US20100048928A1 - Medicine, Food and Drink or Feed Containing Sphingomyelin - Google Patents

Medicine, Food and Drink or Feed Containing Sphingomyelin Download PDF

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US20100048928A1
US20100048928A1 US11/992,365 US99236506A US2010048928A1 US 20100048928 A1 US20100048928 A1 US 20100048928A1 US 99236506 A US99236506 A US 99236506A US 2010048928 A1 US2010048928 A1 US 2010048928A1
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Prior art keywords
sphingomyelin
agent
group
food
effect
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Inventor
Ken Kato
Susumu Miura
Leo Tanaka
Hiroshi Ueno
Noriko Ueda
Yuko Haruta
Toshimitsu Yoshioka
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Megmilk Snow Brand Co Ltd
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Snow Brand Milk Products Co Ltd
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Priority claimed from JP2006068501A external-priority patent/JP2007246404A/ja
Priority claimed from JP2006256536A external-priority patent/JP5179737B2/ja
Application filed by Snow Brand Milk Products Co Ltd filed Critical Snow Brand Milk Products Co Ltd
Assigned to SNOW BRAND MILK PRODUCTS CO., LTD. reassignment SNOW BRAND MILK PRODUCTS CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HARUTA, YUKO, KATO, KEN, TANAKA, LEO, UEDA, NORIKO, UENO, HIROSHI, YOSHIOKA, TOSHIMITSU, MIURA, SUSUMU
Publication of US20100048928A1 publication Critical patent/US20100048928A1/en
Assigned to MEGMILK SNOW BRAND CO., LTD. reassignment MEGMILK SNOW BRAND CO., LTD. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: SNOW BRAND MILK PRODUCTS CO., LTD.
Priority to US13/347,464 priority Critical patent/US20120208783A1/en
Priority to US13/676,430 priority patent/US8486916B2/en
Priority to US13/862,718 priority patent/US9186366B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/688—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols both hydroxy compounds having nitrogen atoms, e.g. sphingomyelins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/158—Fatty acids; Fats; Products containing oils or fats
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/40—Feeding-stuffs specially adapted for particular animals for carnivorous animals, e.g. cats or dogs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/40—Feeding-stuffs specially adapted for particular animals for carnivorous animals, e.g. cats or dogs
    • A23K50/48—Moist feed
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/10—Phosphatides, e.g. lecithin

Definitions

  • the present invention relates to a pharmaceutical agent which contains sphingomyelin and has novel use. More specifically, the present invention relates to a pharmaceutical agent which contains sphingomyelin and is a sialomucin secretion promoter, an agent for preventing drunken sickness (hangover), an antiallergic agent, an antioxidant, an agent for defending against infection, a hair growth agent, a therapeutic agent for demyelinating disease, an anti-pigmentation agent, an anti-inflammatory agent, or an agent for improving learning ability, and to a food and drink product or feed comprising any of these agents.
  • a pharmaceutical agent which contains sphingomyelin and is a sialomucin secretion promoter an agent for preventing drunken sickness (hangover), an antiallergic agent, an antioxidant, an agent for defending against infection, a hair growth agent, a therapeutic agent for demyelinating disease, an anti-pigmentation agent, an anti-inflammatory agent, or an agent for improving learning ability, and to a
  • Sphingomyelin is a type of phospholipid found abundantly in milk and accounts for approximately 30% of phospholipids in cow milk. Sphingomyelin has a structure in which phosphocholine is bound with a ceramide skeleton composed of sphingosine and fatty acid, and has been known to be also found in the brain or nervous tissues. Moreover, sphingomyelin has been reported to be also contained in small amounts in food such as yolk.
  • Sphingomyelin has been known to influence cell growth or differentiation in vivo via the signal transduction system. Moreover, it has also been suggested that sphingomyelin has an effect of suppressing reduction in protein kinase C activity attributed to aging and is effective for the prevention or treatment of Alzheimer-type memory disorder (Patent Document 1). However, its effect of improving learning ability in a general sense has not been known by any means. It has further been known that sphingomyelin has an effect of improving lipid digestion/absorption function associated with aging (Patent Document 2). However, its other effects have been little known. Therefore, the development of a pharmaceutical agent, a food and drink product, or feed comprising sphingomyelin as an active ingredient has been expected.
  • An object of the present invention is to find novel pharmaceutical use of sphingomyelin and to provide a pharmaceutical agent which is effective as preventive or therapeutic agents for various diseases as well as a food and drink product and feed comprising any of these agents.
