JP5300186B2 - Milk-derived composition for pregnant women that suppresses increase in homocysteine concentration in blood - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a drug which is safe and sure and has good storability or a special use food or a nutritional supplement for a pregnant woman and is used to inhibit a rise in blood homocysteine (HCy) concentration in the duration of gestation relating to diseases in the duration of gestation. <P>SOLUTION: The drug for a pregnant woman which prevents or inhibits a rise in blood homocysteine concentration relating to diseases in the duration of gestation comprises a milk-derived phospholipid as an active ingredient and is a drug for a pregnant woman whose disease or state of disease relating to the above rise in blood cysteine concentration is intrauterine growth restriction, preeclampsia, neural tube dysraphism (NTD) or spina bifida. <P>COPYRIGHT: (C)2008,JPO&amp;INPIT

Description

  The present invention relates to the technical field of health and health foods, and more specifically to the technical field of food compositions for suppressing an increase in blood homocysteine (HCy) concentration during pregnancy.

  Homocysteine (hereinafter, homocysteine may be abbreviated as HCy, and total HCy may be abbreviated as tHCy) occurs in the metabolism of methionine, which is a kind of essential amino acid. An excessive increase in HCy concentration (hyperHCyemia) is associated with vascular endothelial damage and is known as a risk factor for heart disease and cerebral infarction.

  In normal pregnancy, blood homocysteine concentration in pregnancy (meaning plasma homocysteine concentration, hereinafter abbreviated as blood HCy concentration) began to decrease after conception, and it decreased to week 32 (the third It is said that it returns to the state before conception at the time of childbirth (Non-patent Document 1). The blood HCy concentration is related to diseases such as intrauterine fetal growth disorder, birth defects and pregnancy toxemia, and it has been reported that a high maternal blood HCy concentration reduces birth weight (non-patented). Reference 2).

  By the way, the necessity of folic acid intake during pregnancy has already been said for more than 40 years, and the relationship between folic acid deficiency and central nervous system inhibition has been pointed out, and neural tube closure disorder (NTD) In order to reduce the risk, folic acid intake is recommended before pregnancy. Neural tube closure disorders include congenital skull and spine closure disorders. For example, spinal cord is damaged due to spinal insufficiency, and spina bifida that causes neuropathy such as lower body paralysis. When the C667T mutation in the Methylene Tetrahydrofolate Reductase gene in the folic acid metabolism process becomes homozygous, the enzyme becomes unstable, the production of 5-methylH4 folic acid decreases, and the increase in blood homocysteine concentration is the cause of neural tube closure disorder. (Id.)

  Conventionally, in Japan, the incidence of spina bifida has been low, but this rate has recently increased, and the former Ministry of Health, The notification entitled “Promotion of Providing Appropriate Information on Intake of Folic Acid” encourages the intake of folic acid before pregnancy, but it is said that the intake of folic acid by pregnant women is low.

  On the other hand, HCy concentration is affected by choline intake. The deficiency of choline increases the HCy concentration (Non-patent Document 3). The amount of phosphatidylcholine (the main source of choline) intake by Japanese pregnant women estimated from the recent National Nutrition Survey (2001 and 2002 National Nutrition Survey) is 5-6 of the American Dietary Reference Intakes (DRI). (Non-Patent Document 4).

Clin Chem. 2004, 50 (8), 1406-1412 Clin Chem. 2004, 50 (8), 1293-1295 Pediatr Res. 2005, 57 (6), 777-782 J Nutr. 2005, 135 (6), 1451-1455

  Maintaining a proper HCy concentration during pregnancy is extremely important for the health of pregnant women and the health of newborn fetuses. On the other hand, regarding choline, which is said to affect Hcy concentration, there is a concern that the intake of choline by Japanese pregnant women does not meet the required amount. In addition, folic acid, which is conventionally prescribed for pregnant women, is a water-soluble vitamin and is known to be vulnerable to light, acid, alkali, heat, etc. In beverages containing folic acid, the concentration of folic acid decreases during long-term storage. The problem was pointed out.

