WO2017191838A1 - Plasmalogène sûr et stable, sa formulation et procédé permettant d'évaluer un état pré-symptomatique de démence - Google Patents

Plasmalogène sûr et stable, sa formulation et procédé permettant d'évaluer un état pré-symptomatique de démence Download PDF

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WO2017191838A1
WO2017191838A1 PCT/JP2017/017210 JP2017017210W WO2017191838A1 WO 2017191838 A1 WO2017191838 A1 WO 2017191838A1 JP 2017017210 W JP2017017210 W JP 2017017210W WO 2017191838 A1 WO2017191838 A1 WO 2017191838A1
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Prior art keywords
pls
plasmalogen
lipid
complex lipid
3hufa
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Japanese (ja)
Inventor
義剛 名達
永田　仁
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P-Solution Co Ltd
Umeda Jimusho Ltd
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P-Solution Co Ltd
Umeda Jimusho Ltd
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Priority claimed from JP2016254187A external-priority patent/JP6603923B2/ja
Application filed by P-Solution Co Ltd, Umeda Jimusho Ltd filed Critical P-Solution Co Ltd
Priority to CN201780027579.2A priority Critical patent/CN109153693B/zh
Priority to KR1020187032946A priority patent/KR20190003570A/ko
Publication of WO2017191838A1 publication Critical patent/WO2017191838A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • 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
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A23L33/28—Substances of animal origin, e.g. gelatin or collagen
    • 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
    • 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
    • A61K35/56—Materials from animals other than mammals
    • A61K35/57—Birds; Materials from birds, e.g. eggs, feathers, egg white, egg yolk or endothelium corneum gigeriae galli
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K8/60—Sugars; Derivatives thereof
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B11/00—Recovery or refining of other fatty substances, e.g. lanolin or waxes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
    • Y02W30/00—Technologies for solid waste management
    • Y02W30/50—Reuse, recycling or recovery technologies
    • Y02W30/74—Recovery of fats, fatty oils, fatty acids or other fatty substances, e.g. lanolin or waxes

Definitions

  • Non-Patent Document 9 central nervous system inflammation and related neuronal cell death
  • Patent Document 7 inhibition of neurogenesis
  • accumulation in A ⁇ brain Preventing neuropathy caused by damage to nerve cells due to inflammation caused by infection, treatment of neurodegenerative diseases such as AD and Parkinson's disease, or mental diseases such as schizophrenia, depression and autism It is expected that developmental disorders can be treated ([Non-Patent Document 8]). Under such circumstances, a method capable of treating central nervous system inflammation and the like effectively and without side effects is desired more than ever before.
  • the inventor has surprisingly found that PLs can be safely removed by introducing DHA at the SN-2 position in the PLs molecule, and also by simply emulsifying (solubilizing) PLs and transforming the shape.
  • DHA disulfide-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-containing lipid-like lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated lipid-associated
  • the present inventor has found that the three methods are effective as a result of earnest research on a method of rationally overcoming the “antagonism”.
  • One is to rationally emulsify PLs, and the second is to rationally introduce DHA into the PLs molecule, ie, SN-2. Integrating the two, that is, nanoemulsifying DHA-bound PLs, is the strongest rational defense.
  • “reasonable” means that the integrated cost-effectiveness ratio is remarkably high, thereby realizing “safe and practical stabilization”.
  • alkylphospholipid-containing material for example, krill unshelled meat
  • the egg yolk of the laying egg is surprisingly 1-alkenyl-2- It was confirmed that docosahexenoyl-glycerophospholipid and 1-alkyl-2-docosahexenoyl-glycerophospholipid were produced with high selectivity, that is, containing almost no EPA conjugate.
  • the anti-central nervous system inflammation of the present invention has an inhibitory effect on the increase and activation of glial cells that accompany the development of inflammation in the central nervous system, and it is possible to alleviate, prevent, improve and treat central nervous system inflammation. it can.
  • PLs is a component that is abundantly contained in living tissue, and the safety has been demonstrated since the living tissue containing PLs has been used for food, and has been extracted from living tissue.
  • the PLs used in the present invention are preferably those extracted and fractionated from chicken biological tissues.
  • a biological tissue is a tissue containing PLs in a living organism.
  • examples of the organism include animals and microorganisms.
  • an anaerobic bacterium is preferable, and for example, an enterobacteria acidaminococaceae bacterium is particularly preferable.
  • living tissue is bacteria itself.
  • animals birds, mammals, fish, krill, shellfish and the like are suitable.
  • livestock is preferable from the viewpoint of both supply stability and safety, and examples thereof include cattle, pigs, horses, sheep, and goats.
  • Specific examples of the process for extracting and purifying PLs include the following processes 1) to 5).