  • the present inventors have examined the pharmacological effects of sphingomyelin in various ways and have consequently completed the present invention by finding that sphingomyelin has an effect of promoting sialomucin secretion, an effect of preventing drunken sickness (hangover), an antiallergic effect, an antioxidative effect, an effect of defending against infection, a hair growth effect, a therapeutic effect on demyelinating disease, an anti-pigmentation effect, an anti-inflammatory effect, or an effect of improving learning ability as novel use.
  • the present invention provides a pharmaceutical agent which contains sphingomyelin as an active ingredient and is any of the following agents: 1) a sialomucin secretion promoter, 2) an agent for preventing drunken sickness (hangover), 3) an antiallergic agent, 4) an antioxidant, 5) an agent for defending against infection, 6) a hair growth agent, 7) a therapeutic agent for demyelinating disease, 8) an anti-pigmentation agent, 9) an anti-inflammatory agent, and 10) an agent for improving learning ability.
  • a sialomucin secretion promoter 2, 2) an agent for preventing drunken sickness (hangover), 3) an antiallergic agent, 4) an antioxidant, 5) an agent for defending against infection, 6) a hair growth agent, 7) a therapeutic agent for demyelinating disease, 8) an anti-pigmentation agent, 9) an anti-inflammatory agent, and 10) an agent for improving learning ability.
  • the present invention also provides the pharmaceutical agent, characterized in that the sphingomyelin is derived from milk.
  • the present invention also provides a food and drink product or feed, characterized by comprising the agent.
  • sphingomyelin can be used as 1) a sialomucin secretion promoter, 2) an agent for preventing drunken sickness (hangover), 3) an antiallergic agent, 4) an antioxidant, 5) an agent for defending against infection, 6) a hair growth agent, 7) a therapeutic agent for demyelinating disease, 8) an anti-pigmentation agent, 9) an anti-inflammatory agent, or 10) an agent for improving learning ability.
  • FIG. 1 is a graph showing results of testing tight junction formation according to the present invention.
  • Sphingomyelin that can be used in the present invention is not particularly limited and is chemically synthesized or naturally occurring sphingomyelin including those derived from milk such as cow milk or goat milk and those derived from yolk such as hen's egg yolk. Sphingomyelin derived from milk is more preferable. Among those derived from milk, a sphingomyelin raw material derived from cow milk has a sphingomyelin content corresponding to a concentration as high as 25% or more and is available inexpensively on the market. Therefore, such a sphingomyelin raw material is particularly preferable.
  • the sphingomyelin may be used in a more highly pure form obtained by purification or may be used in a form of sphingomyelin-containing phospholipid.
  • sphingomyelin or the sphingomyelin-containing phospholipid for example, sphingomyelin-containing phospholipid derived from milk (sphingomyelin content of approximately 28% by weight in phospholipid) can be used which is obtained by a method comprising subjecting milk or a dairy product such as a whey protein concentrate (WPC) to ether or acetone extraction (Japanese Patent Laid-Open No. 3-47192).
  • WPC whey protein concentrate
  • a butter curd or serum-containing aqueous fraction obtained by heat-melting butter can be used as sphingomyelin-containing phospholipid (sphingomyelin content of approximately 9% by weight in phospholipid).
  • a milk fat globule membrane fraction contained in butter milk or serum can be used as sphingomyelin-containing phospholipid (sphingomyelin content of approximately 9% by weight in phospholipid). More highly pure sphingomyelin may be used which is obtained by purifying these sphingomyelin-containing phospholipids by an approach such as dialysis, ammonium sulfate fractionation, gel filtration, isoelectric precipitation, ion-exchange chromatography, or solvent fractionation.
  • a pharmaceutical agent of the present invention can be used as a preparation having any of various dosage forms.
  • dosage forms are not particularly limited.
  • the sphingomyelin and/or the sphingomyelin-containing phospholipid can be formulated into preparations in various dosage forms such as tablets, capsules, granules, powder materials, powdered medicines, and liquid medicines (e.g., syrups).
  • the type of a food and drink product of the present invention is not particularly limited.
  • the agent of the present invention can be formulated into food or drink products (e.g., cow milk, processed milk, milk drinks, yogurt, soft drinks, coffee drinks, juice, cheese, jelly, wafers, biscuits, bread, noodles, and sausages) or nutritional foods, and further into nutritional supplementary compositions.
  • the type of feed of the present invention is not particularly limited.
  • the pharmaceutical agent, the food and drink product, and the feed of the present invention can be produced by a standard method except that it contains sphingomyelin.
