JP5769354B2 - Infusion for central venous administration - Google Patents

Description

  The present invention relates to a transfusion for central venous administration that can be performed for venous nutrition management that does not require acclimation administration and / or step-up administration (acclimation period) to a saccharide, containing a saccharide, an electrolyte component, and an amino acid. Relates to the formulation.

  In many cases, patients who have undergone post-operative invasion in digestive surgery or circulatory surgery cannot perform nutritional management by ingestion. Therefore, such a patient's nutrition management is generally performed by administering a high calorie infusion (IVH: Intravenous Hyperalimentation) from a central vein. This IVH promotes early recovery and healing of patients by improving the nutritional status of these patients and maintaining good nutritional status, and is widely used in the surgical field.

  This IVH usually contains an electrolyte that constitutes a body fluid component in addition to carbohydrates and amino acids, which are nutrients, and further contains vitamins as desired. Generally, a carbohydrate, an electrolyte component, and an amino acid are contained in this IVH. It is provided as an infusion preparation in the form of a single bag having a third chamber chamber filled with vitamins if desired, in a bag consisting of two-chamber containers to be separated and filled.

  Since this high-calorie infusion (IVH) is an infusion preparation for nutritional management for patients who cannot be taken orally, the maintenance liquid has a total calorie of about 1600 to 2400 Kcal as a daily dose, for example. In addition, it contains 350 to 500 g of glucose, which is a carbohydrate serving as a calorie source, and additionally contains 60 to 80 g of essential amino acids and other amino acids, and further contains necessary electrolyte components, and the amount of water is 2000 to 2400 mL. The daily dosage is divided into two bags and is provided as a filled preparation. Usually, these two bags are administered intravenously as a daily dose.

However, in starting this central parenteral nutrition therapy, when the glucose tolerance function is unknown at the start, or when the glucose tolerance function is reduced, the glucose tolerance function is used in the case of invasion immediately after surgery. If it is lowered and it is necessary to limit glucose, which is a carbohydrate, administration of this dose to patients with maintenance fluid causes side effects such as liver damage due to excessive carbohydrate administration (Non-Patent Documents) For 1), a start-up solution as a break-in administration and / or a step-up administration before administration of the maintenance solution is administered for 2 days (acclimation period) after the operation, and then the maintenance solution is administered.
In this central parenteral nutrition therapy, the usual central parenteral nutrition therapy performed at the time of postoperative invasion or when oral or tube feeding cannot be performed or is insufficient is about 7 to 10 days. In the present specification, this is defined as “oral ingestion period or fasting period”.

  This starting solution is set to have a lower total calorie than the maintenance solution, and also has a low content of carbohydrates and amino acids as nutrient sources. Specifically, for example, the starter solution has a total calorie of about 1000 Kcal as a daily dose, and contains a carbohydrate (glucose) as a calorie source at a low dose of about 120 g, In addition, it is an infusion preparation comprising about 20 g of essential amino acids and other amino acids, including necessary electrolyte components, and having a dosage of about 1000 mL as the amount of water.

  Therefore, in the case of performing central parenteral nutrition therapy, as an infusion preparation, two kinds of infusion preparations comprising an infusion preparation as a break-in administration and / or a step-up administration before administration of a maintenance liquid and a subsequent infusion preparation as a maintenance liquid Furthermore, even in the maintenance liquid, the actual situation is that it is provided as two types of maintenance liquids whose total calories are selected according to the symptoms, age, and body weight of the administration subject.

However, central parenteral nutrition has become widespread, and its problems have been pointed out.
In other words, even in the case of central parenteral nutrition therapy, nutrition management that is in line with the actual conditions of recent patients is necessary, and since recent patients are in good nutrition, avoid giving more total calories than necessary. It has been pointed out that it should be.
Resting energy expenditure (REE: Resting Energy Expense) for elderly people who are hospitalized in particular is about 1000 Kcal / day for both men and women (Non-Patent Document 2), and no further energy supplement is required. It has been pointed out.
In addition, the recent treatment policy points out that the use of the digestive system intestinal tract from early stage for postoperative invasive patients is pointed out that the rehabilitation will be accelerated. They are used or eaten with meals such as rice cakes.
Furthermore, the presence of a plurality of different infusion preparations (starting infusion / maintenance infusion) for use in central parenteral nutrition was also prone to medical errors due to misuse.

Japanese Patent Application Laid-Open No. 6-209979 JP-A-8-000709 Tanaka et al., History of Medicine, Vol.218, 409-412 (2006) Sugiyama et al., JJPEN, Vol.24, 627-635 (2002)

In view of the current situation, the present inventors have studied to develop an infusion solution that can be used for central parenteral nutrition therapy that can perform nutritional management in line with the actual conditions of recent patients.
As a basic idea, I thought that it would be possible to provide several different infusion preparations (starting infusion / maintenance infusion) for use in conventional central parenteral nutrition therapy.
That is, in one agent to be administered, it can be a start-up solution as a break-in administration and / or a step-up administration before administration of the maintenance solution, and an infusion preparation as a subsequent maintenance solution, and its convenience is improved, We thought that it would be possible to avoid errors in administration infusions by means of replicated infusion preparations.

  Based on the above idea, the present inventors have reduced the amount of carbohydrates to be contained in central parenteral nutrition therapy, and further added a daily required amount as an amino acid amount, and are often used during postoperative invasion. Increasing the amount of amino acids valine, leucine and isoleucine, and strengthening arginine as an amino acid makes it difficult to cause liver dysfunction even if administered at the time of postoperative invasion. Alternatively, the above-mentioned infusion preparation reduces the total calories to be administered to the amount of calories necessary for actual nutrition maintenance so that the intestinal tract can be used by ingestion of meals, etc. The inventors have newly found that the problem can be solved and have completed the present invention.