  • a step of extracting and fractionating complex lipids having a tissue-specific composition ratio from the total lipid fraction (2) A step of extracting and fractionating complex lipids having a tissue-specific composition ratio from the total lipid fraction. (3) A step of fractionating a water-soluble low molecular weight fraction from the above steps and adding this to the complex lipid fraction to obtain a complex lipid composition. (4) A step of separating the protein fraction from the above steps and adding the complex lipid composition described in the previous section to obtain a protein / lipid complex composition. (5) The enzyme is added to the complex lipid fraction to hydrolyze SN-1-linked fatty acid, and the mixed diacylglycerophospholipid is converted into a lyso form and extracted with a hydrophilic solvent together with by-product fatty acid to purify PLs. Process.
  • the water-containing ethanol phase is obtained by evaporating and concentrating ethanol to separate the aqueous layer, and then adding degassed hexane in advance to extract the phospholipid fraction.
  • the hexane solution is evaporated to dryness by a conventional method to obtain 7 g of a complex lipid fraction.
  • the low molecular weight water-soluble fraction is added to the phospholipid fraction to obtain 25 g of a complex lipid composition.
  • the complex lipids derived from biological tissues (including complex lipid compositions) and the phospholipids of PLs and their composition ratios have unique characteristics depending on the biological tissues. Below, the composition ratio in the case of a laying hen is demonstrated.
  • the complex lipids and PLs extracted from the living tissue used in the present invention have the following ethanol content PLs and choline PLs content as 1) to 2) in terms of dry mass.
  • the upper limit of the complex lipid is 50% by mass, preferably 10% by mass or more, more preferably 20% by mass or more, still more preferably 30% by mass or more, and 40% by mass or more. Is still preferred.
  • the mass ratio and content of ethanolamine PLs and choline PLs can be determined by analyzing complex lipids or plasmalogens extracted from biological tissues by high performance liquid chromatography (HPLC). Specifically, in HPLC, a chromatogram is obtained by evaporative light scattering detection (ELSD; Evaporating Light Scattering Detector), and a mass ratio is obtained by determining respective peak area ratios indicating ethanolamine PLs and choline PLs in the chromatogram. Can be calculated. Further, the content can be obtained by calculating what percentage of the peak area of the entire chromatogram the peak areas showing ethanolamine PLs and choline PLs correspond to.
  • ELSD evaporative light scattering detection
  • a mass ratio is obtained by determining respective peak area ratios indicating ethanolamine PLs and choline PLs in the chromatogram. Can be calculated.
  • the content can be obtained by calculating what percentage of the peak area of the entire chromatogram the peak areas showing ethanolamine PL
  • ⁇ -3HUFA is transferred with high selectivity to lipids, particularly PLs, of tissues, organs and parts thereof.
  • Transesterification of SN-2 conjugated fatty acid and transition ⁇ -3HUFA produces ⁇ -3HUFA-conjugated PLs-containing complex lipids and PLs. Examples of ⁇ -3HUFA-binding PLs suggest a relationship with cognitive dysfunction, which is exemplified below.
  • the emulsification may be a heavy load, for example, avoiding the use of a high-pressure homogenizer or the like, and simple and slow stirring is preferable. High load emulsification impairs the oxidation stability of PUFA.
  • LA linoleic acid
  • AA arachidonic acid
  • DHA were incorporated and oxidized, and in LA and AA addition systems, the amount of peroxide produced increased. There was no increase.
  • Non-patent Documents 11 and 12 The PLs content in the brain of AD patients is significantly reduced.
  • Serum PLs content of AD patients is significantly reduced (Non-patent Document 13).
  • the erythrocyte PLs content of AD patients is significantly reduced (Non-patent Document 14).
  • LPS intraperitoneal injection causes inflammation-induced cognitive impairment
  • PLs in the brain decrease (Non-patent Document 8).
  • Non-patent Document 8 Inhibition of central nervous system inflammation and A ⁇ accumulation in mice with central nervous system inflammation induced by LPS (intraperitoneal injection) (Non-patent Document 8).
  • Non-patent Document 9 In vitro suppression of neuronal cell death (Non-patent Document 9). 6) Other relations (1) Suppression of hyperglycemia and hyperlipidemia, which are risk factors for developing cognitive impairment (Non-patent Document 18). (2) Suppression of cognitive decline due to carnosine diet (Non-patent Document 19).
  • the above-mentioned DHA-bound PLs also has a markedly increased anti-cognitive dysfunction efficacy due to the combination of direct stabilization within the molecule and the synergistic effect on improvement / correction of cognitive dysfunction. It is considered a thing.
  • Procurability is remarkably superior due to the following factors.
  • Poultry farming is a global industry with high quality, uniform quality, low price and high concentration; * Broiler is a vertically integrated industry
  • Abandoned laying hens about 700 days old) (about 70% thinned annually; about 750 days old) is a dedicated slaughter and demolition site
  • the center (with 30 locations all over the country, with an average processing capacity of around 3 million a year and over 10 million) is characterized by high freshness, low cost, domestic production and safety.