  Therefore, it is desired to provide a safe, reliable and well-preserved pharmaceutical that suppresses an increase in blood HCy concentration during pregnancy or a special-purpose food or dietary supplement for pregnant women.

  Milk phospholipid is a safe food ingredient, and also contains phosphatidylcholine, which can be a source of choline. If the increase in blood HCy concentration can be suppressed by ingestion of milk phospholipid, it can greatly contribute to the safety of pregnant women, but it is unclear because there are various opinions and expectations about whether milk phospholipid can limit blood HCy .

  Therefore, the inventors of the present invention evaluated the effect on the pregnant rat by the blood HCy concentration by administering milk phospholipids to the rat in pregnancy, and the effect on the fetal rat in the infant immediately after birth. The body weight, body length, organ weight and blood HCy concentration were evaluated. As a result, it was found that administration of milk phospholipid during pregnancy can suppress (limit) an increase in HCy concentration, and the present invention has been completed.

  The present invention has an extremely excellent effect that it is possible to prevent an increase in blood HCy concentration, which is a problem in pregnancy, by using a safe ingredient taken as a food, milk phospholipid. Furthermore, by using milk phospholipids such as phosphatidylcholine, the concentration of choline in blood can be continuously increased over a long period of time rather than free choline. In addition, choline supplied from milk phospholipid also has secondary effects such as suppressing the accumulation of fat in the liver.

  In addition, since fat-soluble vitamins are generally less likely to be decomposed than water-soluble vitamins, fat-soluble milk phospholipids are considered to be excellent in long-term storage (not decomposed).

  The present invention includes an agent for suppressing an increase in blood HCy concentration during pregnancy, containing milk phospholipid as an active ingredient. The present invention further relates to a pharmaceutical for a pregnant woman that prevents or suppresses an increase in blood homocysteine concentration related to a disease in pregnancy, wherein the disease or symptom related to the increase in blood HCy concentration is an intrauterine fetal growth. Also included are pregnant medications that are impaired, placental early detachment, spontaneous abortion, premature infant (premature birth), pregnancy toxemia, neural tube closure disorder (NTD) or spina bifida. Suitably, the disease or condition associated with elevated blood HCy levels is neural tube closure disorder (NTD) or spina bifida. Further, the present invention further includes a fetal growth disorder preventive agent, placental early peeling preventive agent, spontaneous abortion preventive agent, premature birth preventive agent, neural tube closure disorder preventive agent, spina bifida prevention, containing milk phospholipid as an active ingredient And preeclampsia agents.

1. Suppression of increase in blood homocysteine level in pregnancy The blood HCy concentration during the pregnancy period increases greatly with the progress of pregnancy, and increases to 2 times before pregnancy in pregnancy and 4 times before pregnancy. However, when such a choline-deficient diet is ingested, administration of milk phospholipid, the source of choline, suppresses the increase in blood HCy concentration during pregnancy, and the maximum is 1.6 times or less before pregnancy. The inventors of the present application have found that it is extremely effective that it can be suppressed.

1-1. Composition for Inhibiting Increase in Blood Homocysteine Concentration During Pregnancy As an active ingredient of the agent for suppressing increase in blood HCy concentration during pregnancy of the present invention, milk phospholipid can be mentioned. Examples of milk phospholipids include those obtained by extracting a lipid component from milk with ethanol and the like and further extracting with acetone from the milk.

  For example, phospholipids derived from milk can be prepared by a well-known method disclosed in JP-A-2002-226394. From the butter milk produced as a by-product during butter production, whey produced as a by-product during cheese production, or skim milk, a known method [“Chemistry of Lipids (Biochemistry Experiment Course 3)”, edited by the Japanese Biochemical Society, p23, Tokyo Chemical Doujin, 1974; “Lipid II Phospholipid (Neochemistry Laboratory 4)”, edited by the Japanese Biochemical Society, p7, Tokyo Chemical Doujin, 1991], or fractionating the extract by various chromatographies. Can be prepared. For example, it can also be obtained as an acetone (solvent) insoluble fraction from cream or butter or from Butter Serum which is a by-product in producing butter oil. Bataselam is also used in municipal milk relations and is available (for example, Corman, Belgium). Bataselam contains MFGM in which phospholipids are localized and is suitable as a raw material for extracting phospholipids.