  • the amount of sphingomyelin formulated into the pharmaceutical agent, the food and drink product, or the feed may be adjusted so that approximately 0.1 to 100 mg of sphingomyelin per day can be ingested generally, though the amount differs depending on use.
  • a reaction solution obtained by allowing protease to act on a 10% aqueous solution of a whey protein concentrate (WPC) was subjected to extraction with a chloroform-methanol (2:1) solution, and the extract was then concentrated and further subjected to acetone extraction to obtain a complex lipid fraction.
  • this complex lipid fraction was subjected to stepwise extraction with a chloroform-methanol solution using Florisil column chromatography to obtain a phospholipid fraction.
  • This phospholipid fraction was subjected to stepwise extraction with a chloroform-methanol solution using silica gel chromatography to obtain a fraction, which was then freeze-dried to obtain a sphingomyelin raw material.
  • This sphingomyelin raw material was treated by thin-layer chromatography, followed by color development with a Dittmer reagent. A sphingomyelin content measured by a densitometry method was 95.2%. This sphingomyelin raw material can be used directly as an agent of the present invention.
  • Sphingomyelin was tested for its effect of promoting sialomucin secretion using the method described in “Test Example 1” of Japanese Patent Laid-Open No. 2001-206848.
  • an AIN-93G standard diet was administered as feed to a control group (Control); this standard diet whose sucrose was partially substituted with 1% of the sphingomyelin raw material described in Example 1 in the present specification was administered as feed to a sphingomyelin administration group (SPM); and this standard diet whose sucrose was partially substituted with 1% of sialyllactose was administered as feed to a sialyllactose administration group (SL).
  • SPM sphingomyelin administration group
  • SL sialyllactose administration group
  • mice Seven-week-old male SD rats (manufactured by Charles River Laboratories, Japan, Inc.) were raised under conditions involving humidity of 60%, room temperature of 24° C., and light-dark (12 hour/12 hour) control. All the rats were preliminarily raised for 1 week with a standard diet and then divided into 3 groups each containing 12 individuals. These groups were allowed to freely take their respective experimental diets and raised for 1 week. Rat saliva was collected on the 7th day after the administration of experimental diets. A sialomucin content in the saliva was measured by high-performance liquid chromatography. The results of measuring a sialomucin content in the saliva of each experimental group is shown in Table 1. As is evident from the results shown in Table 1, the sialomucin content in the sphingomyelin administration group was significantly larger than that in the control group and was also larger than that in the sialyllactose administration group.
  • Sphingomyelin was tested for its effect of promoting sialomucin secretion using the method for testing inhibitory activity against cholera toxin binding described in “Test Example 2” of Japanese Patent Laid-Open No. 2001-206848.
  • the saliva of each experimental group of Test Example 1 in the present specification was used to examine inhibitory activity against cholera toxin binding.
  • 200 ⁇ l of an ethanol solution containing 0.1% ganglioside GM1 (w/v) was added to a 96-well plate for ELISA test. Then, the ganglioside GM1 was adsorbed thereonto by air-drying.
  • the saliva of each experimental group was diluted 10 times with PBS containing 1% bovine serum albumin (BSA) and then reacted for 1 hour by the addition of a biotin-conjugated cholera toxin.
  • 100 ⁇ l of the reaction solution was added to the plate for ELISA test, and the plate was left for 30 minutes. Then, the supernatant was removed.
  • BSA bovine serum albumin
  • the plate for ELISA test was washed several times with PBS containing 0.05% Tween 20. Biotin-binding ⁇ -galactosidase was added thereto. The plate for ELISA test was left for a given length of time. Then, the supernatant was removed. The plate for ELISA test was washed several times again with PBS containing 0.05% Tween 20, and the contents in the plate were reacted for 30 minutes by the addition of 4-methylumbelliferyl galactose. Then, 4-methylumbelliferone produced was measured with a fluorophotometer (excitation wavelength: 360 nm, measurement wavelength: 460 nm). Then, an inhibition rate was calculated according to the following formula:
  • Inhibition rate (%) ⁇ 1 ⁇ ( A/B ) ⁇ 100, wherein
  • A represents the fluorescence intensity of the sphingomyelin administration group (SPM) or sialyllactose administration group (SL), and
  • B represents the fluorescence intensity of the control group (Control).