  Therefore, in view of the above-mentioned present situation, the present invention contains a saccharide, an electrolyte component, and an amino acid, and can perform central parenteral nutrition management without performing break-in administration and / or step-up administration to the saccharide. It is an object to provide an infusion preparation for intravenous administration.

  In order to solve such a problem, one basic aspect of the present invention comprises a carbohydrate, an electrolyte and an amino acid composition, and the total daily calories are within a range of 1000 to 1400 kcal, more preferably 1100 to 1300 Kcal. Yes, 45 to 75 g, more preferably 55 to 65 g of amino acid, total water content is 1400 to 1800 mL, more preferably 1500 to 1700 mL, the ratio of non-protein calorie and dose of nitrogen (Cal / N ratio) Is in the range of 90 to 160, more preferably 90 to 130, and in particular, central venous administration characterized by administration without habituation administration and / or step-up administration (acclimation period) to carbohydrates Infusion formulation.

  That is, in the present invention, the carbohydrate contained in the infusion preparation to be administered is a compounded amount that does not require a break-in administration and / or a step-up administration (acclimation period), and at the time of postoperative invasion. The infusion preparation for central venous administration described above, which is less likely to cause liver dysfunction even when administered.

  In the present invention, the above-mentioned infusion preparation for central intravenous administration is characterized by further containing vitamins or trace elements.

  In addition, the carbohydrate as a calorie source in the infusion preparation is not particularly limited as long as it is a carbohydrate used in normal infusion solutions. For example, glucose, fructose and maltose are used as reducing sugars, and trehalose and xylitol are used as non-reducing sugars. , Sorbitol, glycerin and the like, and glucose is preferable from the viewpoint of nutritional effect.

Further, the present invention is the above-mentioned infusion preparation for central venous administration comprising a composition rich in essential amino acids as an amino acid composition and capable of administering 45 to 75 g, more preferably 55 to 65 g of amino acid as a daily dose. .
Furthermore, the present invention is an infusion preparation for central venous administration in which the content of arginine is enhanced as an amino acid composition and reduction of liver function abnormality at the time of high calorie infusion is performed.

Furthermore, the present invention is an infusion preparation for central venous administration characterized in that the ratio (Cal / N ratio) between the non-protein calorie and the administration nitrogen amount in the infusion preparation is in the range of 90 to 160.
In this Cal / N ratio, the high-calorie infusion solution used in conventional central parenteral nutrition therapy shows a value of 160 or more because it contains a large amount of carbohydrates. However, in the present invention, the Cal / N ratio shows a value of 160 or less by reducing the sugar content to a level corresponding to the total required calories and then adding the necessary amount of amino acid on the day. Even if it happened, the nutritional effect of the infusion preparation itself was not changed.

  The infusion preparation for central venous administration of the present invention can be used for post-operative patients in the digestive system or circulatory system at the time of postoperative invasion, and oral and tube feeding such as dysphagia and sequelae of cerebral infarction. It is an infusion preparation for central venous administration that can be used even for patients who cannot take or are insufficient and whose energy demand is low, such as elderly people.

That is, the present invention provides, as another aspect, a system for managing central venous nutrition during postoperative invasion that is an ingestion period or a fasting period, and a dosage unit for infusion for central venous administration administered for the management system It is also a (unit).
Infusion for central venous administration used in this central venous nutrition management system can be administered without performing break-in administration and / or step-up administration (acclimation period) to carbohydrates. The ratio of protein calorie and dose of nitrogen (Cal / N ratio) is in the range of 90 to 160, more preferably 90 to 130, and can further contain vitamins and trace elements, In addition, it is an infusion for central venous administration used in a central venous nutrition management system that is filled in one bag or divided into two bags as a daily dose.

Therefore, more specifically, the present invention specifically includes the following configuration.
That is, as one basic aspect,
(1) It consists of carbohydrate, electrolyte and amino acid composition, and as a daily dose, the total calories are in the range of 1000-1400 kcal, contain 45-75 g of amino acids, and the total water content is 1400-1800 mL, Infusion preparation for central venous administration, wherein the ratio of non-protein calorie and administration nitrogen amount (Cal / N ratio) is in the range of 90-160;
(2) The infusion preparation for central venous administration according to (1), comprising an abundance of essential amino acids as the amino acid composition;
(3) An infusion preparation for central vein administration according to (1) or (2), wherein the amino acid composition is an amino acid composition in which arginine is reinforced;
(4) The infusion preparation for central venous administration according to (1), (2) or (3), further comprising vitamins;
(5) The infusion preparation for central vein administration according to (1), (2) or (3), further comprising trace elements;
(6) The infusion preparation for central vein administration according to any one of (1) to (5), wherein the sugar is glucose.
(7) Administering the infusion preparation described in (1) to (6) above during a period incapable of oral intake or during a fasting period, without a break-in administration and / or step-up administration (acclimation period) to carbohydrates Central intravenous administration infusion method characterized by:
It is.