  In order to separate phospholipids from Bataselam, the property that phospholipids are insoluble in acetone is utilized. By acetone extraction multiple times, the acetone soluble fraction containing neutral lipid is removed, and the acetone insoluble fraction enriched in phospholipid is obtained. The acetone insoluble fraction is concentrated under reduced pressure to remove acetone, and the concentrate is sterilized and lyophilized. This dried product is pulverized to obtain a milk-derived phospholipid fraction. An example of the composition of the phospholipid fraction thus obtained contains 85% (weight%) of phospholipid, and this phospholipid fraction contains components containing choline such as phosphatidylcholine and sphingomyelin. To do.

  Furthermore, milk phospholipids include “milk phospholipid concentrate” (containing about 5% by weight as choline. Lipids 85% by weight, ash 10% by weight, carbohydrates 4% by weight, water 1% by weight) and milk phospholipids. A dairy product “Hohoemi” (produced by Meiji Dairies Co., Ltd.) containing

2. Pharmaceuticals for pregnant women that prevent or suppress the increase in blood homocysteine concentration The pharmaceuticals for pregnant women of the present invention that prevent or suppress the increase in blood homocysteine concentration are suitable for powders, granules, tablets, capsules, liquids, etc. It can be made into a dosage form. For formulation, adjuvants commonly used for formulation, such as excipients, binders, disintegrants, and lubricants, can be added. Examples of excipients include starch, lactose, sucrose, methylcellulose, carboxymethylcellulose, sodium alginate, calcium hydrogen phosphate, synthetic aluminum silicate, microcrystalline cellulose, polyvinylpyrrolidone (PVP), and hydroxypropyl starch (HPS). is there. Examples of the binder include starch, microcrystalline cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), gum arabic powder, gelatin, glucose, sucrose, and aqueous / ethanol solutions thereof. Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, microcrystalline cellulose, hydroxypropyl starch, and calcium phosphate. Lubricants include carnauba wax, light anhydrous silicic acid, synthetic aluminum silicate, natural aluminum silicate, synthetic magnesium silicate, hardened oil, hardened vegetable oil derivative (Sterotex HM), sesame oil, white beeswax, titanium oxide, dry water Aluminum oxide gel stearic acid, calcium stearate, magnesium stearate, talc, calcium hydrogen phosphate, and sodium lauryl sulfate.

2-1. Administration form of a pharmaceutical for pregnant women that prevents or suppresses an increase in blood homocysteine concentration The pharmaceutical for a pregnant woman that prevents or suppresses an increase in the blood HCy concentration of the present invention can be administered orally or enterally. Preferably, it can be administered orally. In addition, the medicament of the present invention contains, for example, 350 mg / day to 3.5 g / day as choline and “milk phospholipid concentrate” (about 5% by weight as choline. 7.5% / day to 75g / day are desirable (% by weight, carbohydrate 4% by weight, water 1% by weight) (American Journal of Clinical Nutrition, 2005, 82, p111-117, Dietary Reference Intakes, p411, etc.).

  It is desirable to take a pharmaceutical for pregnant women that prevents or suppresses an increase in blood HCy concentration of the present invention from before pregnancy, preferably at least once during pregnancy, preferably continuously during pregnancy, for example, It is desirable to take every day.

3. Special-purpose foods or nutritional supplements for pregnant women that prevent or suppress the increase in blood homocysteine concentration during pregnancy The special-purpose foods or nutrition for pregnant women that prevent or suppress the increase in blood homocysteine concentration of the present invention Supplements may be solid (powder, granule, etc.), paste, liquid or suspension. For example, in the case of a drink, sweeteners, acidulants, vitamins, and other drinks Additives commonly used in production can also be added. In addition, the special-purpose food for pregnant women or the dietary supplement for pregnant women can be supplements in appropriate dosage forms such as powders, granules, tablets, capsules, and liquids.