  • Formd molting is an artificial means of regenerating laying hens whose egg-laying efficiency has dropped, and fasting old hens about 700 days old for about 10 days.
  • a poultry farming style in which the animals are bred again after being in condition. Although it is a single piece of paper with animal damage, it is acquiesced as an emergency measure when egg prices are sluggish or sales volume is sluggish. It is interesting as a specific individual for biofunctional regeneration, for example, as a chicken for transferring ⁇ -3HUFA derivative containing DHA. One of the peculiarities of poultry is that this type of measure can be realized on a large scale.
  • the egg yolk derived from the laying hen has a PLs composition ratio of PL-PC >> PL-PE (substantially zero) specifically in the gold crown of its precursor.
  • PLs are not included.
  • the following * was surprisingly found in the egg yolk of the laying hen.
  • PLs were detected * Most of them were DHA-PLs * However, the composition ratio was PL-PE >> PL-PC, as opposed to the gold crown of the precursor.
  • DHA produced PLs in the yolk as a result of enhancing the expression of the rate-limiting enzyme Far1 in the biosynthetic pathway of the PLs neoplasmic reticulum “peroxisome” in vivo. Furthermore, it is interpreted that the PLs specifically supplemented DHA in egg yolk to generate DHA-PLs.
  • ⁇ -3HUFA derivatives to be tested Meat derived from seafood, sardines, mackerel, sanma, tuna, bonito, scallops, squirts, krill, etc., and combinations of two or more of these, leftover seafood-derived meal by-products Examples include meals derived from reproductive tissues of seafood, by-product oil on the left, derived from fermentation medium of microorganisms, and the like. 4). ⁇ -3HUFA-containing feed and feeding conditions The following are exemplified.
  • Feeding conditions 1) Chicken species Julia species and / or Boris Brown species 2) Feed Corn 62%, ⁇ -3HUFA-containing feed 15% register, vegetable oil 15%, basic animal feed 6% and other grains 2% register 3) Feeding conditions ( 1) Feeding period is 1 to 5 weeks, preferably 1 to 3 weeks (2) Chickens are 40 weeks old (3) Feeding place is Kyushu poultry farm (4) The number of breeding birds is about 50 and 4 ) Slaughter and dismantlement primary processing storage Kyushu waste chicken processing center
  • Nano-emulsification step Add the above complex lipid into a degassed aqueous Quillaja saponin solution while stirring with a magnetic stirrer under a nitrogen gas atmosphere and stir until it is no longer cloudy to obtain a transparent solubilized solution. It is done. 3. Properties of nanoemulsified solution The prepared solution is diluted 10,100,1000 times, and the transparency is visually confirmed. 4). Stability test ([Patent Document 12]) For example, the prepared solution is diluted to 500 times with a transparent aqueous solution, adjusted to pH 4 using citric acid, visually checked for change, and heated at 95 ° C. for 30 minutes, and then returned to room temperature. Visually check for changes.
  • a hexane extract is obtained by a conventional method, and an unheated solubilized liquid is used as a control, and a peak area comparison analysis is performed on an HPLC / ELSD chart to test residual plasmalogen. .
  • Complex lipids according to the present invention compositions thereof and PLs and aqueous preparations thereof, protein / lipid composite compositions, complex lipids containing ⁇ -3HUFA-binding PLs, compositions thereof, PLs, and aqueous preparations thereof, Furthermore, protein-lipid complexes composition (hereinafter sometimes referred to as "various PLs such”.) the central nervous system inflammation, neurogenesis ataxia, brain apoptosis diseases and a beta and ⁇ in neurons accumulation It can be used in foods, cosmetics, pharmaceuticals or feeds as an active ingredient for alleviating, preventing, improving and treating symptom (hereinafter referred to as “cognitive dysfunction”).
  • the various foods may be various PLs preparations themselves, A material, a carrier, an additive acceptable in food hygiene, and other components and materials that can be used as food may be appropriately blended.
  • various food forms include, but are not limited to, liquid, powder, flake, granule, and paste foods.
  • the types of supplements and foods are not particularly limited, and include, for example, processed foods such as hamburger, meatballs, wieners, bird rags, chicken skin chips, etc., which are mixed with various PLs preparations, processed meat foods, etc.
  • Examples include health foods (functional nutritional foods, foods for specified health use), supplements, foods for the sick, and the like.
  • various PLs preparations for example, powdered, beverages (juice etc.), confectionery (eg gum, chocolate, candy, biscuits, cookies, rice crackers, rice crackers, pudding, jelly-like confectionery, Examples thereof include apricot tofu and the like, breads, soups (including powdered soups), and various foods and beverages such as processed foods.
