JP2015067559A - Iron metabolism-improving infusion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an infusion which promotes reusing iron, reduces a concentration of intracellular free iron, inhibits production of hydroxy radical, and inhibits induction of DNA damage or apoptosis in patients who excessively accumulate iron by stagnation of reusing iron in vivo when performing intravenous nutrition.SOLUTION: The invention provides an intravenous hyperalimentation produced by containing choline as an iron metabolism-improving infusion. Choline is preferable to be a choline chloride or a CDP-choline.

Description

  The present invention relates to an infusion solution for improving iron metabolism that is used for patients who have stagnated in vivo reutilization of iron and have excessive iron accumulation during intravenous nutrition. More specifically, iron reuse can be reduced by administering it to patients with functional iron deficiency who have suppressed iron release from the reticuloendothelial system, excessive iron accumulation in cells, and high serum ferritin levels. It relates to a high-calorie infusion solution to be promoted.

Iron is an essential element involved in hemoglobin synthesis, whole body redox reactions, division and proliferation. Since iron causes oxidative stress when excessive, iron metabolism is skillfully controlled by a number of related molecules (Non-Patent Document 1). There are 3000 to 4000 mg of iron in the body, about 2/3 of which is erythrocyte hemoglobin iron, and most of the remainder is stored in the liver, kidney and bone marrow with iron binding proteins such as ferritin and hemosiderin as storage iron Has been. Some iron exists as free iron that is not bound to iron-binding proteins, and the concentration of free iron increases when the body becomes iron-rich. These free irons produce hydroxy radicals through the Fenton reaction and are associated with DNA damage and apoptosis induction (Non-patent Documents 2 and 3).
Serum ferritin is a part of the ferritin in the tissue released into the serum and reflects the stored iron in the tissue. Serum ferritin is low in an iron deficiency state and high in an iron excess state.
A characteristic of iron metabolism is that it does not have an active excretion route and most irons build a semi-closed circuit that can be reused. About 1 mg of iron is absorbed from the upper gastrointestinal tract per day, enters the blood, is combined with transferrin, and is transported throughout the body. Most of the iron used in the body is regenerated by erythrocyte hemoglobin iron by the reticuloendothelial system. It is covered by use. The average life span of erythrocytes is 120 days, and 20 mg of iron per day is processed by reticulomacrophages. Iron extracted from hemoglobin is re-entered into the blood and reused through ferroportin, the only iron exporter in the living body. When the release of iron from the reticulated system is suppressed, the reuse of iron stagnates, iron accumulates excessively as ferritin, and falls into functional iron deficiency where iron is deficient despite high serum ferritin .
However, at present, no solution is disclosed that promotes the reuse of iron that has accumulated excessively in the network.

Yutaka Takago et al .: Iron Overload and iron chelation therapy. 25-35 (2007) Katsuya Ikuta et al .: Blood Frontier. 21 (6), 23-30 (2011) Katsuya Ikuta et al .: Blood Frontier. 19 (2), 31-39 (2009)

  The present invention was made in view of such problems, and promotes the reuse of iron for patients in whom the reuse of iron in the living body is stagnant and the stored iron is increasing at the time of parenteral nutrition enforcement, Furthermore, it aims at avoiding the oxidative stress caused by iron accumulated in various organs and tissues.

Such an object is achieved by the present inventions (1) to (5) below.
(1) An iron metabolism improving infusion solution comprising an infusion agent containing choline.
(2) The infusion solution for improving iron metabolism according to (1) above, wherein the choline content is in the range of 0.4 to 4 g / L.
(3) The amino acid concentration in the infusion preparation is in the range of 20 to 70 g / L, and the following amino acid free form, derivative or salt is contained in the following range, as described in (1) or (2) above Infusions for improving iron metabolism.
Isoleucine 0.5-6.5g / L
Leucine 0.5-10.0 g / L
Valine 0.5-7.5g / L
Lysine 0.5-7.0g / L
Methionine 0.1 ~ 3.0g / L
Phenylalanine 0.5-6.0g / L
Threonine 0.1 ~ 4.0g / L
Tryptophan 0.1 ~ 2.0g / L
Glycine 0.1 ~ 5.0g / L
Alanine 0.5-7.5g / L
Arginine 0.5-8.5g / L
Histidine 0.5 ~ 6.0g / L
Proline 0.5-6.0g / L
Serine 0.5-4.5g / L
Tyrozine 0.05 ~ 1.0g / L
Cysteine 0.05-2.0g / L
Aspartic acid 0.05-4.0 g / L
Glutamic acid 0.05-4.0 g / L
(4) The above-mentioned (contains at least one kind selected from the group consisting of glucose, fructose, xylitol, sorbitol, maltose, and glycerol as the sugar, wherein the sugar concentration in the infusion solution is in the range of 70 to 250 g / L. The iron metabolism improving infusion solution according to any one of 1) to (3).
(5) The iron metabolism improving infusion agent according to any one of (1) to (4), wherein the choline is choline chloride or CDP-choline.