Furthermore, the present invention provides, as another aspect,
(8) Consisting of carbohydrate, electrolyte and essential amino acid composition, the total calories are in the range of 1000-1400 Kcal as daily dose, contain 55-65 g of amino acids, and the total water content is 1400-1800 mL An administration unit for central venous nutrition therapy, comprising an infusion preparation for central venous administration in which the ratio of non-protein calorie to administration nitrogen amount (Cal / N ratio) is in the range of 90 to 160;
(9) An administration unit for a patient whose energy demand is in a reduced state during an ingestion period or a fasting period, characterized by not performing a break-in administration and / or a step-up administration (acclimation period) to a carbohydrate. The administration unit according to (8);
(10) The administration unit according to (8) or (9), wherein the period of ingestion or fasting is during postoperative invasion of the digestive system or circulatory system;
(11) The administration unit according to (8) to (10) above, wherein the infusion used for administration is the infusion according to any of (1) to (6);
(12) The administration unit according to any one of (8) to (11), characterized in that it is in a two-bag form as a daily dose;
It is.

As still another aspect,
(13) When administering an infusion preparation for central venous administration during the period of ingestion or fasting, it consists of carbohydrate, electrolyte and essential amino acid composition, and the total calories are within the range of 1000 to 1400 Kcal as the daily dose. Intravenous fluid for central venous administration containing 55 to 65 g of amino acid, having a total water content of 1400 to 1800 mL and a ratio of non-protein calorie to dose of nitrogen (Cal / N ratio) in the range of 90 to 160 A central parenteral nutrition management system characterized by not administering a break-in and / or step-up (acclimation period) to carbohydrates
(14) The central parenteral nutrition management system according to (13), wherein the ingestible period or the fasting period is a postoperative invasion of the digestive system or circulatory system;
(15) The central parenteral nutrition management system according to (13) or (14), wherein the amino acid composition is rich in essential amino acids;
(16) The central parenteral nutrition management system according to any one of (13) to (15) above, wherein the amino acid composition is an amino acid composition in which arginine is reinforced;
(17) The central parenteral nutrition management system according to any one of (13) to (16), further comprising vitamins;
(18) The central parenteral nutrition management system according to any one of (13) to (16), further containing trace elements;
(19) The central parenteral nutrition management system according to any one of (13) to (16), wherein the sugar is glucose.
It is.

The present invention configured as described above specifically has the following effects.
(1) Since the central parenteral nutrition management at the time of postoperative invasion is performed with one agent, it is possible to avoid the conventional infusion and / or the administration of the starting infusion for performing the step-up management. It is possible to improve and avoid the occurrence of medical errors due to erroneous administration.
(2) By reducing the total calories in the infusion preparation to the necessary calories for nutrition maintenance during postoperative invasion, the amount of sugar to be contained can be reduced, and therefore the sugar load during step-up is reduced. , Can reduce the occurrence of liver damage.
(3) The burden on the kidney can be reduced by reducing the amount of water.
That is, the conventional infusion preparation for central venous administration has a daily dose of 2000 to 2400 mL. Therefore, when an antibiotic or an anticancer agent is administered in combination as a drug during postoperative invasion, total administration The amount of water is well over 2000 mL. This large amount of water administration has caused a considerable burden on the kidney for patients during postoperative invasion whose visceral function has been reduced.
In the present invention, this burden on the kidney is reduced.

(4) In addition, the total calorie amount is reduced to about 1000 Kcal / day, which is a necessary calorie maintenance for postoperative invasion, and the intestinal tract can be obtained by administration of enteral nutrients or intake of meals (such as sputum) at an early stage. Can be activated, thereby enabling early reintegration.
(5) In addition, the transfusion for central venous administration of the present invention supplements calorie sources with carbohydrates, and therefore can be applied to all patients as patients during postoperative invasion compared to fat emulsions. is there.
(6) It is an infusion solution for central venous administration by reducing the amount of sugar to be contained while containing the daily necessary amount of amino acids, and also because the content of branched chain amino acids of valine, leucine and isoleucine is increased. It is possible to improve nutritional status by enhancing protein synthesis and reducing protein degradation.
(7) In addition, by strengthening the content of arginine as an amino acid composition, there is an advantage that reduction of liver function abnormality at the time of high calorie infusion can be achieved.
(8) In addition, it is possible to replenish all necessary vitamins a day, and a transfusion for central intravenous administration having an extremely ideal composition from the viewpoint of nutritional management is provided.

  As described above, the present invention comprises a carbohydrate, an electrolyte, and an amino acid composition as a basic aspect, and the total calories are within a range of 1000 to 1400 kcal, more preferably 1100 to 1300 Kcal, and 45 to 45 days. 75 g, more preferably 55 to 65 g of amino acid, total water content is 1400 to 1800 mL, more preferably 1500 to 1700 mL, and the ratio of non-protein calorie to the dose of nitrogen (Cal / N ratio) is 90 to 160 More preferably, it is an infusion preparation for central venous administration, characterized in that it is in the range of 90 to 130, and in particular, it is not subjected to break-in administration and / or step-up administration (acclimation period) to carbohydrates.

The sugar that can be used is not particularly limited as long as it is a sugar used for normal infusion. For example, glucose, fructose, and maltose are examples of reducing sugars, and trehalose, xylitol, sorbitol, and glycerin are examples of non-reducing sugars. Of these various carbohydrates, glucose is preferably added from the viewpoint of nutritional effect.
This carbohydrate is a nutrient source that bears most of the total calories in the infusion preparation for central intravenous administration of the present invention. Among conventional infusion preparations of this type, there are preparations that depend on fat for their calorie source, but fat administration is not necessarily acceptable for all patients, such as hyperlipidemia, liver damage, thrombus The administration of fat is contraindicated for patients with diabetes and diabetic ketosis.
On the other hand, in the infusion preparation for central venous administration provided by the present invention, the above-mentioned hyperlipidemia is obtained by using a carbohydrate, preferably glucose, as a nutrient source that bears most of the total calories. It can be applied to all patients including patients with hepatic disorder, thrombosis, diabetic ketosis and the like.
In addition, the conventional infusion and / or step-up administration (acclimation period) to complicated carbohydrates is avoided.