  • granules, capsules, tablets (chewable agents) so as to facilitate continuous intake Etc.), beverages (drinks, etc.), etc. are preferably prepared.
  • capsules, tablets, tablets, jellies and the like are more preferable from the viewpoint of easy intake.
  • the form of granules, capsules, tablets, jelly and the like can be appropriately prepared according to a conventional method using a pharmaceutically and / or food hygienically acceptable carrier.
  • the blending amount of PLs in the food or drink according to the present invention is preferably 0.00005 to 100% by mass, more preferably 0.0005 to 75% by mass, and still more preferably 0.005 to 50% by mass.
  • the food / beverage products according to the present invention can be used for the prevention / mitigation / improvement of cognitive impairment.
  • the measurement of the intake amount, the intake target, the amount of contained PLs, and the like are the same as, for example, the pharmaceutical product according to the present invention described later.
  • the hospital food is a meal provided when hospitalized, the sick food is a meal for the sick, and the care food is a meal for the care recipient.
  • the food / beverage products according to the present invention can be used as hospital foods, sick foods or nursing foods for patients who are hospitalized, treated at home due to the above-exemplified diseases, or who are receiving nursing care.
  • a person who is highly likely to suffer from the above-illustrated diseases such as the elderly can be ingested prophylactically.
  • the preparation may be composed solely of PLs, or may be formulated with other components (ie, a pharmaceutical containing PLs).
  • a pharmaceutical containing PLs ie, a pharmaceutical containing PLs.
  • various PLs preparations which are active ingredients are optionally added to pharmaceutically acceptable bases, carriers, additives (for example, excipients, binders, disintegrants, Lubricants, solvents, sweeteners, colorants, flavoring agents, surfactants, humectants, preservatives, pH adjusters, thickeners, and the like can be blended.
  • it is prepared by a conventional method such as tablets, coated tablets, powders, granules, fine granules, capsules, pills, solutions, suspensions, emulsions, jellies, chewables, soft tablets, etc. be able to.
  • it may be prepared as a solution, suspension, emulsion, etc. and used as an injection or infusion, or as an oral preparation.
  • the amount of PLs in the pharmaceutical product according to the present invention is not particularly limited as long as the anticognitive dysfunction is exerted, and can be appropriately set according to the preferred daily intake of PLs.
  • the blending amount is preferably 0.0005 to 100% by mass, more preferably 0.005 to 90% by mass, and still more preferably 0.05 to 80% by mass.
  • the subject to which the pharmaceutical product according to the present invention is administered is preferably a subject suffering from cognitive dysfunction. Examples of such diseases include neurodegenerative diseases and mental diseases. Specific examples of neurodegenerative diseases include AD, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis.
  • the pharmaceutical product according to the present invention may be administered to a subject who is likely to suffer from such a disease in the future.
  • it can be administered prophylactically to subjects who are genetically highly likely to suffer from the above exemplified diseases, elderly people (especially 60 years or older) and the like.
  • the subject to which the pharmaceutical product according to the present invention is administered is not limited to humans but may be other mammals for feed. Examples of such mammals include animals raised as livestock and pets, and examples include dogs, cats, cows, horses, pigs, sheep, goats, monkeys, rabbits, mice, rats, and hamsters. .
  • the administration time of the anticognitive dysfunction agent according to the present invention is required to be administered preferably 5 years ago, more preferably 10 years ago, and even more preferably 15 years before the onset of the cognitive dysfunction. It has been clarified that end-stage disease has been reached at the time of onset diagnosis ([Non-Patent Document 20]).
  • a preferred dosage form is oral administration in view of its long administration period.
  • the dosage of the anticognitive dysfunction agent according to the present invention is appropriately selected according to the age of the patient, the degree of symptoms of the patient, other conditions, and the like.
  • the amount of PLs in the agent is preferably within a range of 0.001 to 1000 mg, more preferably 0.01 to 100 mg per day for an adult.
  • the administration can be performed once or a plurality of times (preferably 2 to 3 times) a day.
  • the present invention also includes a method for treating cognitive dysfunction comprising a step of administering (in particular, oral administration or transvascular administration) an effective amount of the anticognitive dysfunction agent of the present invention to a subject suffering from cognitive dysfunction.
  • a step of administering in particular, oral administration or transvascular administration
  • the present invention administers an effective amount of the anticognitive dysfunction agent of the present invention to a subject suffering from or likely to suffer from a neurodegenerative disease or psychiatric disorder (particularly oral administration or transvascular administration).
  • a method for preventing or treating these diseases is carried out by administering the aforementioned anticognitive dysfunction agent of the present invention.
  • contrast and intake, in the said method is as above-mentioned.
  • the following 1) to 7) can be exemplified as unique clinical test methods for the predetermined efficacy (prevention and treatment of neurodegenerative diseases and psychiatric disorders) of PLs and their preparations according to the present invention.