  As described above, the present invention is an iron metabolism-improving infusion solution containing choline, and according to the iron metabolism-improving infusion agent of the present invention, the reuse of body iron is stagnant and iron is contained in the body. It has the effect of promoting the reuse of iron for accumulated patients. In addition, the iron metabolism-improving infusion of the present invention reduces the concentration of free iron in the cell by promoting the reuse of iron that has accumulated excessively in the reticulum system, suppresses the production of hydroxy radicals, It suppresses the induction of damage and apoptosis.

It is a figure which shows the result of the serum iron of Test Example 1. It is a figure which shows the result of the total iron binding ability of Test Example 1. It is a figure which shows the result of the transferrin saturation of Test Example 1. It is a figure which shows the result of the serum ferritin of Test Example 1.

The iron metabolism improvement infusion preparation provided by the present invention is an iron metabolism improvement infusion preparation comprising choline. More specifically, the iron metabolism improving infusion preparation contains choline chloride or CDP-choline as choline, and further contains a combination of glucose, amino acids, electrolytes and vitamins. Known physiological actions of choline include structural integrity of the cell membrane and intracellular signaling, neurotransmitters in cholinergic neurons, and functions as a methyl group donor. This time, we have discovered that there is a new iron metabolism improvement effect due to functional iron deficiency.
That is, the present invention is an iron metabolism-improving infusion agent containing choline as an active ingredient, and is administered to a patient with high serum ferritin that has suffered from functional iron deficiency due to stagnation of iron reuse during intravenous nutrition. , Can promote the reuse of iron. Moreover, by reusing excessively accumulated iron, it is possible to reduce the free iron concentration in the cell, suppress the production of hydroxy radicals, and prevent DNA damage and apoptosis induction.

Examples of choline contained in the iron metabolism-improving infusion solution of the present invention include choline chloride, CDP-choline, choline bitartrate, choline bicarbonate, choline phosphate, choline dihydrogen citrate, phosphatidylcholine, preferably chloride. Choline or CDP-choline.
The infusion in the iron metabolism improving infusion of the present invention is preferably a high calorie infusion from the viewpoint of nutritional status improvement, and the sugar concentration is preferably 70 to 250 g / L, and 120 to 250 g / L is more preferable. Moreover, it is preferable that an amino acid is mix | blended with the said infusion agent, and it is preferable that an amino acid concentration is 20-70 g / L in that case. Moreover, it is preferable that electrolyte and vitamin are mix | blended with the said infusion solution. Furthermore, the infusion can be adjusted to a desired pH with a pH adjuster. In the present invention, succinic acid, (dilute) hydrochloric acid, sodium hydroxide and the like can be used as the pH adjuster, and succinic acid is preferably used. . The pH of the infusion solution is preferably set to a value at which the infusion agent whose pH is adjusted is stably stored and does not adversely affect the living body at the time of administration. Specifically, the pH is 3.8 to 7.0, preferably 4.0 to 6.7.
The iron metabolism improving infusion preparation of the present invention is preferably housed in a container such as an infusion bag, and the infusion bag is preferably formed from a synthetic resin such as polypropylene or polyethylene. These components can be blended or provided as part of the layer components of the multilayer bag.
In addition, as a liquid volume of the iron metabolism improvement infusion agent of this invention, it is preferable to set it as 500-2500 mL, and it is more preferable if it is 900-2000 mL.

Hereinafter, the present invention will be described with reference to specific test examples and examples, but the present invention is not limited thereto.
(Example 1) Each component listed in Table 1 is dissolved in water for injection, and an infusion containing 1 g / L of choline chloride is prepared by adjusting the pH to 4.5 to 5.9 with citric acid hydrate, and made of plastic. The infusion bag was filled.
(Comparative Example 1) A choline chloride-free infusion solution was prepared and filled in a plastic infusion bag in the same manner as in Example 1 except that each component was listed in Table 2.