  • a sialomucin content in the saliva was measured by the following method:
  • 0.2 ml of a Nembutal solution was intramuscularly injected to rats fasted for 2 hours or longer. After anesthesia, a solution of pilocarpine hydrochloride serving as a saliva secretion promoter was intramuscularly injected thereto. After 3 minutes, saliva secreted beneath the rat tongue was collected into a microtube using an autopipette, and this procedure was performed for exactly 9 minutes. After the completion of saliva collection, the saliva collection was terminated by the injection of 0.1 ml of 0.1% atropine sulfate serving as a saliva secretion inhibitor.
  • the collected saliva was rapidly stored at a low temperature of 0° C. or lower and then treated using a centrifuge (11,000 rpm, 60 min.) cooled to 4° C. to obtain a supernatant.
  • the supernatant was dialyzed against a saline for 3 days using a micro-dialysis tube with a molecular weight cut off of 100,000 to collect the content solution as a sialomucin fraction in the saliva.
  • a sialomucin content in the sialomucin fraction was quantified with a Sialic Acid Fluorescence Labeling Kit (Takara Bio Inc.). An aliquot of the sialomucin fraction was collected into a test tube and dried under reduced pressure using a rotary evaporator. Then, the dried product was hydrolyzed at 80° C. for 3 hours by the addition of 2 N acetic acid. Free N-acetyl sialic acid or O-acetylated sialic acid was reacted at 55° C. for 2.5 hours by the addition of a DMB reagent as a fluorescence labeling agent and then quantified by high-performance liquid chromatography.
  • Sphingomyelin was tested for its effect of preventing drunken sickness (hangover) using the method described in “Example 1” of Japanese Patent Laid-Open No. 2001-199880.
  • mice Male Wistar rats were preliminarily raised for 1 week. Then, the rats of 110 to 120 g in body weight were used. The rats were fasted overnight before the experiment and given neither food nor water during the experiment. The rats were divided into an alcohol single administration group (control group) and a sphingomyelin administration group. Each group contained 5 individuals.
  • the alcohol single administration group spent 5 hours to recover from drunken symptoms and was observed to exhibit lying in a prone position, staggering gait, and reduced grip strength as symptoms after administration.
  • the sphingomyelin administration group recovered from drunken symptoms within 1 hour and exhibited only staggering gait as symptoms after administration. This demonstrated that sphingomyelin has a significant effect of preventing drunken sickness (hangover) symptoms caused by drinking.
  • Sphingomyelin was tested for its antiallergic effect using the method described in “Test Example 1” of Japanese Patent Laid-Open No. 8-109133.
  • Ganglioside GM3 (manufactured by Sigma) or the sphingomyelin raw material of Example 1 in the present specification was added at a concentration of 2 ⁇ g/ml (medium) to a serum-free medium Cosmedium 001 (manufactured by Cosmo Bio Co., Ltd.).
  • Millicell-CM manufactured by Millipore; pore size: 0.4 ⁇ m; 0.6 cm 2
  • the membrane surface was treated with collagen (manufactured by Koken Co., Ltd.). Then, a human colon adenocarcinoma cell line Caco-2 was cultured.
  • sphingomyelin has an effect of forming the tight junction of intestinal mucosal cells and has an antiallergic effect brought about by the prevention of allergens from invading living bodies.
  • Sphingomyelin was tested for its antiallergic effect using the method described in “Test Example 2” of Japanese Patent Laid-Open No. 8-109133.
  • the lymphocytes were dispersed and washed in 10 ml of PBS and then centrifuged at 150 ⁇ G for 10 minutes. This washing procedure was repeated three times. Then, 12 ml of an RPMI-1640 medium containing insulin (10 ⁇ g/ml) and transferrin (5 ⁇ g/ml) was added thereto, and the mixture was dispensed in an amount of 3 ml/Petri dish into 3 Petri dishes (A; B; and C). 0.3 ml of fetus calf serum (FCS) was added to the Petri dish A; 3 ⁇ g of the sphingomyelin raw material of Example 1 in the present specification was added to the Petri dish B; and the Petri dish C was nonsupplemented.
  • FCS fetus calf serum
  • an IgA content in the culture solution was 3.89 ⁇ g/ml in the Petri dish A, 3.11 ⁇ g/ml in the Petri dish B, and less than 0.1 ⁇ g/ml in the Petri dish C.
  • the Petri dishes A and B exhibited a high IgA yield, whereas the Petri dish C had little IgA production. This result demonstrated that sphingomyelin has an effect of enhancing the IgA producing ability of lymphocytes and has an antiallergic effect.
  • Sphingomyelin was tested for its antiallergic effect using the method described in “Test Example 3” of Japanese Patent Laid-Open No. 8-109133.