  As a blending amount of glucose, the daily water content is preferably about 200 to 300 g per 1600 mL, and by blending about 60 g as an amino acid blending amount, the total calorie amount is equivalent to 1000 to 1400 Kcal basal metabolic calorie. It becomes possible. In addition, for patients with high calorie infusions where this total calorie content is insufficient, it is desirable that the amino acid content is the same, and about 350 g per 1600 mL of daily water content is added as the glucose content. Thereby, 1500-1700 Kcal can be administered as a total calorie amount per day, and it becomes a composition similar to the maintenance liquid of the existing high calorie infusion kit preparation. The present invention proposes a new concept of nutritional management of high-calorie infusion solutions by using two preparations having different total calorie amounts as described above.

In addition, the electrolyte contained is not particularly limited as long as it is used for normal electrolyte infusions, and examples thereof include sodium, potassium, calcium, magnesium, phosphorus, chlorine, zinc, and the like. An inorganic salt, an organic salt, or the like that generates water is preferable. In particular, the following electrolyte is preferably blended as a daily dose.
Na ⁺ 50-150 mEq
K ⁺ 30-90 mEq
Ca ²⁺ 5-10 mEq
Mg ²⁺ 5-10 mEq
Cl ^- 50 to 150 mEq
Glycerophosphoric acid 0-40mEq
Acetic acid 0-40mEq
Lactic acid 0-40mEq
Citric acid 0-40mEq
Malic acid 0-40mEq
Succinic acid 0-40mEq

  The electrolyte component is separately filled in a bag consisting of a two-chamber container in which the infusion preparation for central intravenous administration of the present invention separates and fills a carbohydrate, an electrolyte component, and an amino acid. It is preferable to be blended into a saccharide solution because it is preferably provided as a one-bag infusion preparation having a filled third chamber, but an amino acid solution for an electrolyte component that does not react with amino acids. It is also possible to mix in.

  The amino acids contained in the infusion preparation for central intravenous administration provided by the present invention are L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, L- Valine, L-alanine, L-arginine, L-aspartic acid, L-glutamic acid, L-histidine, L-proline, L-serine, L-tyrosine, glycine and L-cysteine, among which L-isoleucine, L It is essential to use nine essential amino acids: leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan and L-valine, and the E / N ratio is, for example, 1 An amino acid composition containing abundant essential amino acids such as .7 or more can also be used.

  Specifically, the blending amount is, for example, preferably 55 to 65 g of amino acids as the total daily required amino acid amount, more specifically 60 g / day of amino acid, and the amounts shown in Table 1 below are used respectively. Is preferred.

  In the infusion solution for central intravenous administration provided by the present invention, it is important to increase the amount of L-isoleucine, L-leucine, and L-valine branched chain amino acid (BCAA). By increasing the amount of this branched-chain amino acid, it can be activated to liver function and improve immunity, and proved to be extremely effective as an infusion for postoperative invasion. did.

In addition, it has been found that increasing the amount of arginine as an amino acid composition can reduce the occurrence of abnormal liver function during high-calorie infusion. In this case, the blending amount of arginine is preferably strengthened by an amount of about 110 to 200% with respect to the blending amount of arginine in the existing total amino acid composition.
By strengthening the compounding amount of this arginine, it is difficult to cause liver function abnormalities even if administered during postoperative invasion, so that conventional break-in administration and / or step-up administration (acclimation period) is not required It is very specific.

  Each amino acid to be contained does not necessarily need to be used as a free amino acid, and may be in the form of a salt acceptable for pharmaceuticals or foods and drinks, for example, an inorganic acid salt, an organic acid salt, an ester that can be hydrolyzed in vivo, You may use with forms, such as a N-acyl derivative. Further, it may be used in the form of peptides in which the same or different amino acids are peptide-bonded.

In the transfusion for central intravenous administration of the present invention, the above-mentioned carbohydrates and amino acids are basically the basis of total calories. In this case, it was found that the ratio of the non-protein calorie and the dose of nitrogen in the infusion preparation (Cal / N ratio) should be in the range of 90 to 160.
Regarding the Cal / N ratio in the total calories, the high calorie infusion solution used in the conventional central parenteral nutrition therapy shows a value of 160 or more because it contains a large amount of carbohydrates. However, in the present invention, the Cal / N ratio shows a value of 160 or less by reducing the sugar content to a level corresponding to the total required calories and then adding the necessary amount of amino acid on the day. Even if it happened, the nutritional effect of the infusion preparation itself was not changed.

In addition, in the infusion for central intravenous administration provided by the present invention, the total water content is preferably in the range of 1400 to 1800 mL, more preferably 1500 to 1700 mL.
In conventional infusion preparations for central intravenous administration, the daily dose is 2000 to 2400 mL, and the total amount of water is inevitably high. Therefore, when an antibiotic or an anticancer agent is administered in combination as a drug at the time of postoperative invasion, the total amount of water to be administered is well over 2000 mL. This amount of water places a considerable burden on the kidneys for patients whose visceral function during postoperative invasion is reduced.
In the present invention, it is possible to reduce the burden on the kidney and further accelerate recovery from postoperative invasion.

