JP2008050277A - Composition for treating sideropenic anemia - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composition for mitigating, ameliorating or treating sideropenic anemia or latent sideropenic anemia. <P>SOLUTION: The composition comprises 2 mg or more of iron and more than 1 g but not more than 12 g of at least one amino acid selected from the group consisting of isoleucine, valine, leucine and arginine. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a composition for reducing, ameliorating or treating iron deficiency anemia or latent iron deficiency anemia.

Iron deficiency anemia is the most common nutrient deficiency in the world, and it is said that 25-50% of people in developing countries and 10-20% of people in developed countries are affected.
About 70% of iron exists as hemoglobin (Hb) in vivo, and has a function of transporting oxygen throughout the body. Such iron is called functional iron. The remaining 30% is substantially stored in organs such as the liver and spleen and is called stored iron. When iron in the body is insufficient, Hb is made by breaking up stored iron. Furthermore, when the iron deficiency continues and the stored iron is depleted, functional iron is used, resulting in latent iron deficiency anemia. Furthermore, if the state of iron deficiency continues and the stored iron and functional iron are depleted, iron deficiency anemia results. In order to reduce, ameliorate, or treat these symptoms, it is essential to take iron. However, when iron is taken, the amount of functional iron first increases, and then the amount of stored iron increases. Therefore, in order to reduce, ameliorate, or treat iron deficiency anemia or latent iron deficiency anemia, it is desired that not only functional iron but also stored iron be sufficiently present in the body.
On the other hand, since iron is poorly absorbed, long-term ingestion is necessary. In addition, iron intake may cause gastrointestinal disorders such as vomiting, diarrhea, and loss of appetite. Therefore, it is desired to shorten the intake period as much as possible or to reduce the intake amount as much as possible.
So far, administration of iron and proline in combination to anemia model rats has promoted Hb recovery (Non-patent Document 1), and the blood hemoglobin concentration of athletes who have eaten normally has five types of amino acids (arginine, Glutamine, valine, isoleucine, leucine) intake (Patent Document 1), glutamine or valine promotes iron absorption (Patent Document 2, Non-Patent Document 2), Arginine intake causes blood in patients with renal anemia It has been reported that medium hemoglobin concentration increases (Patent Document 3).

JP 2002-3372 International Patent Publication 2006/046880 A1 International Patent Publication 2005/089743 A1 J. Nutr Sci Vitaminol, 49, 7-12, 2003. Br. J. Nutr. (1975), 33, 351.

  An object of the present invention is to provide a composition for reducing, improving or treating iron deficiency anemia or latent iron deficiency anemia.

As a result of intensive studies to find a composition for reducing, ameliorating, or treating excellent iron deficiency anemia, the present inventors have selected from the group consisting of a specific amount of iron and isoleucine, valine, leucine and arginine. In combination with at least one amino acid, it has been found that it has an excellent alleviation, amelioration or therapeutic effect of iron deficiency anemia or latent iron deficiency anemia, and the present invention has been completed.
That is, the present invention provides a composition containing 2 mg or more of iron and at least one amino acid selected from the group consisting of isoleucine, valine, leucine and arginine in an amount of 1 to 12 g.

The present invention also reduces or improves iron deficiency anemia or latent iron deficiency anemia comprising 2 mg or more of iron and at least one amino acid selected from the group consisting of isoleucine, valine, leucine and arginine. Alternatively, a composition for treatment is provided.
The present invention also reduces, ameliorates or treats iron deficiency anemia or latent iron deficiency anemia comprising 2 mg or more of iron and at least one amino acid selected from the group consisting of isoleucine, valine, leucine and arginine. Provided is a use for producing a composition for

According to the present invention, iron deficiency anemia or latent iron deficiency anemia can be reduced, ameliorated or treated, reduced willingness to work with anemia, fatigue, shortness of breath, standing dizziness, palpitation, headache, Clinical symptoms such as stiff shoulders and coldness can be improved.
According to the present invention, the iron intake period until recovery can be shortened, or the amount of iron intake can be reduced, so that digestive tracts such as vomiting, diarrhea, and anorexia associated with iron intake It can reduce, ameliorate, or treat iron deficiency anemia or latent iron deficiency anemia with almost no side effects such as disability.
Furthermore, according to the present invention, since it can be easily taken every day at home, it is possible to reliably reduce, improve or treat iron deficiency anemia or latent iron deficiency anemia.