  • Infant Wistar rats (14 day old, body weight: around 20 g, 8 individuals, Charles River Laboratories, Japan) were divided into a control group and sphingomyelin administration groups (SPM administration groups), and all the groups were raised using artificial milk having composition closely analogous to that of rat milk.
  • SPM administration groups sphingomyelin administration groups
  • a sphingomyelin solution (1 mg/ml) prepared from the sphingomyelin raw material of Example 1 in the present specification was orally administered at a daily dose of 50 ⁇ l to the SPM administration groups using a micropipette.
  • 100 ⁇ l of a ⁇ -Lg solution (10 mg/ml) was orally administered thereto.
  • anti- ⁇ -Lg IgE in the above-described blood after 2 weeks was measured by an ELISA method using ⁇ -Lg and a PO-labeled anti-rat IgE antibody (manufactured by Nordic).
  • the results are shown in Table 3 below.
  • the mucosal permeability of ⁇ -Lg in the digestive tract of the groups to which sphingomyelin was administered at a dose of 0.1 mg/kg (body weight)/day or more was observed to be significantly smaller than that in the control group, showing suppressed IgE production. Therefore, it was demonstrated that sphingomyelin has an antiallergic effect.
  • Sphingomyelin was tested for its antioxidative effect according to the method described in “Test Example 1” of Japanese Patent Laid-Open No. 11-209756.
  • the antioxidative activity of sphingomyelin was measured according to the method of Osawa et al. (J. Agric. Food Chem., vol. 35, pp. 809-812, 1987). Specifically, preserved rabbit blood was mixed with an equal amount of an isotonic solution (10 mM phosphate buffer/152 mM sodium chloride, pH 7.4), followed by centrifugation at 1,500 ⁇ g (3,500 rpm) at 4° C. for 20 minutes. Blood corpuscles washed by repeating this procedure three times were mixed with an equal amount of a hypotonic solution (10 mM phosphate buffer, pH 7.4), followed by centrifugation at 20,000 ⁇ g (11,000 rpm) at 4° C. for 40 minutes.
  • Sphingomyelin was prepared at each initial concentration of 0 mM, 0.01 mM, 0.1 mM, 1 mM, or 10 mM using the sphingomyelin raw material of Example 1 in the present specification and then mixed with the erythrocyte membrane ghost.
  • An oxidation reaction was performed by the addition of an oxidizing agent.
  • a TBA reaction was performed.
  • absorbance at 532 nm was measured to quantify an oxidation product.
  • Sphingomyelin was tested for its antioxidative effect according to the method described in “Test Example 2” of Japanese Patent Laid-Open No. 11-209756.
  • the antioxidative activity of sphingomyelin was measured according to the method of Nakayama et al. (Mutation Research, vol. 281, pp. 77-80, 1992). Specifically, a Chinese hamster lung fibroblast cell line V79 was inoculated at a cell density of 200 cells/Petri dish into an MEM medium (manufactured by Flow Laboratories) containing 10% fetus calf serum and cultured at 37° C. for 5 days in the presence of 5% carbon dioxide to prepare cultured cells for test.
  • MEM medium manufactured by Flow Laboratories
  • the antioxidative activity of sphingomyelin was determined using reduction in colony forming activity attributed to hydrogen peroxide as an index for toxicity and assessed based on the extent to which the colony forming activity recovered from such reduction by adding sphingomyelin to the cultured cells for test.
  • the cultured cells for test were inoculated onto a plate and precultured (cell adhesion) for 2 hours. Then, a sphingomyelin solution prepared at each initial concentration of 0 mM, 0.01 mM, 0.1 mM, 1 mM, or 10 mm using the sphingomyelin raw material of Example 1 in the present specification was added thereto.
  • the cultured cells for test were incubated for 4 hours so that the cells were allowed to take up sphingomyelin, prior to hydrogen peroxide. Next, the cells were reacted for 30 minutes by the addition of hydrogen peroxide and damaged. After reaction, the cells were cultured for 5 days in a medium containing serum.
  • the concentration of hydrogen peroxide was set to 60 ⁇ M at which colony forming activity was decreased to a few % to approximately 40%.
  • sphingomyelin was examined in advance for its own toxicity, and it was confirmed in advance that its own toxicity caused no reduction in colony forming activity.
  • the antioxidative activity was evaluated by confirming colony formation after the 5-day culture and measuring the total colony count after Giemsa staining and indicated in each cell viability (%) with respect to cell viability of a sphingomyelin- and hydrogen peroxide-nonsupplemented control defined as 100%.
  • higher cell viability indicates the higher antioxidative activity of the added sphingomyelin.