In the above-mentioned basic intravenous infusion preparation of the present invention, vitamins are preferably further added from the viewpoint of nutritional management.
Examples of such vitamins include vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin A, vitamin D, vitamin E, vitamin K, vitamin H, folic acid, pantothenic acids, nicotinic acids, and the like. it can. By using these vitamins, it is possible to realize maintenance and improvement of nutritional status at an early stage.

  As for the vitamins, the following 13 types of vitamins based on an AMA prescription in which the amount of vitamin B1 and vitamin B6 is increased based on the American Medical Association Guidelines (1975) are preferably contained. In particular, vitamin B1 is a vitamin necessary for facilitating sugar metabolism, and in particular, it can prevent the occurrence of lactic acidosis and Wernicke encephalopathy during vitamin high-calorie infusion. As vitamin B1 derivatives, thiamine derivatives such as prosultiamine, actiamine, thiamine disulfide, fursultiamine and salts thereof conventionally used for infusion can also be used.

  To the infusion preparation of the present invention, 13 kinds of vitamins can be appropriately added together with appropriate additives to a container equipped with 1 to 3 rooms. As other physiological effects and deficiency symptoms of vitamins, vitamin B2 is related to sugar, amino acid and lipid metabolism, and ocular symptoms, stomatitis and dermatitis are known as deficiency symptoms. Vitamin B6 is mainly related to amino acid metabolism and hemoglobin synthesis, and dermatitis around the eyes and mouth, glossitis, anemia, and peripheral neuritis are known as deficiency symptoms. Vitamin B12 is involved in DNA and protein synthesis, hematopoiesis and nerve function, and known deficiency symptoms include pernicious anemia, pancytopenia, peripheral neuritis and the like. Nicotinic acid is involved in peripheral vasodilation and redox reactions, and pellagra (dermatitis, diarrhea, dementia) and anorexia are known as deficiency symptoms. Pantothenic acid is involved in fatty acid / steroid metabolism and carbohydrate oxidation. Known deficiency symptoms include headache, malaise, movement disorders, muscle spasms, gastrointestinal disorders and dermatitis.

  Biotin is involved in sugar, fatty acid and amino acid metabolism, and dermatitis, hair loss, central nervous system ataxia and the like are known as deficiency symptoms. Folic acid is involved in amino acid metabolism and hematopoiesis, and megaloblastic anemia is known as a deficiency symptom. Vitamin C is involved in intercellular supporting tissue / collagenous fibrosis, amino acid / lipid / folate metabolism and hematopoiesis. Deficiency symptoms include scurvy, anemia, wound healing delay, bone growth failure, weakness / malaise, anorexia The skin is dry.

  On the other hand, as for fat-soluble vitamins, vitamin A is involved in maintaining ocular function, protecting epithelial mucosa, growth and bone development, and deficiency symptoms include night blindness, dry eye, softening of cornea, keratinization of skin mucosa, growth / reproductive dysfunction Etc. are known. Vitamin D is known to have anti-rickety factor, Ca / P absorption / utilization regulation, bone mineralization, and the like. Vitamin E is involved in membrane stability / antioxidation, cell proliferation, antithrombosis / arteriosclerosis, and known deficiency symptoms include hemolytic anemia, lipid peroxide production, and the like. Vitamin K is involved in prothrombin synthesis, blood coagulation ability, increased Ca permeability, and the like, and bleeding is known as a deficiency symptom. When it is necessary to take warfarin, which is a blood coagulation inhibitor, it is necessary to refrain from administration because vitamin K antagonizes its action.

  At the time of high calorie infusion, vitamin deficiency and excess are easily caused, and not only vitamin B1 but also patients who need high calorie infusion, it is not enough to take oral intake. The amount should be considered inadequate and should be supplemented with at least the following amounts of vitamins: The American Medical Association (AMA) standard does not contain vitamin K. In addition, the existing high-calorie infusion comprehensive vitamin preparation contains all 13 types, most of which have been developed based on AMA standards, and each vitamin content of the existing comprehensive vitamin preparation may be used.

  Table 2 below shows the amounts of 13 types of vitamins based on American Medical Community (AMA) guidelines (1975). Vitamin B1 and vitamin B6 were revised in 1985.

出典：静脈経腸栄養ガイドライン、日本静脈・経腸栄養研究会編、へるす出版（東京）、１９９８年

Source: Parenteral Enteral Nutrition Guidelines, Japan Parenteral and Enteral Nutrition Study Group, Helus Publishing (Tokyo), 1998

Trace elements can also be added to the infusion preparation for central intravenous administration of the present invention. The trace element in the present invention is a metal element which is indispensable for a living body although it is a trace amount. Among them, in particular, inorganic salts and organic salts of zinc, copper and selenium which are deficient during postoperative invasion can be mentioned. This trace element supplementation is expected not only to prevent deficiency, but also to greatly contribute to the promotion of protein synthesis and the maintenance and improvement of nutritional status. What is necessary is just to mix | blend each trace element in consideration of a daily required amount.
Particularly in the present invention, as a trace element, for example, a trace element in the range shown in Table 3 below is preferably blended.

  The pH of the infusion preparation for central intravenous administration of the present invention is preferably adjusted to 5-6. In order to adjust the pH, a pH adjuster usually used in the infusion field can be used. As the pH adjuster, inorganic acids such as hydrochloric acid, organic acids such as acetic acid and citric acid, and gases such as carbon dioxide can be used. In particular, use of an organic acid is preferable.

  The infusion preparation for central intravenous administration of the present invention is preferably filled in a container, and is preferably separated and filled into a plurality of chambers partitioned by isolation means capable of communicating each component as necessary.