  • the subject is an adult (healthy person) before the onset of dementia who is in a state where accumulation of physiologically innocuous amounts of A ⁇ and ⁇ is recognized in the brain. It is characterized by being a subject.
  • Non-Patent Document 20 brain accumulation of A beta and ⁇ protein than traditional onset diagnosis period, at least 10 years, usually accumulated from 15-20 years ago is started in As a result, a kind of “paradigm shift” has occurred.
  • safe, stable and inexpensive plasmalogen is an essential requirement for ingredients for prevention, alleviation, improvement and treatment of neurodegenerative diseases and psychiatric disorders, as compared with conventional ingredients It is said.
  • the administration period is at most 2 years, preferably 18 months, more preferably 12 months, and preferably 6 months or less, compared to 1 year or more of the usual clinical trial period for the disease subject. It is as short as more than a month, and can reduce the burden on the subject.
  • An innovative method for the prevention and treatment of neurodegenerative and psychiatric disorders characterized in that the main essential measurement efficacy includes three or more items selected from the following groups marked with *. .
  • Non-patent Document 17 Uchida / Kraepelin test * MMSE * Resting functional MRI (rs-fMRI) image analysis (Non-patent Document 17) * Measurement of PLs content in erythrocytes (Non-patent Document 24) * PSOL "Cognitive function self-diagnosis test" * RBANS ([Non-Patent Document 21]) * Cognitax ([Non-Patent Document 21]) * Wexler memory test ([Non-Patent Document 22])
  • the rs-fMRI image is useful for analysis and evaluation of the default mode network (DMN) of the brain.
  • DNN default mode network
  • the brain was also resting when conscious activity was not performed, but in recent years, a surprising fact has been revealed by functional brain imaging research, and important activities have been carried out even at rest. It is said that the energy consumed for the activity in the basal state of the brain reaches 20 times the brain energy used for the conscious reaction ([Non-Patent Document 17]).
  • DMN a network composed of a plurality of brain regions called DMN, which acts to synchronize with various neural activities in the brain.
  • DMN a network composed of a plurality of brain regions
  • the brain area where significant atrophy is observed in AD patients almost overlaps with the main brain area that constitutes DMN, which is a clue for understanding new neurological diseases by fMRI image analysis at rest. Is expected to be.
  • Non-patent Document 17 discloses the small-world nature and modularity of the resting brain functional network decrease with age, and these functional changes generally precede anatomical changes such as brain atrophy. Therefore, it has been announced that it may be a useful marker in the study of aging and dementia.
  • Non-patent Document 28 It is said that the sensitivity in the vicinity of the hippocampus has also been successfully improved (Non-patent Document 28). Further, in the orthotopic have became to be observed by [tau protein] also succeeded in developing a test agent [pBB3] for viewing by PET, [tau protein] with A beta also PET. The present inventor has performed the [DHA-PLs] vs. [PLs] efficacy evaluation [clinical study] in the cognitive improvement of concern using the [amyloid PET-PIB], and obtained extremely interesting results. .
  • Preparation Example 1 [Production of PLs-containing phospholipid for biological tissue extraction] [Production of biological tissue-extracted PLs-containing phospholipids] 1. Preparation of complex lipids from the skins of the laying hens The complex lipids were prepared from the freshly peeled pupae of the laying laying hens, which were the chicken tissues (the carcass from which the "thigh" had been removed). Skin peeled rice was procured from the waste chicken processing center to prepare 1 kg of minced meat of about 8 mm. The mince was stored frozen slowly. In use, it was dehydrated and deoiled by pressing after forced thawing with warm running water.
  • Preparation Example 2 [Preparation of purified PLs from complex lipids] 1. Preparation of Purified PLs from Waste Chicken Skin Lipid Complex Lipid 20 g of the above PLs-containing phospholipid (complex lipid) was added to 400 ml of phospholipase A1 (Mitsubishi Chemical Foods) solution (10 mg / ml 0.1 M citric acid-hydrochloric acid buffer). The mixture was dispersed and stirred at 50 ° C. for 2 hours under nitrogen gas filling. Under ice cooling, 2 volumes of hexane was added, and the mixture was stirred and distributed twice. The upper layer was collected and concentrated to dryness. Furthermore, the operation of adding 60 ml of acetone to the dried product, stirring and centrifuging, and collecting the precipitate was repeated twice.
  • phospholipase A1 Mitsubishi Chemical Foods
  • the liquid layer was concentrated to dryness, 240 ml of hexane / acetone (1: 1) was added and transferred to a separatory funnel, and 36 ml of water was added, stirred and distributed. The lower layer was discarded, and 96 ml of acetone / water (5: 3) was added to the upper layer and stirred and distributed. The upper layer was collected and quickly dried under reduced pressure to obtain purified PLs derived from raw chicken waste. [Assessment of Purity of Purified PLs from Waste Raw Chicken] Purity test was performed according to the method of Nana et al. The purity was 94.3% by mass.