  • Table 5 As is evident from the results shown in Table 5, it was demonstrated that sphingomyelin has a high antioxidative effect.
  • Sphingomyelin was tested for its effect of defending against infection using the method described in Japanese Patent Laid-Open No. 62-208261.
  • 30-day-old male SD rats were used as test animals.
  • Test groups each containing 10 individuals of these rats were given feed prepared using the sphingomyelin raw material of Example 1 in the present specification so that sphingomyelin was taken at a dose of 0 (control), 0.1, 1.0, 5.0, or 10.0 mg/day.
  • Each rat was given a fixed amount of enteropathogenic E. coli .
  • the incidence of diarrhea was examined. The results are shown in Table 6. As is evident from Table 6, it was demonstrated that rats to which sphingomyelin has been administered at a dose of 1.0 mg/day or more have the significantly reduced incidence of diarrhea.
  • Sphingomyelin was tested for its effect of preventing enteropathogenic E. coli O-157 infection according to the method described in “Test Example 1” of Japanese Patent Laid-Open No. 2001-2704.
  • mice 20 five-week-old BALB/c germ-free mice were allowed to orally take a saline (control group) or the sphingomyelin raw material of Example 1 in the present specification (SPM group) on a daily basis.
  • the intake of sphingomyelin was 5 mg/day.
  • the mice On the 3rd day from the start of taking, the mice were infected with enteropathogenic E. coli O-157 by oral administration at a dose of 8.5 ⁇ 10 6 cfu/mouse. After infection, the mice were also allowed to orally take sphingomyelin on a daily basis. The mice were observed for their lives and deaths for 8 days after the administration of E. coli .
  • the survival rate of the rats depending on the number of days after the administration of enteropathogenic E. coli O-157 is shown in Table 7. As is evident from the results of Table 7, the survival rate of the germ-free mice was enhanced by the administration of sphingomyelin.
  • Sphingomyelin was tested for its effect of preventing enteropathogenic E. coli O-157 infection according to the method described in “Test Example 2” of Japanese Patent Laid-Open No. 2001-2704.
  • mice on the 8th day after the administration of E. coli was measured in the same way as in Test Example 10 except that the intake of sphingomyelin was changed to 0.1 to 10 mg/day.
  • the results are shown in Table 8. As is evident from the results shown in Table 8, the survival rate was significantly improved in the groups that took sphingomyelin at a dose of 1.0 mg/day or more.
  • Sphingomyelin was tested for its therapeutic effect on demyelinating disease according to the method described in “Example 3” of Japanese Patent Laid-Open No. 2-250834.
  • the hind footpad of Lewis rats (female, 6 week old) in groups each containing 5 individuals was immunized with a mixture of syngeneic rat brain homogenates with an equal amount of a complete Freund adjuvant (manufactured by Difco) as an antigen for inducing EAE at a dose of 8.0 mg in terms of the amount of the brain homogenates.
  • a complete Freund adjuvant manufactured by Difco
  • Sphingomyelin was intraperitoneally administered at a dose shown in Table 9 for 18 days from the immunization day.
  • the measurement of body weights and the observation of EAE symptoms were performed every day.
  • the EAE symptoms were rated by six-grade evaluation: 0: no abnormality, 1: tail paralysis, 2 tail paralysis plus hindlimb weakness, 3: tail paralysis plus hindlimb paralysis, 4: hindlimb paralysis plus forelimb weakness, and 5: hindlimb and forelimb paralysis or moribund.
  • the therapeutic effect was assessed based on the cumulative score of the symptoms in each group.
  • sphingomyelin The administration of sphingomyelin was performed by suspending the sphingomyelin raw material of Example 1 in the present specification at a concentration of 1 mg/ml or 2 mg/ml in a sterilized aqueous solution containing 0.5% methyl cellulose sodium and intraperitoneally administering this suspension to the rats. Only a saline was administered to the control group. The results are shown in Table 10 below. As is evident from the results of Table 10, sphingomyelin significantly curbed the onset of EAE as compared with the control group to which only a saline was administered. This result demonstrated that sphingomyelin can be utilized usefully in the treatment or prevention of multiple sclerosis.
  • Sphingomyelin was tested for its therapeutic effect on demyelinating disease according to the method described in “Example 4” of Japanese Patent Laid-Open No. 2-250834.
  • SRBC sheep red blood cell
  • the number of plaque-forming cells against the sheep red blood cells was counted according to the method of Jerne and used as the number of IgM PEC. The results are shown in Table 11. From the results shown in Table 11, it was confirmed that sphingomyelin has inhibitory activity against antibody production. This suggests that sphingomyelin inhibits the onset of EAE based on this activity.