When glucose, which is a reducing sugar, is blended as the sugar, since the amino acid and glucose may cause a Maillard reaction over time, it is preferable that the amino acid and the sugar (glucose) are stored separately. In order to avoid this problem, for example, the first chamber may be filled with a solution containing an amino acid, and the second chamber may be filled with a solution containing an electrolyte component and a saccharide.
When vitamins are contained, a third chamber is preferably provided, and a solution containing vitamins is preferably filled there.

  As a method of partitioning into each chamber, a method of partitioning with a seal part that can be peeled off by pressing from the outside during use is preferable. The liquids separated and accommodated in the plurality of chambers partitioned by the communicating isolating means can be mixed and used after communicating at the time of administration. In this case, considering the liquidity of the liquid stored in each chamber of the container, each component is separately stored in a plurality of chambers partitioned by isolation means that can be communicated by the above-described means, and is blended at the time of administration. Good. Also, some electrolytes such as trace elements and vitamins may be stored spatially separated from sugars, amino acids and other electrolytes.

  The material constituting the container body of the infusion preparation for central venous administration 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 being stored at low temperature. 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 divide the container 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 produced using a communication member having a thin portion communicating with each other (Japanese Patent Laid-Open Nos. 2000-167022 and 2001-87350).
In addition, when separating and enclosing medicinal liquids such as vitamins 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. 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 (registered trademark)] and cyclic olefin copolymers.

In the present invention, it is possible to fill the above-mentioned container with all of the daily dose. However, since the capacity when filled is large, the daily dose is divided into two bags and filled. It is good.
Accordingly, the present invention is also an infusion preparation for central intravenous administration characterized in that the daily dose is divided into two bags and filled.

  The infusion preparation for central venous administration provided by the present invention reduces the amount of sugar to be contained, particularly by reducing the total calories in the infusion preparation to the necessary calories for nutrition maintenance during postoperative invasion. Therefore, the sugar load at the time of step-up is reduced, and the occurrence of liver damage can be reduced.

  In recent years, with the increase in the number of elderly people, both the calorie content and the water content tend to decrease, the nutritional status of the surgical patient is not so bad, the conventional calorie of 2000-2400 Kcal is not necessary, and IVH The period of practicing is being shortened, and it is becoming possible to promptly shift to peripheral parenteral nutrition, enteral nutrition, and oral intake and to discharge early after surgery.

  Considering the transition of nutrition therapy in the future, the IVH composition is within the range of 1000 to 1400 Kcal daily, the amino acid content is 45 to 75 g, the water content is 1400 to 1600 mL, and Cal / N IVH having a ratio in the range of 90 to 160 is a composition that will become more mainstream in the future. Furthermore, by using this composition, it is not necessary to perform break-in administration and / or step-up administration (acclimation period) to carbohydrates, and as a side effect at the time of IVH administration, liver function abnormality and hyperglycemia can be expected to be reduced. As a characteristic of the amino acid composition, it is possible to expect a reduction effect on abnormal liver function at the time of IVH administration by strengthening arginine.

  These excellent effects will be described below by describing specific test examples instead of the examples, but the present invention is not limited to these examples.

  Table 4 below shows the compositions of the test liquid of the present invention used in each test example and the commercial high calorie infusion kit formulations of the control liquids 1 to 5.

Test Example 1: Pharmacological effect test 1 Confirmation of nutritional effect In order to confirm the nutritional effect of the test liquid of the present invention shown in Table 4, the following animal experiments were conducted. In addition, the commercially available high calorie infusion kit formulation of Table 4 was used as a control solution.
Rats fasted overnight (9-week-old male: 6 to 7 animals per group, weight 198.2 to 212.4 g) were placed with a silicone catheter from the right external jugular vein to the origin of the right upper vena cava under penbarbital anesthesia. The infusion solution was continuously administered for 7 days without restriction.
Test solution and control solution 1 are continuously administered in the same infusion for 7 days, and control solution 1 is maintained as control solution 1 → control solution 2 in consideration of the conventional management method of high-calorie infusion preparations for the first 3 days. After administration, the infusion solution was switched, and then the control solution 2 was continuously administered for 4 days.
The flow rate was 2.5 mL / hr.

The amount of change in body weight for 7 days is shown in FIG. As is apparent from the figure, the administration of all the infusions was negative, but the degree was similar to that of the control solution 1 → control solution 2 and smaller than that of the control solution 1 due to the administration of the test solution. Met.
The cumulative nitrogen balance is shown in FIG. As can be seen from the results in the figure, the administration of the test solution showed a significantly higher value compared to the administration of the control solution 1, and was also higher than the control solution 1 → the target solution 2. .

  From this test result, the test solution of the present invention shows an excellent nutritional effect compared to the control solution 1 which is the starting solution at the start of the high calorie infusion, and in the conventional management method of the high calorie infusion preparation, the infusion is switched, It was clarified that the nutritional effect was equivalent to that of the control solution 2 (the maintenance solution (No. 2 solution)).

Test Example 2: Pharmacological effect test 2 Effect of reducing liver function abnormality (Part 1)
In order to confirm the mitigating effect on liver function abnormalities during high calorie infusion, the following animal experiments were conducted.
The test solution and control solution 3 described in Table 4 were used as infusion agents.
A hypoxic model rat (6 weeks old male, 5 per group, body weight 192.2 to 211.6 g) that had been restricted to 85% of food intake and bred for 4 days under a pentobarbital anesthesia with a silicone catheter on the right From the external jugular vein, it was placed at the origin of the right upper vena cava, and the test solution and the control solution 3 were administered continuously for 5 days without restriction.
The administration rate was 3 mL / hr, and the control solution 3 as a maintenance solution was administered without acclimation of sugar (at the start, without using the start solution).
During the infusion administration period, blood was collected from the tail vein every day. After administration, blood was lethal from the abdominal vena cava under pentobarbital anesthesia, and the liver was removed.