  • the liquid layer was concentrated to dryness, 240 ml of hexane / acetone (1: 1) was added and transferred to a separatory funnel, and 36 ml of water was added, stirred and distributed. The lower layer was discarded, and 96 ml of acetone / water (5: 3) was added to the upper layer and stirred and distributed.
  • the upper layer was collected and quickly dried under reduced pressure to obtain purified PLs derived from waste chicken intestine. [Purification of purified plasmalogen derived from the intestines of waste chicken] Purity test was performed according to the method of Nana et al. The purity was 91% by mass.
  • the liquid layer was concentrated to dryness, 240 ml of hexane / acetone (1: 1) was added and transferred to a separatory funnel, and 36 ml of water was added, stirred and distributed. The lower layer was discarded, and 96 ml of acetone / water (5: 3) was added to the upper layer and stirred and distributed. The upper layer was collected and quickly dried under reduced pressure to obtain 3 g of purified plasmalogen derived from waste chicken sand liver. [Purification of purified PLs derived from chicken gizzards] Purity test was performed according to the method of Nana et al. The purity was 95.4% by mass.
  • the liquid layer was concentrated to dryness, 240 ml of hexane / acetone (1: 1) was added and transferred to a separatory funnel, and 36 ml of water was added, stirred and distributed. The lower layer was discarded, and 96 ml of acetone / water (5: 3) was added to the upper layer and stirred and distributed. The upper layer was collected and quickly dried under reduced pressure to obtain purified PLs derived from a waste chicken crown. [Purification of Purified Plasmalogen from Waste Chicken Gold Crown] Purity test was performed according to the method of Nana et al. The purity was 95.6% by mass.
  • Preparation Example 4 Extraction and separation of egg yolk-derived PLs-containing phospholipids (complex lipids)] 100 g of raw egg yolk is mixed with 20 g of ethanol and allowed to stand at room temperature for 10 minutes, and then 120 g of 20% aqueous ethanol is added and stirred. When this is centrifuged at 2000 rpm for 5 minutes, it is separated from the upper layer into three phases: a yellow transparent egg yolk oil phase, a yellow-white complex lipid emulsion phase, and an almost white egg yolk protein precipitate.
  • the gold crown oil phase and the emulsified phase are separated, the precipitated phase is extracted with 50 g of 20% aqueous ethanol, centrifuged in the same manner, and the supernatant is combined with the emulsified phase and concentrated under reduced pressure to give 12.2 g of yellow gold crown complex lipid ( Acetone insoluble part 80%) was obtained.
  • Preparation Example 5 Composition of two products made from waste chicken fillet.
  • Complex lipid composition mg / g PLs 6-60, non-plasmalogen phospholipids 9.6-84.3, anserine 0.4-3.6, carnosine 0.07-0.6, free amino acids 0.24-2.4, vitamin E0. 12-1.2, carnitine 0.3-3, coenzyme Q10 0.12 to 1.2 2.
  • Protein / lipid complex composition Protein content 87.1, complex lipid content 1.4, low molecular water soluble fraction 3.2
  • Verification example 1 Example of measurement (assay) of effects of chicken-derived PLs on cognitive function and related events
  • the PLs for measurement test were prepared as follows. [Chicken species and their parts] Skinned breast minced minced hens were procured from an abandoned chicken processing center. [Preparation of total lipids] The mince was externally freeze-dried and slowly extracted with ethanol in the usual manner to prepare breast-derived total lipids. [Preparation of complex lipid] The composite lipid was prepared by appropriately adding water to the total lipid ethanol solution and degumming (de-neutral lipid).
  • Non-patent Document 8 By increasing the PLs concentration in the brain of LPS-induced central nervous system inflammation model mice, the absorption of orally administered PLs from the brain blood barrier was confirmed (Non-patent Document 8). (3) The effectiveness of oral administration for humans, especially AD patients, was verified by increasing the blood PLs concentration in AD patients (Non-patent Document 16). 3. Example of suppression (prevention) and alleviation of treatment of cognitive dysfunction of breast chicken breast meat PLs and verification of therapeutic effects (1) Cognition by waste chicken breast PLs due to renewal of neurons in aging model rats (SAMP8) The possibility of alleviating dysfunction and its therapeutic effect was verified (Patent Document 7). (2) A suppressive effect expression of the spatial cognitive learning dysfunctions by waste chicken breast plasmalogen against either side injection model rat ⁇ is to demonstrate the potential therapeutic effects of cognitive dysfunction waste chicken breast PLs (Non-patent document 16).
