be blended in consideration of the daily required amount.

In addition to sugars, amino acids, and electrolytes, optional components required according to the patient's condition can be added to the infusion solution for peripheral intravenous administration of the present invention. In particular, vitamins can be added. Examples of vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, vitamin A, vitamin D, vitamin E, vitamin K, vitamin H, folic acid, pantothenic acids, nicotinic acids, etc. Can do. By using these vitamins, it is possible to realize maintenance and improvement of nutritional status at an early stage. Vitamin B ₁ can increase the efficiency of sugar metabolism in vivo. Vitamin B ₁ is known as thiamine, but thiamine derivatives such as prosultiamine, actiamine, thiamine disulfide, fursultiamine and their salts conventionally used for infusion are also used as vitamins in the present invention. Can do.

  In order to avoid the Maillard reaction when the sugar and amino acid are mixed, the infusion solution of the present invention accommodates the sugar solution and the amino acid solution in a multi-chamber container partitioned by a communicating partition wall. Furthermore, in order to cope with an unexpected situation where both solutions are not mixed before administration, an amino acid solution not containing potassium ions is accommodated in the first chamber on the administration side to the vein, and the second chamber separated from the administration side. Contains a sugar solution containing potassium ions. To prevent calcium ions and phosphate ions from reacting and precipitating as calcium phosphate, calcium ions are added to the amino acid solution in the first chamber and phosphate ions are added to the sugar solution in the second chamber.

  The sugar concentration is adjusted so that the osmotic pressure ratio of the infusion solution after mixing the amino acid solution and the sugar solution to physiological saline (280 mOsm / L) is 3 or less, preferably 1 to 2.5. Therefore, the sugar concentration is determined in consideration of the concentration after mixing and the volume of the sugar solution. When glucose alone is used as the sugar, the glucose concentration in the infusion solution in which the amino acid solution and the sugar solution are mixed is generally preferably 10 w / v% or less, more preferably 2.5 to 7.5 w / v%, still more preferably Is 3 to 5 w / v%.

  Examples of the potassium ion source added to the sugar solution include potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium acetate, and the like. In view of the purpose of serving as a phosphate ion supply source and supplying potassium in a small amount, It is desirable to use dipotassium hydrogen phosphate. The sugar solution is preferably adjusted to a low pH from the viewpoint of sterilization and storage stability, but the pH of the infusion when mixed with the amino acid solution is kept at pH 6.3 to 7.4 where phlebitis does not occur. It is determined in consideration of the volume of the amino acid solution from the necessity. In general, the pH of the sugar solution is preferably about 4.2. The potassium ion concentration in the sugar solution is 40 mEq / L or less, in which even if the sugar solution is administered without mixing with the amino acid solution, the heart function is not impaired by the high concentration potassium, and vascular pain is not caused. In particular, it is preferably 30 mEq / L or less. This sugar solution preferably does not contain sulfite ions. When sulfite ions are not included, other components such as vitamins can be added as they are.

  The amino acid concentration of the amino acid solution is preferably 1 to 20 w / v%, more preferably 3 to 10 w / v% as the concentration in the infusion after mixing the amino acid solution and the sugar solution. Examples of the calcium source added to the amino acid solution include calcium gluconate, calcium chloride, and calcium aspartate, and calcium gluconate is most preferable. The pH of the amino acid solution is not particularly limited, but is almost neutral, for example, around pH 6.5-7. A small amount of sulfite ion necessary for amino acid stabilization can be added as sodium bisulfite.

  In order to adjust the pH of the sugar solution and the amino acid solution, a pH adjuster usually used in the field of infusion can be used. Examples of the pH adjuster include inorganic acids such as hydrochloric acid and organic acids such as acetic acid and citric acid. Although an acid can be used, it is preferable to use an organic acid that can be expected to suppress phlebitis and vascular pain.

Vitamins that are preferred as other components are preferably placed in the sugar solution when the sugar solution in the second chamber does not contain sulfite ions. Furthermore, vitamins can be accommodated in a chamber other than the first chamber and the second chamber, and the chamber can be isolated so as to communicate with the first chamber and / or the second chamber. Vitamins can be stored in solution or powder in an isolated room for stability. Furthermore, trace elements and other pharmaceuticals can be placed as solutions or powders in the isolated chambers other than the first chamber and the second chamber, as necessary.