<Iron (iron agent)>
Iron that can be used in the present invention is a salt with an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, a salt with an organic carboxylic acid such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid or succinic acid. Further, it can take the form of an iron complex composed of a salt with an organic sulfonic acid such as methanesulfonic acid or p-toluenesulfonic acid and a chelating agent such as EDTA or DTPA or a protein such as transferrin or lactoferrin.
The amount of iron in the composition of the present invention is 2 mg or more, preferably 3 to 10 mg. In addition, when taking the form of a salt and a complex, it means that the amount when converted to an iron element is within the above range. When the amount of iron is within such a range, it is preferable from the viewpoint of reducing the side effects caused by the required amount of human iron and iron intake.

<Amino acid>
The amino acid used in the present invention is at least one amino acid selected from the group consisting of isoleucine, valine, leucine and arginine. These amino acids may be in any form of a free form, a salt, and a solvate. Examples of the salt include, for the carboxyl group in the formula, ammonium salt, salt with alkali metal such as sodium and potassium, salt with alkaline earth metal such as calcium and magnesium, aluminum salt, zinc salt and triethylamine. , Salts with organic amines such as ethanolamine, for basic groups, salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, Examples thereof include salts with organic carboxylic acids such as succinic acid and salts with organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid. Examples of solvates include hydrates and alcohol adducts. These amino acids may be any of L-form, D-form, DL-form, and a mixture of L-form and D-form in any ratio. Needless to say, these amino acids can be used in combination of two or more of the above substances.
The total amount of amino acids in the composition of the present invention, that is, the amount when the amino acid is a single type, and the total amount when there are two or more amino acids. The total amount of amino acids is preferably 2 g or more, and more preferably 4 g or more. The upper limit of the total amount of amino acids is preferably 12 g or less, and more preferably 10 g or less. Such a range was set by estimating the amount of effect in humans based on the amino acid dose and the amount of ingested protein at that time, which was shown in the Examples below, and can provide a sufficient anemia improvement effect. This is preferable.
The composition of the present invention may further contain glutamine. Among these, it is preferable to contain 3 types, isoleucine, valine, and leucine. These three amino acids are also referred to as BCAA (branched-chain amino acids). Containing these three amino acids is preferable from the viewpoint of promoting protein synthesis. It is also preferable to contain five kinds of isoleucine, valine, leucine, arginine and glutamine. Containing all five amino acids is preferable from the viewpoint of reducing the risk of amino acid imbalance.
In the composition of the present invention, isoleucine is 10-40 parts by weight, valine is 5-20 parts by weight, leucine is 10-35 parts by weight, arginine is 10-40 parts by weight, and glutamine is 10-40 parts by weight. preferable. When the amount of each amino acid is in such a range, it is preferable from the viewpoint of reducing the amino acid imbalance and expressing the effect of improving anemia.

The composition of the present invention may be absorbed into growing children, young women, especially pregnant women, people with chronic bleeding due to gastrointestinal bleeding or hemorrhoids due to ulcers or tumors, malabsorption after stomach or duodenal resection, etc. Can continuously reduce or ameliorate or treat iron deficiency anemia or latent iron deficiency anemia by administration or oral intake for several tens of days.
The dose or intake used for the above purpose is determined by age, body weight, etc., but usually the amount per day for an adult is 2 to 12 g for oral administration or intake, for parenteral administration or intake, The desired effect can be expected in the range of 2 g to 6 g, and the amount that provides the most excellent effect in this range can be selected. What is necessary is just to set the administration thru | or intake per time so that the administration thru | or intake per day may be in the said range, for example, it can be set as 2g-6g.
The composition of the present invention, in addition to the form of a pharmaceutical composition, is a food, health food, supplement, nutritional composition or a label with an indication that it is used for the reduction, improvement or treatment of the above-mentioned disease or condition It can also take the form of feed.

In the case of a pharmaceutical composition form, a pharmaceutically acceptable carrier or diluent, for example, cellulose derivatives such as carboxymethyl cellulose and ethyl cellulose, starches such as potato starch and corn starch, sugars such as lactose and sucrose, peanut oil, corn oil, Mixed with vegetable oils such as sesame oil, polyethylene glycol, alginic acid, gelatin, talc, etc., and oral preparations such as tablets, powders, pills, granules, capsules, syrups, subcutaneous injections, intravenous injections, intramuscular Injections, injections such as epidural injections, subarachnoid injections, external preparations such as nasal preparations, transdermal preparations, ointments, suppositories such as rectal suppositories and vaginal suppositories, infusions Etc. can be used.
The pharmaceutical composition of the present invention can be administered orally or parenterally, for example, enterally or intravenously.