  Furthermore, this invention can also be made into the food additive for preparing the special use food for pregnant women or a dietary supplement which contains a phospholipid as an active ingredient.

  The special-purpose food or dietary supplement of the present invention includes, for example, 350 mg / day to 3.5 g / day as choline and “milk phospholipid concentrate” (about 5% by weight as choline. 85% by weight of lipid). , 10% by weight of ash, 4% by weight of carbohydrates, 1% by weight of water) containing 7.5 g / day to 75 g / day is desirable (American Journal of Clinical Nutrition, 2005, 82, p111 to 117, Dietary Reference Intakes, p411).

[Example 1] Effect of intake of milk phospholipids during pregnancy (1) This experiment was carried out by dividing 9 groups of 3 animals into 3 groups. Specifically, the procedure described later was followed. Prior to pregnancy, approximately 0.1 ml of blood was collected from the tail vein in advance, and the blood HCy concentration was measured. Next, the day when mating (plug) was confirmed was defined as the 0th day of pregnancy, and after 1 day of pregnancy, the received rats were divided into 3 groups (9 animals each). After 1 day of pregnancy in rats, choline-deficient diet (choline-deficient diet group), choline-deficient diet + 2.6% milk phospholipids (milk phospholipid group: 0.1% as choline) or normal diet (control group: 0.1 as choline) %, Also called choline diet) at 20g per day (20g / day). The actual food intake is 10 to 11 g / day, and in the milk phospholipid group, the intake of milk phospholipid corresponds to 260 to 290 mg / day and the intake of choline corresponds to 10 to 11 mg / day. While continuing this diet, the average weight of the mother rats increased from the initial 150-200 g to 260-280 g.

  Specifically, choline-deficient diet (choline-deficient diet group), choline-deficient diet + 2.6% milk phospholipid content (milk phospholipid group: 0.1% as choline) and normal diet (control group: 0.1% as choline, The components of the choline diet) are as shown in the table below.

  About 10 ml of blood was collected from the tail vein after 10 and 20 days of pregnancy, and the blood HCy concentration was measured. At this time, blood was collected while confirming whether or not the rats showed signs of distress (FIG. 1). In addition, pups born from pregnant rats were decapitated on day 1 after birth, and the blood HCy concentration was measured (FIG. 2). In the group fed with milk phospholipids, the blood HCy concentration during pregnancy was significantly reduced, and even in the born rat, the mother rat was fed milk phospholipid. There was a tendency to reduce the medium HCy concentration. The results are shown in the drawing.

  The maternity medicine, special-purpose food, or dietary supplement for maternal use of the present invention can be used in the pharmaceutical or food manufacturing industry because it has an excellent effect of suppressing or reducing the tHCy concentration in the pregnant woman's blood. .

In rats, choline-deficient diet (choline-deficient diet group), choline-deficient diet + 2.6% milk phospholipid (milk phospholipid group: 0.1% as choline) or normal diet (control group: 0.1% as choline, choline diet) This shows the results of measuring blood HCy concentration before pregnancy, 10 days after pregnancy, and 20 days after pregnancy. The result of having measured the blood HCy density | concentration one day after the birth of the pup rat born from the pregnant rat is shown.

Claims (3)

Containing phospholipids derived from milk as an active ingredient, utero fetal growth disorder, gestosis, neural tube closure disorders (NTD) or binary blood homocysteine levels increase in the prophylactic agent for pregnant women for the prevention of spondylosis Or an inhibitor . Prophylactic or inhibitor according to claim 1 phospholipid comprises phosphatidylcholine derived from milk. The preventive agent or inhibitor according to claim 1 or 2, wherein the milk-derived phospholipid contains at least 350 mg / day as the amount of choline.

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