  In order to adjust the infusion solution of the present invention, the above sugar, amino acid and electrolyte are mixed for the above purpose and dissolved in distilled water for injection or the like, or a sugar solution, amino acid solution, electrolyte solution and the like prepared in advance are used. A method such as mixing can be employed.

In the present invention, the infusion after mixing the sugar solution and the amino acid solution preferably has the following composition.
Glucose 2.5 to 7.5 w / v%, more preferably 3 to 5.0 w / v%
Total amino acid 1.0-5.0 w / v%
Each amino acid
L-isoleucine 0.1-5.0 g / L, more preferably 0.8-5.0 g / L
L-leucine 0.2 to 9.0 g / L, more preferably 1.0 to 9.0 g / L
L-valine 0.2 to 10.0 g / L, more preferably 1.0 to 10.0 g / L
L-lysine 0.15-6.0 g / L, more preferably 0.8-6.0 g / L
L-methionine 0.1-7.0 g / L, more preferably 0.4-5.0 g / L
L-phenylalanine 0.1-7.7 g / L, more preferably 0.5-5.0 g / L
L-threonine 0.1-5.0 g / L, more preferably 0.5-5.0 g / L
L-tryptophan 0.02-3.0 g / L, more preferably 0.05-1.0 g / L
L-alanine 0.1-6.8 g / L, more preferably 0.5-5.0 g / L
L-arginine 0.1-11.3 g / L, more preferably 1.0-10.0 g / L
L-aspartic acid 0.02 to 5.0 g / L, more preferably 0.08 to 2.0 g / L
L-cysteine 0.01-0.7 g / L, more preferably 0.02-0.4 g / L
L-glutamic acid 0.01-3.6 g / L, more preferably 0.04-2.0 g / L
L-histidine 0.1-4.1 g / L, more preferably 0.3-3.0 g / L
L-proline 0.1-5.9 g / L, more preferably 0.4-5.0 g / L
L-serine 0.05-2.0 g / L, more preferably 0.1-1.0 g / L
L-tyrosine 0.0-1.0 g / L, more preferably 0.0-0.5 g / L
Glycine 0.1-5.4 g / L, more preferably 0.5-4.0 g / L
Electrolytes
Na ⁺ 20 to 150 mEq / L, more preferably 30 to 40 mEq / L
K ⁺ 2-40 mEq / L, more preferably 15-25 mEq / L
Ca ²⁺ 1-15 mEq / L, more preferably 3-6 mEq / L
Mg ²⁺ 0-15 mEq / L, more preferably 3-6 mEq / L
Cl ^- 20 to 150 mEq / L, more preferably 30 to 60 mEq / L
P 0-20 mmol / L, more preferably 5-15 mmol / L
Zn ²⁺ 0-20 mmol / L, more preferably 2-10 mmol / L

  As an example of the administration method of this infusion solution, it can be administered by inserting and placing an indwelling needle such as a surf flow needle, an injection needle, or a winged needle through any peripheral blood vessel. In such an administration method, continuous administration is possible, and nutritional management appropriate for recovery from surgical invasion can be performed in a state in which oral intake after light to moderate surgical invasion is not possible.

  The material constituting the main body of the infusion container in the present invention is preferably a soft resin material that is excellent in flexibility and transparency, and that does not easily break even if dropped after low-temperature storage. Particularly preferred are those made of polyolefins usually used in medical containers. Examples of polyolefins include polymerized polymers such as polyethylene, polypropylene, poly 1-butene, poly 4-methyl-1-pentene. As the container body, any of those obtained by blow molding, inflation or deflation molding of the resin can be used. Moreover, what formed by welding the peripheral part of two resin sheets may be used.

In order to partition the container main body into a plurality of spaces, for example, a method of forming a plurality of spaces in the container by partitioning with a seal part that can be peeled off by external pressure during use (Japanese Patent Laid-Open No. 2-4671) or breaking Can be created using a communication member having a thin portion that communicates with each other (Japanese Patent Laid-Open Nos. 2000-167022, 2001-87350).
When other chemicals such as vitamins are separated and sealed in a container, a sachet having a plurality of spaces can be provided in any space of the container body or in the peripheral edge of the container and accommodated in the sachet. it can. At this time, it is preferable to select a material that does not easily adsorb the components to be filled, and preferred examples include polyfluorinated ethylene (Teflon ^(R), etc.) and cyclic olefin copolymers.