In the case of a food form, it can be prepared by a conventional method using appropriate additives. Such additives include fruit juice, dextrin, cyclic oligosaccharide, sugar (fructose, glucose, liquid sugar, sucrose), acidulant, fragrance, powdered green tea powder, fats and oils, emulsifier that improves texture, collagen, Mention may be made of those usually used as components of health foods or functional foods such as whole milk powder, thickening polysaccharides and agar (in the case of jelly drinks).
The food of the present invention further comprises amino acids, vitamins, particularly vitamin B2, vitamin C, eggshell calcium calcium pantothenate, other minerals, particularly calcium, royal jelly, propolis, honey, dietary fiber, agaric, chitin, chitosan, capsaicin. In addition, a health food or a nutritional functional food can be prepared by blending polyphenols, carotenoids, fatty acids, mucopolysaccharides, coenzymes, antioxidants, and the like. These amounts are not particularly limited, but when the composition of the present invention takes the form of a nutritionally functional food, it is preferable to contain 0.33 to 12 mg of vitamin B2. When the composition of the present invention takes the form of a nutritional functional food, it preferably contains 24-1000 mg of vitamin C. In the case of calcium, it is preferable to contain 210 to 600 mg.

In the case of a supplement form, it can be mixed with an emulsifier, a pigment, a fragrance and the like to take a dosage form such as a tablet, a capsule or a liquid.
The composition of the present invention may be used as a feed for mammals such as pigs, cows, sheep, dogs, cats, mice, rats, monkeys, or birds such as chickens, pheasants, ostriches, etc., for example, methods well known in the art. Accordingly, it may be a solid or liquid additive for feed.
There is no special restriction | limiting in the product form of the composition of this invention, Any form may be sufficient if it is a form which can ingest the amino acid normally used. As such forms, powders, granules, tablets, liquids (beverages, jelly beverages), candy (chocolate etc.), bar-shaped or stick-shaped confectionery, or one of the above-mentioned types using appropriate excipients if taken orally Alternatively, a simple mixture of two amino acids can be mentioned. In addition, for intravenous administration, infusion solutions, aqueous solutions, and amino acid powders for adjustment at the time of use can be mentioned.

  Hereinafter, the present invention will be specifically described with reference to examples. The analysis items used here are blood hemoglobin concentration, hematocrit value, red blood cell count, serum ferritin concentration, which are generally measured to determine the degree of anemia diagnosis or anemia recovery, pharmacology and It is reasonable from the viewpoint of physiology. All the results of this time are expressed as mean ± standard error. In addition, in the statistical analysis, an average value between all test groups was tested for each measurement item using a T test (for the iron agent alone group) or a Tukey-Kramer multiple test. In the present specification, when “%” is simply described, it represents mass%.

Test Example 1 (Confirmation of blood components of anemia index when an iron-deficient anemia model rat is given with iron and various amino acids in combination)
(1) Outline of the test:
(A) It has been reported that an iron-deficient anemia model rat can be prepared by iron-deficient diet supply and hemoptysis for 3 weeks (Journal of Japanese Society of Nutrition 57, 89-97, 2004). Therefore, for this iron deficiency anemia model rat, by combining with iron preparations, 5 types of mixed amino acids (valine, isoleucine, leucine (hereinafter collectively referred to as BCAA), arginine, and glutamine are appropriately combined for 3 weeks. We investigated whether improvement of anemia could be promoted.
(B) The experiment was started using Wistar male rats aged 3 weeks.
(C) Forty-two rats were given an iron-deficient diet (containing 2 to 3 mg / kg as iron) for 3 weeks, and during that time, blood was phlebotomized three times in total (anemia induction period). After that, based on the blood hemoglobin concentration, hematocrit value, and red blood cell count, it was divided into the following 7 groups. (I) Iron agent alone group: iron deficient diet + ferrous citrate (ii) Proline combination group: iron deficiency Food + Ferrous citrate + Proline (iii) Alanine combination group: Iron deficient diet + Ferrous citrate + alanine (iv) Glycine combination group: Iron deficient diet + Ferrous citrate + Glycine (v) Combination of 3AA Group: iron deficient diet + ferrous citrate + proline & alanine & glycine (vi) 5AA combined group: iron deficient diet + ferrous citrate + BCAA & arginine & glutamine (vii) FRT composition AA combined group: iron deficient diet + Feeds corresponding to each ferrous citrate + ferritin protein composition amino acid were provided (anemia recovery period). Blood was collected after 3 weeks, and blood hemoglobin concentration, hematocrit value, red blood cell count and serum ferritin concentration were measured.