  • Non-patent Document 8 Example of verification of the alleviation of inflammatory symptoms in LPS-induced central nervous system inflammation model mice (Non-patent Document 8) 1) Suppression of microglia activation by waste chicken fillet PLs demonstrates the possibility of alleviating and treating cognitive impairment through central nervous system inflammation. 2) Increase of TNF ⁇ m-RNA in brain cytokine and suppression of IL-2 ⁇ expression in brain by waste chicken fillet PLs alleviates and treats cognitive impairment through central nervous system inflammation by waste chicken fillet PLs This proves the possibility. 3) accumulation inhibition in A beta brain by waste chicken breast PLs is to demonstrate the possibility of alleviating or treating cognitive dysfunction through its central nervous system inflammation. 5).
  • Waste chicken fillet PLs demonstrates the possibility of an inhibitory effect on cognitive dysfunction through suppression of decrease in PLs caused by inflammation induced by intraperitoneal injection of LPS.
  • Waste chicken fillet PLs demonstrates the possibility of exerting an effect of directly treating cognitive impairment associated with nerve cell death through suppression of nerve cell death in a nerve cell culture system.
  • Non-patent document 9 5) Others (1) The composite lipid fraction derived from waste chicken fillet has the potential to exert an action to delay the onset of cognitive dysfunction through the suppression of hyperglycemia and hyperlipidemia, which are risk factors for the development of cognitive dysfunction It is proved.
  • the waste chicken fillet-derived complex lipid composition demonstrates the possibility of preventing and / or alleviating cognitive dysfunction through the suppression of cognitive decline caused by the carnosine diet.
  • Verification example 2 1. Verification example of whether or not the suppression effect of cognitive dysfunction of chicken-derived DHA-binding PLs corresponding to the suppression effect of cognitive dysfunction of waste chicken fillet PLs is increased.
  • PLs are the main phospholipids that store DHA ([Non-Patent Document 26]). 2) Verification of biochemical / physiological specificity of DHA-PLs (1) In the case of a single molecule (free), the aqueous system (emulsion) is more stable ([Non-Patent Document 1]). (2) In a complex system (lipid bilayer), since it is a main membrane constituent, it is far more stable than a monomolecular system.
  • Uchida-Kreppelin test (hereinafter referred to as “UK test”) A simple one-digit addition is continuously performed for a certain period of time, and the calculation ability test that determines "ability when a person calculates” and “characteristics when the calculation ability is demonstrated” by a curve expressed by the amount of calculation. It is. Usually, 2 sets of 1 minute ⁇ 15 times are performed. 4) PSOL cognitive function self-diagnosis test Refer to Fig. 3 in the form of answering a highly comprehensive question on cognitive function originally devised. 2 is the reference point (baseline) in a four-step evaluation from 0 to 4. It is good evaluation when it exceeds 2.
  • test sample 3 types of soft capsules
  • the evaluation was made in a daily report from the subjects.
  • Data analysis method In this test, it was carried out using all the analysis results without arranging the number of specimens. All statistically processed values are expressed in mean ⁇ SD. The difference between the measured values at 0, 6 and 12 weeks was statistically processed using the paired t test. The comparative evaluation of the measured values of the MMSE, UK test, and PSOL cognitive function self-diagnostic test within the same group was performed using the pair t test. Using the Student t test, intergroup comparisons were made between the measured values at 0, 6 and 12 weeks and the deviation from baseline ( ⁇ 0-6 weeks and ⁇ 0-12 weeks). Background comparison of subjects within the group was performed using unidirectional square deviation analysis. This was not adjusted for fluctuations associated with the implementation period. Mislisted subjects were completely excluded from statistical processing. Statistical processing was performed using Statcell 4 and Excel statistics. The test statistical processing result between two samples was judged to be significant at ⁇ 5%.
  • Test results 1 Statistical information of subjects The ingestion test started by dividing 81 people into 3 wards, but 6 people dropped out. The reason is that poor physical condition 2, sudden work convenience 3, housework convenience 1, and 75 people completed the test after all. The breakdown was test-1; 27, test-2; 23, placebo; 25, but there was no significant difference between age, sex and UK test (Table 3).
  • Table 4 shows the contents of statistical processing on subjects.
  • the composition of men and women is 5 men and 10 women.
  • the test agents of the A beta PET using PIB Non-Patent Document 31.
  • the amount of accumulation is an SUVR (Standardized Uptake Value Ratio) of PET images corresponding to the degree of progression of cognitive dysfunction. Tables 10 to 11 show the SUVR scores of the PET images.