  • Sphingomyelin was tested for its anti-pigmentation effect according to the method described in Japanese Patent Laid-Open No. 1-163112.
  • Sphingomyelin was tested for its anti-pigmentation effect by oral administration.
  • UVA maximum. 360 nm
  • UVB maximum. 312 nm
  • the guinea pigs were divided into 4 test groups (each containing 10 individuals), a group to which a saline was administered at a dose of 10 g/kg (guinea pig body weight) without administering sphingomyelin (group A), a group to which the sphingomyelin raw material of Example 1 was administered at a dose of 2 mg/kg (guinea pig body weight) in terms of the amount of sphingomyelin (group B), a group to which the sphingomyelin raw material of Example 1 was administered at a dose of 5 mg/kg (guinea pig body weight) in terms of the amount of sphingomyelin (group C), and a group to which the sphingomyelin raw material of Example 1 was administered at a dose of 10 mg/kg (guinea pig body weight) in terms of the amount of sphingomyelin (group D).
  • the oral administration to each group was performed once daily using a sonde, and the guinea pigs were raised for 4 weeks.
  • the sphingomyelin raw material of Example 1 was suspended in 10 g of a saline, and this suspension was orally administered to each of the groups B to D.
  • Influence on pigmentation in the back skin of the guinea pigs in each group was measured with a colorimeter (CHROMA METER CR-200) manufactured by MINOLTA at the start of sample administration and at the completion of sample administration. A lightness recovery rate from the start of sample administration was calculated. The results are shown in Table 14.
  • the lightness recovery rate after the 4-week oral administration was as low as 31% in the group A but was 48% in the group B, 62% in the group C, and 78% in the group D, up to 2.5 times larger than that in the group A.
  • Sphingomyelin was tested for its anti-inflammatory effect according to the method described in Japanese Patent Laid-Open No. 1-163125.
  • the anti-inflammatory effect of sphingomyelin was tested by a carrageenin-induced footpad edema method.
  • a test subject shown in Table 15 was suspended in an aqueous solution containing 0.5% carboxymethylcellulose and orally administered (100 mg/kg) to male Wistar rats (body weight: 110 to 130 g, 8 individuals per group) according to the method of Winter et al. (Proceedings of the Society for Experimental Biology & Medicine, vol. 111, pp. 554, 1962). After 1 hour, 0.1 ml of a saline solution containing 1% ⁇ -carrageenin serving as an inflammatory substance was hypodermically administered to either hind footpad of the rats to induce edema.
  • the volume of the footpad of each rat was measured in a given period of time before and after inflammatory substance administration, and a rate of increase in footpad volume (V1) was determined.
  • An aqueous solution containing 0.5% carboxymethylcellulose and no test substance was administered to rats in a control group.
  • a rate of increase in footpad volume (V0) attributed to the injection of ⁇ -carrageenin was measured in the control group in the same way as above.
  • An carrageenin-induced edema inhibition rate (%) was calculated according to the calculation formula: (V0 ⁇ V1) ⁇ 100/V0 and used as the anti-inflammatory activity of the test substance. A higher value of this inhibition rate indicates higher anti-inflammatory activity.
  • the inhibition rate values measured 5 hours after ⁇ -carrageenin injection are shown in Table 15. As is evident from the results shown in Table 15, it was demonstrated that sphingomyelin exhibits a stronger edema inhibition rate than that of indomethacin or sialic acid and has a strong anti-inflammatory
  • the sphingomyelin raw material obtained in Example 1 was used to conduct a water maze experiment for the purpose of examining the influence of orally taken sphingomyelin on learned behavior.
  • the experiment was conducted according to the method described in “Test Example 2” of Japanese Patent Laid-Open No. 9-301874.
  • 8-week-old male SD rats (Charles River Laboratories, Japan) were preliminarily raised for 7 days using a standard diet (AIN-93G) and then divided into 3 groups each containing 6 individuals. Each group was allowed to take feed having composition shown in Table 16 for 10 days.
  • the rats were raised under conditions involving room temperature of 24° C., humidity of 60%, and light-dark (12 hour/12 hour) control and were allowed to freely take deionized water.
  • a “water filled multiple T-maze” was prepared by arranging combined T-mazes with 11 choice points in a water tank of 120 cm long, 120 cm wide, and 40 cm deep.
  • a water maze experiment was conducted at a water temperature of 23 to 24° C. according to the method of Ishizaki (Ishizaki, Exp. Anim., vol. 27, pp. 9-12, 1978).