(D) Serum ferritin levels increased in all groups to which amino acids were added in combination with ferrous citrate compared to the iron agent alone group. In particular, the increase was remarkable in the group to which BCAA & arginine & glutamine was added, and the average value increased to about 3 times that of the iron agent alone group (see FIG. 1). The number of red blood cells also increased significantly in the 5AA combination group compared to the iron agent alone group (see Table 4).
(E) From the above results, it was confirmed that the intake of five types of amino acids BCAA, arginine, and glutamine together with the iron agent significantly increased both the red blood cell count and the serum ferritin concentration as compared with the iron agent alone group. An increase in red blood cell count is an indicator of functional iron recovery, and an increase in serum ferritin concentration indicates recovery of stored iron. Therefore, from this result, it is considered that when iron and five types of amino acids BCAA, arginine, and glutamine are used in combination, there is an effect of promoting recovery from iron deficiency anemia or iron deficiency.

(2) Details of experiment (a) Configuration of each group: shown in Table 1 below.

  (C) Feed preparation: The anemia induction feed was prepared according to the iron-deficient diet composition shown in Table 2 below. As for the anemia recovery period feed, 288 mg / kg of ferrous citrate (30 mg / kg as iron element) and 20 g / kg of various amino acids were mixed with the anemia induction period feed to prepare each group of feeds during the anemia recovery period. .

  (D) Amino acid ratio: BCAA & arginine & glutamine and ferritin protein composition amino acid ratios are shown in Table 3 below. The feed in the anemia recovery period of the 5AA combination group and the FRT composition AA combination group was added at 20 g / kg to the feed at this amino acid ratio.

(E) Animal breeding: Forty-two Wistar male rats (7 test groups x 6), 3 weeks old, were purchased from Charles River, Japan, 12 hours light / dark cycle (7: 00-19: 00), room temperature 25 Every two animals were bred in a cage in an animal breeding room at 0 ° C. After acclimatization for 1 week, an iron-deficient diet (containing 2 to 3 mg / kg as iron) was given, and about 1 ml of phlebotomy was performed once a week (anemia induction period). After 3 weeks, the blood hemoglobin concentration, hematocrit value, red blood cell count, and serum ferritin concentration were divided into 7 groups, and each group was divided into (i) ferrous citrate ( ii) ferrous citrate + proline (iii) ferrous citrate + alanine (iv) ferrous citrate + glycine (v) ferrous citrate + proline & alanine & glycine (vi) ferrous citrate Iron + BCAA & Arginine & Glutamine (vii) Various diets supplemented with ferrous citrate + ferritin protein composition amino acids were fed for 3 weeks (anemia recovery phase). Ferrous citrate was added to the feed at 288 mg / kg (30 mg / kg as iron element), and various amino acids were added at 20 g / kg.
(F) Measurement of blood component of anemia index: Blood was collected from the tail vein and posterior vena cava at the end of the anemia recovery period, and blood hemoglobin concentration, hematocrit value, red blood cell count and serum ferritin concentration were measured using the blood. . The blood hemoglobin concentration was measured immediately after blood collection using an automatic biochemical analyzer for animals (Fuji Photo Film, Fuji Dry Chem 5500). The hematocrit value and the red blood cell count were analyzed by a multi-item automatic blood cell counter (manufactured by Sysmex) using whole blood. The serum ferritin concentration was measured using a rat ferritin measurement kit (Panafarm Laboratories) after centrifuging the collected blood with a centrifuge (himacCF15D manufactured by Hitachi, Ltd.).
(G) Test results: The blood hemoglobin concentration, hematocrit value, and red blood cell count after giving iron agent and various amino acids in combination for 3 weeks are summarized in Table 4 below. * (I) Compared with the iron agent alone group, there is a significant difference at a risk factor P <0.05. The results of serum ferritin concentration are shown in FIG.

Test Example 2 (Confirmation of the amount of stored iron when an iron-deficient anemia model rat is given with iron and various amino acids in combination)
(1) Outline of the test:
(A) As in Test Example 1, anemia was induced by giving arginine, glutamine, isoleucine, leucine, valine or a mixture of these five amino acids together with an iron agent for 2 weeks to increase the iron content in the spleen and liver. We examined what to do.
(B) In the same manner as in Test 1, 3-week-old Wistar male rats were given an iron-deficient diet for 3 weeks to prepare anemia model rats, which were divided into 6 groups. Each group was given ferrous citrate alone or ferrous citrate + amino acid (arginine, glutamine, isoleucine, leucine, valine or a mixture of these five amino acids) for 2 weeks, and iron content in spleen and liver Was measured.