  • Example 13 [Elucidation of changes in hippocampal volume reduction in comparison with -PLs derived from gold crowns of ⁇ -3HUFA derivative transfer females, breast-derived PLs derived from laying hens, and placebo settings] Single-blind open trial clinical trial ] 1) Specimen (1) DHA-PLs; 96.7% purity, DHA binding rate is 75 mol% According to Preparation Example 2 5.2) in [DHA migrating chicken female gold crown] (2) PLs; 92% by mass [derived from waste chicken fillet] 2) Men and women of 15 subjects and 5 wards (3 DHA-PLs x [0.25 mg, 0.5 mg], 3 PLs x [0.25 mg, 0.5 mg] and 3 placebo)) Selected at 60 ⁇ 5 years old.
  • the composition of men and women is 5 men and 10 women.
  • the present invention relates to a safe and stable plasmalogen and its preparation and use.
  • a safe and stable plasmalogen derived from a safe biological material more specifically, Provides a safe and stable plasmalogen-containing complex lipid formed by binding DHA (docosahexaenoic acid) to SN-2 of plasmalogen as an essential requirement.
  • DHA docosahexaenoic acid
  • aqueous preparations emulsions, jellies, granules, powders
  • aqueous preparations that are easily nano-emulsified (or solubilized) using 3) Specific to living tissue in the aqueous phase in the presence of saponins Complex lipid and ⁇ -3 HUFA-conjugated complex lipid having a structural composition ratio, and complex lipid and ⁇ -3 HUFA-binding wherein the complex lipid composition is nanoemulsified or solubilized Type complex lipids and aqueous preparations of these complex lipid compositions, 4) provide their use, 5) neurodegenerative diseases containing ⁇ -3HUFA-bound crude or high-purity plasmalogen, etc. as active ingredients, and Provided with various effects such as providing various processed products, supplements, preventive or therapeutic agents for the prevention or treatment of mental illness, 6) providing a method for determining the non-demented state of dementia, etc.
  • the present invention has industrial applicability.

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Abstract

L'invention concerne un plasmalogène sûr et stable, sa formulation, et un procédé permettant d'évaluer la démence pré-symptomatique. Plus précisément, l'invention comprend : un supplément ou un aliment en tant que produit traité permettant d'atténuer, d'améliorer, ou de prévenir la démence présentant comme principe actif un plasmalogène avec des liaisons d'acides gras polyinsaturés à longue chaîne ω-3 (ω-3HUFA), etc. ; une formulation permettant de soigner une maladie neurodégénérative et/ou une maladie mentale ; et un procédé permettant d'évaluer la démence pré-symptomatique chez un sujet, le sujet étant un adulte qui n'a pas encore développé de démence (sujet normal). Le supplément ou l'aliment comprend un lipide complexe comportant un plasmalogène, etc. qui a été extrait et séparé des organes et des sites spécifiques dans le tissu vivant d'un poulet, et présente un rapport de composition propre au tissu vivant dans lequel un dérivé de ω-3HUFA comportant du DHA est transféré au tissu vivant d'un poulet élevé avec des aliments pour animaux comportant le dérivé de ω-3HUFA.
PCT/JP2017/017210 2016-05-02 2017-05-01 Plasmalogène sûr et stable, sa formulation et procédé permettant d'évaluer un état pré-symptomatique de démence Ceased WO2017191838A1 (fr)

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JP2019142818A (ja) * 2018-02-21 2019-08-29 丸大食品株式会社 リン脂質濃縮物生産方法
WO2020040291A1 (fr) * 2018-08-24 2020-02-27 日本薬品株式会社 Composition contenant du plasmalogène pour augmenter la capacité de mémorisation
US11142537B2 (en) 2018-02-21 2021-10-12 Marudai Food Co., Ltd. Phospholipid concentrate manufacturing method

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019142818A (ja) * 2018-02-21 2019-08-29 丸大食品株式会社 リン脂質濃縮物生産方法
WO2019163856A1 (fr) * 2018-02-21 2019-08-29 丸大食品株式会社 Procédé de production d'un concentré de phospholipides
KR20200122315A (ko) * 2018-02-21 2020-10-27 마루다이 푸드 가부시키가이샤 인지질 농축물 생산 방법
US11091720B2 (en) 2018-02-21 2021-08-17 Marudai Food Co., Ltd. Method for producing phospholipid concentrate
US11142537B2 (en) 2018-02-21 2021-10-12 Marudai Food Co., Ltd. Phospholipid concentrate manufacturing method
KR102802151B1 (ko) 2018-02-21 2025-05-02 마루다이 푸드 가부시키가이샤 인지질 농축물 생산 방법
WO2020040291A1 (fr) * 2018-08-24 2020-02-27 日本薬品株式会社 Composition contenant du plasmalogène pour augmenter la capacité de mémorisation
JPWO2020040291A1 (ja) * 2018-08-24 2021-10-07 日本薬品株式会社 記憶能力を増強するための、プラズマローゲンを含有する組成物
JP7751846B2 (ja) 2018-08-24 2025-10-09 日本薬品株式会社 記憶能力を増強するための、プラズマローゲンを含有する組成物

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