(Test Example 1) An animal experiment was conducted using the infusion solution for parenteral nutrition prepared in Example 1 and Comparative Example 1. The animals used were rats fed with a protein-free diet for 2 weeks. In this model, serum ferritin increased to 2634 ± 620 ng / mL (n = 5) versus 1888 ± 361 ng / mL (n = 5) in healthy rats, while reticulocytes were 56 ± 11 ‰ (n Since it decreased to 6 ± 4 ‰ (n = 5) compared to = 5), it was judged to be a model for stagnation of internal iron reuse with reduced hematopoietic ability.
A catheter was placed in the right external jugular vein of these rats, and the infusions of Example 1 and Comparative Example 1 were continuously administered for 3 days under no restraint. The infusion dose was 406 mL / kg / day. After the administration of the infusion for 3 days, blood was collected from the abdominal aorta under isoflurane anesthesia, serum was separated, and serum iron, total iron binding ability and serum ferritin concentration were measured. Serum iron and total iron binding ability was measured by a colorimetric method, and serum ferritin was measured by an ELISA method. Transferrin saturation is a calculated value, and was calculated as serum iron / total iron binding capacity × 100. A t-test was performed between the two groups of Example 1 and Comparative Example 1, and p <0.05 was considered significant.
The results are shown in FIGS. The serum iron in Example 1 was 387 ± 101 μg / dL (n = 5), which was significantly higher than that in Comparative Example 1 (158 ± 29 μg / dL (n = 5) (FIG. 1)). The total iron binding capacity was 770 ± 15 μg / dL (n = 5) in Example 1, which was significantly higher than that of 694 ± 59 μg / dL (n = 5) in Comparative Example 1 (FIG. 2). The transferrin saturation was 50.4 ± 13.4% (n = 5) in Example 1, which was significantly higher than 22.6 ± 2.4% (n = 5) in Comparative Example 1 (FIG. 3). Serum ferritin was 1566 ± 233 ng / mL (n = 5) in Example 1, which was significantly lower than 2859 ± 782 ng / mL (n = 5) in Comparative Example 1 (FIG. 4).
When the infusion containing the choline of Example 1 was administered, the serum iron, total iron binding ability and transferrin saturation increased significantly compared to Comparative Example 1 without the choline, and the serum ferritin decreased significantly. From these facts, when the infusion of Example 1 formulated with choline was administered to the internal iron reuse stagnation model, the reuse of stored iron was promoted and the stored iron was released into the blood. As a result, serum iron and transferrin saturation The serum ferritin was thought to have decreased. Moreover, it became clear that the administration of the infusion solution of Example 1 also increased the total iron binding ability (indicating the total amount of iron that can bind to transferrin) and promoted the reuse of stored iron to improve the functional iron deficiency state.

(Example 2) In the first chamber of the plastic infusion bag in which two chambers were formed by the isolating means, each component described in Table 3 was dissolved in water for injection, and the pH was adjusted to 4.5 to 5.9 with citric acid hydrate. By adjusting, sugar, electrolyte, vitamin and amino acid solutions were prepared and filled. In the second chamber, choline chloride listed in Table 4 was dissolved in water for injection to prepare and fill a choline chloride solution. The composition shown in Table 5 is obtained when the separating means is released and both liquids are mixed at the time of use.

(Example 3) In the first chamber of the plastic infusion bag in which two chambers are formed by the isolating means, the sugar / electrolyte and vitamin solution are added in the same manner as in Example 2 except that each component is listed in Table 6. Prepared and filled. Further, an amino acid and a choline chloride solution were prepared and filled in the same manner as in Example 2 except that each component was listed in Table 7 in the second chamber. The composition shown in Table 5 is obtained when the separating means is released and both liquids are mixed at the time of use.

Claims (5)

An infusion for improving iron metabolism comprising an infusion containing choline. The iron metabolism improving infusion preparation according to claim 1, wherein the choline content is in the range of 0.4 to 4 g / L. The infusion solution for improving iron metabolism according to claim 1 or 2, wherein the amino acid concentration in the infusion solution is in the range of 20 to 70 g / L and the following free form, derivative or salt of amino acid is contained in the following range. .
Isoleucine 0.5-6.5g / L
Leucine 0.5-10.0 g / L
Valine 0.5-7.5g / L
Lysine 0.5-7.0g / L
Methionine 0.1 ~ 3.0g / L
Phenylalanine 0.5-6.0g / L
Threonine 0.1 ~ 4.0g / L
Tryptophan 0.1 ~ 2.0g / L
Glycine 0.1 ~ 5.0g / L
Alanine 0.5-7.5g / L
Arginine 0.5-8.5g / L
Histidine 0.5 ~ 6.0g / L
Proline 0.5-6.0g / L
Serine 0.5-4.5g / L
Tyrozine 0.05 ~ 1.0g / L
Cysteine 0.05-2.0g / L
Aspartic acid 0.05-4.0 g / L
Glutamic acid 0.05-4.0 g / L The sugar concentration in the infusion preparation is in the range of 70 to 250 g / L, and contains at least one selected from the group consisting of glucose, fructose, xylitol, sorbitol, maltose, and glycerol as sugar. The infusion solution for improving iron metabolism according to any one of the above. The iron metabolism improving infusion according to any one of claims 1 to 4, wherein the choline is choline chloride or CDP-choline.

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