Changes in blood glucose level, AST, and ALT during the infusion administration period are shown in FIG. 3, FIG. 4, and FIG. 5, respectively. As can be seen from the results, there was almost no change in blood glucose level and AST and ALT, which are indicators of liver damage in the blood, by administration of the test solution. AST and ALT increased after 3 days.
From this test result, it was revealed that the test solution, which is the infusion solution of the present invention, is an infusion agent that is less likely to cause abnormal liver function when the high-calorie infusion solution is performed compared to the control solution 3, which is a maintenance solution.

Test Example 3: Pharmacological effect test 3 Effect of reducing liver function abnormality (2)
As in Test Example 2, the following animal experiment was conducted using the control solutions 4 and 5 shown in Table 4 for the effect of reducing liver function abnormality during high-calorie infusion.
A hypotrophic model rat (7-week-old male, 6-7 rats per group, body weight 210-217.9 g) prepared and bred with a restriction of 85% of the feed amount was similarly placed with a catheter, and an infusion solution without restriction Was administered continuously for 7 days as follows.
The test solution and the control solution 5 are continuously administered in the same infusion solution for 7 days, and the control solution 4 is continuously maintained as the control solution 4 → control solution 5 in consideration of the conventional management method of the high calorie infusion preparation. After administration, the infusion solution was switched, and then the control solution 5 was continuously administered for 5 days.
The flow rate was 3 mL / hr.

Changes in AST and ALT during the infusion administration period are shown in FIGS. 6 and 7, respectively.
As can be seen from the results, when the control solution 5 was administered, AST and ALT, which are indicators of liver damage, increased on the third day, but the administration of the test solution and the control solution 4 → the control solution 5 There was no change.
From this test result, it was clarified that the test solution, which is the infusion solution of the present invention, is an infusion agent that is less likely to cause liver function abnormalities when the high-calorie infusion solution is performed compared to the control solution 5 that is a maintenance solution. It was also revealed that abnormal liver function at the time of high calorie infusion can be reduced by setting the acclimatization period by sugar break-in administration as in Control Solution 4 → Control Solution 5.

Test Example 4: Pharmacological effect test 4 Examination of Cal / N ratio In order to find the optimum Cal / N ratio of the infusion preparation of the present invention, the following animal experiment was conducted.
An infusion solution containing the total calorie content (620 kcal / 800 mL) at a constant ratio of glucose and nitrogen content (amino acid content) as shown in Table 5 below was used. After a laparotomy was performed under pentobarbital anesthesia in a hypotrophic model rat (male 9-week-old male, weight 243.6-314.5 g) that had been restricted to 85% of food intake and bred for 4 days, a silicon catheter Was placed from the right external jugular vein to the origin of the right upper vena cava, and each test solution was continuously administered for 7 days without restriction. The flow rate was 3.0 mL / hr. Urine volume measurement and urine collection were performed every day during the infusion administration period.

The amount of change in body weight for 7 days is shown in FIG. Although weight loss was observed only when free of amino acids, it remained positive by administration of amino acids (NPC / N300 to 75), and was significant relative to free of amino acids. The cumulative nitrogen balance is shown in FIG. Amino acid-free negative balance was shown, positive balance was maintained by administration of amino acids, the degree of positive balance increased as NPC / N300 decreased, and was almost flat with NPC / N110. Table 6 shows BUN values after administration of each infusion solution in the blood biochemical examination. In NPC / N75, the BUN value increased to a level similar to that of the fed rat.
From these test results, it was revealed that a Cal / N ratio of 110 is optimal in the composition of the infusion preparation of the present invention.

Mean ± SD (n = 4-5)
*: P <0.05 vs. amino acid free (Tukey-Kramer)
#: P <0.05 vs. NPC / N 300 (Tukey-Kramer)
&: P <0.05 vs. NPC / N 150 (Tukey-Kramer)
$: P <0.05 vs. NPC / N 110 (Tukey-Kramer)
Free feeding: Excluded from the test

Test Example 5: Pharmacological effect test 5 Effect of reducing arginine-enhanced amino acid composition on liver function abnormality As an amino acid composition in the infusion preparation of the present invention, arginine-enhanced amino acid composition confirms the effect of reducing liver function abnormality upon high-calorie infusion In order to do this, the following animal experiments were conducted.
As the infusion agent, a test solution and a control solution having an infusion composition described in Table 7 below were used.
The infusion composition is a composition containing a sugar concentration of 17.5%, an amino acid concentration of 3%, and an electrolyte for both the test solution and the control solution. Of these, the amino acid composition is the existing total amino acid composition for the test solution. It was set as the composition which strengthened 20% arginine with respect to the thing (the total amount of both amino acids is constant: 30 g / L).

  A hypoxic model rat (9-week-old male, 1 group, 7 animals, body weight 200.2-223.9 g) that had been kept for 7 days with a restriction of 85% of food intake under pentobarbital anesthesia with a silicone catheter on the right The test solution was placed from the external jugular vein to the origin of the right upper vena cava, and each test solution was continuously administered for 3 days without restriction. The flow rate was 300 mL / kg body weight per day. During the infusion administration period, blood was collected from the tail vein every day.