  • the rats were separately acclimatized by 5 trials in a straight waterway a day before the test.
  • each rat was given 3 trials in the water maze for 4 consecutive days of the test. The length of time taken to swim from the start to the goal of the water maze was measured. The results are shown in Table 17.
  • Raw materials were mixed according to formulation shown in Table 18 and then compressed into 1 g by a standard method to produce the pharmaceutical agent of the present invention in a tablet form.
  • a sphingomyelin raw material having a sphingomyelin content of 25% (Phospholipid 700, manufactured by Fonterra) was dissolved as the agent of the present invention in 4950 g of deionized water, and the solution was heated to 50° C. and then mixed by stirring at 6000 rpm for 30 minutes using a TK homomixer (TK ROBO MICS; manufactured by Tokushu Kika Kogyo Co., Ltd.) to obtain a sphingomyelin solution having a sphingomyelin content of 250 mg/100 g.
  • TK ROBO MICS manufactured by Tokushu Kika Kogyo Co., Ltd.
  • this sphingomyelin solution Into 4.0 kg of this sphingomyelin solution, 5.0 kg of casein, 5.0 kg of soybean proteins, 1.0 kg of fish oil, 3.0 kg of perilla oil, 18.0 kg of dextrin, 6.0 kg of a mineral mixture, 1.95 kg of a vitamin mixture, 2.0 kg of an emulsifier, 4.0 kg of a stabilizer, and 0.05 kg of a flavor were formulated, and this formulation was packaged into a 200-ml retort pouch and sterilized at 121° C. for 20 minutes using a retort sterilizer (primary pressure vessel, TYPE: RCS-4CRTGN, manufactured by Hisaka Works, Ltd.) to produce 50 kg of a liquid nutritional composition comprising the agent of the present invention.
  • this liquid nutritional composition contained 20 mg of sphingomyelin per 100 g.
  • a sphingomyelin raw material having a sphingomyelin content of 10% (Phospholipid 500, manufactured by Fonterra) was dissolved as the agent of the present invention in 700 g of deionized water, and the solution was heated to 50° C. and then mixed by stirring at 9500 rpm for 30 minutes using an ultra-disperser (ULTRA-TURRAX T-25; manufactured by IKA, Japan).
  • a sphingomyelin raw material having a sphingomyelin content of 4% (SM-4, manufactured by Corman) was dissolved as the agent of the present invention in 98 kg of deionized water, and the solution was heated to 50° C. and then mixed by stirring at 3600 rpm for 40 minutes using a TK homomixer (MARK II 160 model, manufactured by Tokushu Kika Kogyo Co., Ltd.) to obtain a sphingomyelin solution having a sphingomyelin content of 80 mg/100 g.
  • SM-4 sphingomyelin content of 4%
  • this sphingomyelin solution 12 kg of soybean cake, 14 kg of skimmed milk powder, 4 kg of soybean oil, 2 kg of corn oil, 23.2 kg of palm oil, 14 kg of corn starch, 9 kg of flour, 2 kg of bran, 5 kg of a vitamin mixture, 2.8 kg of cellulose, and 2 kg of a mineral mixture were formulated, and this formulation was sterilized at 120° C. for 4 minutes to produce 100 kg of feed for dog raising comprising the agent of the present invention.
  • this feed for dogs contained 8 mg of sphingomyelin per 100 g.
  • a pharmaceutical agent of the present invention which contains sphingomyelin as an active ingredient and is any of preventive or therapeutic agents for various diseases, or a food and drink product or feed comprising any of these agents can be used in the prevention or treatment of the disease, improvement in symptoms, and so on, and is therefore very useful.

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US20130225526A1 (en) 2013-08-29
US9186366B2 (en) 2015-11-17
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KR101324076B1 (ko) 2013-10-31
CA2623304A1 (fr) 2007-03-29
NZ566842A (en) 2011-12-22
KR101442047B1 (ko) 2014-09-18
HK1122732A1 (en) 2009-05-29
CA2623304C (fr) 2014-07-29
EP1938824A4 (fr) 2009-07-22
CN101272793B (zh) 2011-02-09
CN101272793A (zh) 2008-09-24
AU2006293026A1 (en) 2007-03-29
AU2006293026B2 (en) 2012-08-16
KR20130058083A (ko) 2013-06-03
US20130079307A1 (en) 2013-03-28
US8486916B2 (en) 2013-07-16
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WO2007034927A1 (fr) 2007-03-29
EP1938824B1 (fr) 2011-11-30

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