A sugar solution containing a part of the electrolyte and an amino acid solution containing a part of the electrolyte were prepared as follows.
(1) Preparation of sugar solution Glucose, sodium chloride, magnesium sulfate, sodium lactate, dipotassium hydrogen phosphate and zinc sulfate are dissolved in water for injection according to the following blending amounts, and then adjusted to pH 5.4 with the pH adjuster glacial acetic acid. Then, a sugar / electrolyte solution was prepared.
Glucose 10.714 w / v%
Sodium chloride 0.114 w / v%
Magnesium sulfate (7 water salt) 0.089 w / v%
Sodium lactate 0.327 w / v%
Dipotassium hydrogen phosphate 0.249 w / v%
Zinc sulfate (7-hydrate) 0.0002 w / v%

(2) Preparation of Amino Acid Solution According to the following blending amounts, amino acid and dipotassium hydrogen phosphate were dissolved in water for injection and then adjusted to pH 7.7 with glacial acetic acid to prepare an amino acid solution.
L-isoleucine 0.800 w / v%
L-Leucine 1.400 w / v%
L-Valine 0.800 w / v%
Hydrochloric acid L-lysine 1.310 w / v%
L-methionine 0.390 w / v%
L-Phenylalanine 0.700 w / v%
L-threonine 0.570 w / v%
L-tryptophan 0.200 w / v%
L-alanine 0.800 w / v%
L-Arginine 1.050 w / v%
L-aspartic acid 0.100 w / v%
L-cysteine 0.100 w / v%
L-glutamic acid 0.100 w / v%
L-Histidine 0.500 w / v%
L-proline 0.500 w / v%
L-serine 0.300 w / v%
L-tyrosine 0.500 w / v%
Glycine 0.590 w / v%
Calcium gluconate (monohydrate) 0.373 w / v%

(3) Filling, sterilizing, and packaging into plastic containers Each of the prepared sugar solution and amino acid solution is aseptically filtered, and 800 mL of the sugar solution is filled into the second chamber of a plastic two-chamber container partitioned by a partition wall. did. After sealing the second chamber, the first chamber of the plastic container was filled with 200 mL of the amino acid solution and sealed. A plastic container filled and sealed with both solutions was packaged with an outer packaging material together with an oxygen scavenger.

(4) Mixing at the time of use The pH when the both solutions were mixed by allowing the partition walls of both the sugar / electrolyte solution and amino acid solution prepared in (3) to communicate with each other was 6.7.

Claims (9)

A transfusion for peripheral venous administration in which amino acids, sugars and electrolytes are housed in a multi-chamber container configured to be communicable so as to be mixed at the time of use , and (1) calcium ions are contained in the first chamber on the administration side (2) the second chamber away from the administration side contains phosphate ions and potassium ions, and contains amino acids and calcium ions. (3) The osmotic pressure ratio of the infusion solution to the physiological saline after mixing both solutions is 3 or less, and (4) the pH of the infusion solution after mixing is 6.3--3. 7.4 , (5) the sugar concentration of the infusion after mixing is 2.5-7.5 w / v%, (6) the mixture injection port for mixing other drugs into the second chamber (7) Housed in the second chamber An infusion for peripheral intravenous administration, wherein the sugar solution is free of sulfite ions .   The infusion for peripheral vein administration according to claim 1, wherein the concentration of potassium ions in the second chamber is 40 mEq / L or less.   The infusion solution for peripheral vein administration according to claim 1, which contains 10 mmol / L or more of phosphorus element.   The infusion for peripheral vein administration according to claim 1, wherein the volume ratio of the amino acid solution accommodated in the first chamber and the volume of the sugar solution in the second chamber is 1: 1.5 to 1: 3. The infusion for peripheral vein administration according to any one of claims 1 to 4 , further comprising vitamins. Vitamins, vitamin B _1, vitamin B _2, vitamin B _6, vitamin B _12, vitamin C, vitamin A, vitamin D, vitamin E, vitamin K, claim 5 vitamin H, folic acid, pantothenic acid and nicotinic acids The infusion for peripheral vein administration as described. Vitamins, for intravenous administration infusion claim 5, wherein the vitamin B _1. The infusion solution for peripheral vein administration according to any one of claims 5 to 7 , wherein vitamins are contained in the sugar solution in the second chamber. Vitamins are contained in the chamber other than the first chamber and the second chamber, according to claim 5-7, characterized in that said chamber is isolated first chamber and / or allow the second chamber communicating with The infusion for peripheral vein administration in any one.