The AST value during the infusion administration period is shown in FIG. 10, and the ALT value is shown in FIG.
As can be seen from these results, administration of a test solution containing an amino acid composition in which the blending amount of arginine was strengthened caused AST and ALT, which are blood liver injury indicators, to be lower than those in the control solution.
From this test result, the test infusion containing the amino acid composition reinforced with arginine, which is the infusion of the present invention, is less likely to cause liver function abnormality at the time of high calorie infusion compared to the control solution containing the existing amino acid composition. It became clear that.

Test Example 6: Pharmacological effect test 6-Effect of reducing arginine-enhanced amino acid composition on liver function abnormalities-Dose study of arginine As an amino acid composition in the infusion preparation of the present invention, the amino acid composition further strengthened with arginine is a liver at the time of high-calorie infusion. The reduction effect on functional abnormality was confirmed.
As the infusion agent, two test solutions and a control solution described in Table 8 below were used.
Test solutions 1 and 2 containing a sugar concentration of 17.5%, an amino acid concentration of 3%, and an electrolyte, wherein the arginine content was enhanced to 4.52 g / L and 5.43 g / L in the amino acid composition with respect to the control solution, respectively. The total amount of amino acids was constant: 30 g / L.
A hypoxic model rat (9-week-old male, 1 group, 7 animals, body weight 195.2-218.2 g) that had been restricted to 85% of food intake and bred for 7 days under a pentobarbital anesthesia with a silicone catheter on the right The test solution was placed from the external jugular vein to the origin of the right upper vena cava, and each test solution was continuously administered for 3 days without restriction. The flow rate was 300 mL / kg body weight per day. During the infusion administration period, blood was collected from the tail vein every day.

The transition of AST during the infusion administration period is shown in FIG.
From this result, in the test liquids 1 and 2 in which arginine was strengthened, the blood liver injury index (AST) changed at a lower value than the control liquid, and the effect was strong.
From this test result, it was clarified that an amino acid composition in which arginine is reinforced results in an infusion that hardly causes liver function abnormality.

Table 8: Infusion composition

As described above, according to the present invention, central parenteral nutrition management is performed that contains a carbohydrate, an electrolyte component, and an amino acid, and does not require a break-in administration and / or step-up administration (acclimation period) to the carbohydrate. An infusion formulation for central intravenous administration is provided.
That is, the infusion preparation for central venous administration provided by the present invention performs central venous nutrition management at the time of postoperative invasion with a single agent, and thus performs conventional administration to complicated carbohydrates and / or step-up management. The administration of the starting infusion is avoided, the convenience is improved, and the occurrence of medical errors due to erroneous administration can be avoided.
In addition, the total calorie content is reduced to the level required for maintaining nutrition during postoperative invasion, and the intestinal tract is activated by early administration of enteral nutrients or intake of meals (such as sputum). This makes it possible to quickly return to society, and its industrial utility is enormous.

It is a figure which shows the result of the test example 1, and is a figure which showed the weight change. It is a figure which shows the result of the test example 1, and is a figure which showed the cumulative nitrogen balance. (However, the legend in the figure is the same as in FIG. 1) It is a figure which shows the result of the test example 2, and is a figure which showed transition of the blood glucose level. It is a figure which shows the result of the test example 2, and is a figure which showed transition of the AST value. (However, the legend in the figure is the same as in FIG. 3) It is a figure which shows the result of the test example 2, and is a figure which showed transition of the ALT value. (However, the legend in the figure is the same as in FIG. 3) It is a figure which shows the result of the test example 3, and is a figure which showed transition of AST value. It is a figure which shows the result of the test example 3, and is a figure which showed transition of the ALT value. (However, the legend in the figure is the same as in FIG. 6) It is a figure which shows the result of the test example 4, and is a figure which showed the body weight change amount. It is a figure which shows the result of the test example 4, and is a figure which showed cumulative nitrogen balance. It is a figure which shows the result of the test example 5, and is a figure which showed transition of the AST value. It is a figure which shows the result of the test example 5, and is a figure which showed transition of the ALT value. It is a figure which shows the result of the test example 6, and is a figure which showed transition of AST during an infusion administration period.

Claims (6)

It consists of an amino acid composition containing at least glucose , an electrolyte, and essential amino acids. As a daily dose, the total calories are in the range of 1000 to 1400 Kcal, contain 55 to 75 g of amino acids, and the total water content is 1400 to 1800 mL. And the ratio of non-protein calories to administered nitrogen amount (Cal / N ratio) is in the range of 90 to 130, and the energy requirement during postoperative invasion of the digestive system or circulatory system is in a reduced state An infusion preparation for central venous administration , which is administered to a patient with reduced function, and is not subjected to a break-in administration and / or a step-up administration (acclimation period) to a carbohydrate . The infusion preparation for central intravenous administration according to claim 1, wherein the amino acid composition comprises a composition containing 30% by weight or more of branched chain amino acid (BCAA) in the amino acid composition . As amino acid composition, the daily dose is 3.0 to 7.0 g of L-isoleucine which is a branched chain amino acid (BCAA), 6.0 to 9.2 g of L-leucine and 2.4 to 2.4 of L-valine. The infusion preparation for central venous administration according to claim 2, which has an amino acid composition containing 10.0 g . The infusion preparation for central venous administration according to claim 1 or 2, wherein the amino acid composition is an amino acid composition containing arginine in an amount of 10 to 18% by weight of the daily dose of amino acid and fortifying arginine.   Furthermore, vitamins are contained, The infusion preparation for central vein administration of Claim 1, 2, or 3 characterized by the above-mentioned.   The infusion preparation for central intravenous administration according to claim 1, 2, or 3, further comprising trace elements.

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