(C) It was confirmed that the group to which the amino acid was supplied increased the iron content in the spleen as compared with the iron agent alone group. In particular, the iron content in the spleen increased in the group to which a mixture of five amino acids was given (see Table 6). However, in this study, the iron content in the liver was not particularly changed by amino acid donation.
(D) From the above results, it was confirmed that the stored iron increased by ingesting five types of amino acids BCAA, arginine, and glutamine together with the iron agent compared to the iron agent alone group. Therefore, from this result, it was shown that the combined use of the iron agent and five types of amino acids BCAA, arginine, and glutamine promotes recovery from iron deficiency anemia or iron deficiency as compared with intake of the iron agent alone.

(2) Details of experiment (a) Configuration of each group: shown in Table 5 below.

  (C) Feed adjustment: The feed was adjusted in the same manner as in Test 1 (see Table 2). Ferrous citrate and various amino acids were added in the same amount as in Test 1.

  (D) Amino acid ratio: The amino acid ratio of BCAA & arginine & glutamine was adjusted in the same manner as in Test 1 (see Table 3).

(E) Animal breeding: Twenty-eight Wistar male rats (7 test groups × 4) were purchased from Charles River, Japan, and breeding was started under the same conditions as in Test 1. After one week of acclimation, anemia was induced in rats as in Test 1. After 3 weeks, the blood hemoglobin concentration, hematocrit value, red blood cell count, and serum ferritin concentration were divided into 7 groups, and each group was divided into (i) ferrous citrate ( ii) ferrous citrate + arginine (iii) ferrous citrate + glutamine (iv) ferrous citrate + isoleucine (v) ferrous citrate + leucine (vi) ferrous citrate + valine ( vii) Various diets supplemented with ferrous citrate + BCAA & arginine & glutamine were fed for 2 weeks (anemia recovery period).
(F) Measurement of iron content in spleen and liver: At the end of the anemia recovery period, the spleen and liver were excised from the rat under overanesthesia, and the weight was measured. They were dried using a freeze dryer and pulverized using an agate mortar. Iron was extracted from the sample ground with nitric acid and perchloric acid, and the iron ion concentration was measured using an atomic absorption photometer.
(G) Test results: Table 6 summarizes the iron content in the spleen after giving the iron agent and various amino acids in combination for 2 weeks. * Indicates that (i) there is a significant difference at a risk P <0.1 compared to the iron agent alone group. The iron content in the liver did not change with the addition of amino acids in this test.

FIG. 1 is a diagram showing the serum ferritin concentration at the end of the anemia recovery period in Test 1. FIG. Serum ferritin concentration is known to have a positive correlation with the amount of stored iron, and is used to estimate the amount of stored iron. * Indicates that there is a significant difference in risk factor P <0.05 compared to the iron agent alone group.

Claims (10)

  A composition comprising 2 mg or more of iron and at least one amino acid selected from the group consisting of isoleucine, valine, leucine and arginine in an amount of 1 g to 12 g.   Furthermore, the composition of Claim 1 containing glutamine.   The composition according to claim 1, wherein the amino acids are isoleucine, valine and leucine.   Amino acids are isoleucine, valine, leucine, arginine and glutamine, isoleucine 10-40 parts by weight, valine 5-20 parts by weight, leucine 10-35 parts by weight, arginine 10-40 parts by weight, glutamine 10 The composition according to claim 2, which is -40 parts by weight.   The composition according to any one of claims 1 to 4, which is in the form of an oral pharmaceutical, food, nutritional supplement or supplement.   To reduce, ameliorate, or treat iron deficiency anemia or latent iron deficiency anemia, comprising 2 mg or more of iron and at least one amino acid selected from the group consisting of isoleucine, valine, leucine and arginine Composition.   Furthermore, the composition of Claim 6 containing glutamine.   The composition according to claim 6, wherein the amino acids are isoleucine, valine and leucine.   Amino acids are isoleucine, valine, leucine, arginine and glutamine, isoleucine 10-40 parts by weight, valine 5-20 parts by weight, leucine 10-35 parts by weight, arginine 10-40 parts by weight, glutamine 10 The composition according to claim 7, which is -40 parts by weight.   A composition for reducing, ameliorating or treating iron deficiency anemia or latent iron deficiency anemia comprising 2 mg or more of iron and at least one amino acid selected from the group consisting of isoleucine, valine, leucine and arginine Use for manufacturing.

Images