KR20190003570A - Methods for Determining Infectious Conditions of Safe, Stable Plasma Genogens, Agents and Dyslipidemia - Google Patents

Abstract

The present invention provides a safe and stable plasmaprogen, a preparation thereof, and a method for judging whether or not a cognitive impairment state exists. More particularly, the present invention relates to a method for determining containing complex lipid having a biomass-specific composition ratio in which the above-mentioned? -3HUFA derivative is transferred to the living tissue of a chicken raised with a feed containing an? -3-polyunsaturated fatty acid (? -3HUFA) derivative, Improvement or prevention of cognitive impairment with 3HUFA-binding plasma genogens or the like as an active ingredient, processed products as foods or preparations for treating neurodegenerative diseases and / or psychiatric disorders, Box) is used as a subject to determine the cognitive impairment state of the subject.

Description

Methods for Determining Infectious Conditions of Safe, Stable Plasma Genogens, Agents and Dyslipidemia

The present invention relates to a safe and stable plasma genome derived from a safe biological material, a preparation thereof, and a method for determining an incomplete state of dementia in which the subject is an adult (dry box) before the onset of dementia. More specifically, the present invention relates to a method for the production of EPA (eicosapentaenoic acid: a kind of ω-3 highly unsaturated fatty acid) at the SN-2 position of plasmarogens (hereinafter also referred to as "PLs" Stable PLA genogens by increasing the binding ratio of DHA (docosahexaenoic acid; representative omega-3 highly unsaturated fatty acid) to the PLA (minimizing the detection level (practically 0) Preparation of safe and stable aqueous preparations (laxates, jellies, solid, powders) made by simple nano-emulsification (or solubilization) using a safe surfactant and determination of the incidence of dementia by oral ingestion of these as supplements or foods And to new technologies and new products that contribute to inhibition, alleviation, and prevention of dementia caused by it for a long time.

Recently, a family that is likely to have a causative gene for familial Alzheimer's disease is traced to a long-term from a state before the onset of Alzheimer's disease (hereinafter referred to as " AD ") to 1) whether or not a change toward AD can be detected 2) research with a focus on Washington University DIAN ^* (John Morris, professor of unification) was carried out somewhat before symptoms appear in order to discover whether changes in the brain that appears.

* Dominantly Inherited Alzheimer's Network

According to Professor Maurice, the main target of the study is two-way analysis of the brain's image interpretation and the cerebrospinal fluid composition. Specifically, PET (Positron Emission Tomography) was used to examine accumulation of amyloid beta (hereinafter referred to as " A _beta "), which is considered to be one of the causes of AD, ) And the variance of A _β .

Based on the age of the subjects and the age at which the parents developed AD, we started the study by predicting the years until the onset of the subject. A are a number of materials, for example, that τ _β involved in the onset, including the data obtained were compared to determine what is going to change during the training a predictive carrier and non carrier. As a result, more than 25 from around the onset of the carrier brain A _β was confirmed clearly that starting gathering. However, after the onset, the curve was changed to decrease. In the case of τ, it became clear that τ of the carrier began to increase in cerebrospinal fluid from about 15 years before the onset. This indicates that nerve cells in the brain are beginning to die. In addition, the hippocampus responsible for memory began to gradually diminish about 15 years ago when AD developed. Ten years before the onset of illness, the weakness of memory and other symptoms gradually began to appear. However, it was after the onset of AD that forgetfulness, forgetfulness of the name of a close person, forgetting a promise to a person, or starting to cause disruption in daily life.

The outcome of this breakthrough DIAN study is a strong demand for a "paradigm shift" that forces a fundamental change in the medical coping strategies of conventional dementia. That is, in the case of conventional diagnosis, in case of manifestation of dementia, most end donation is caused, and the root indicates desperation. It is that contrast, that the beat of the certificate, the early prevention and that coming is an essential requirement as well, the brain accumulation of re-A _β and τ be a direct indicator of hospital beds progression of dementia, including Alzheimer's disease, and their The challenge is to demonstrate that the use of low-invasive, visualizable PET can not be missed.

In recent years, PLs have attracted attention as an active ingredient for the treatment and / or prevention of neurodegenerative diseases and psychiatric disorders (for example, Patent Document 1). PLs are a special phospholipid in vivo-reshaped, have a vinyl ether linkage at the SN-1 position, and thus have specificity for reducing properties. These PLs are specific and account for 18% by mass of the total phospholipids in the human in vivo, among which 20% by mass of the total phospholipids in the brain. It is not an exaggeration to say that it is one kind of universal phospholipid rather from the high content.

These PLs are functionally specific in that they exert an important reducing action in vivo, and their presence positions are localized in important membranes in vivo, directly preventing oxidation of various membranes. In addition, PLs have become increasingly attracting attention because it becomes clear that they express multifunctional functions particularly in the brain. However, as apparent from its molecular structure, PLs are susceptible to oxidation by inversion of the reducing nature (high susceptibility to radical scavenging) and are highly hydrolyzable by hydration under acidic conditions (decomposition into liposomes and aliphatic aldehydes of phospholipids). This is considered to be one of the causes that hinders practical organic synthesis of PLs.

As a result, PLs depend exclusively on extraction and purification from living tissues (for example, Patent Literature 2, Patent Literature 3, Patent Literature 4, etc.). In the living body, it is stabilized by a variety of endogenous structures depending on its importance, and it is always supplied by production from peroxisome of biosynthesis system, that is, an endoplasmic reticulum.

The following two tasks are required for PLs after the paradigm shift.

(1) In vivo, a variety of protecting-modifying functions for maintaining the homeostasis of PLs are automatically activated and stabilized, but in vivo, these protective functions are lost, so intentional artificial prescription or formulation is essential. Development of a safe and inexpensive stabilization technology of PLs to materialize this.

(2) Development of techniques to supplement and maintain the amount of PLs in the brain, especially in the living body, which decreases with aging.

[Safe and cheap stabilization technology]

Considering that the in vivo resurfacing structure plays an important role in maintaining the homeostasis of life by defending against various cell membrane attacks utilizing its strong antioxidative action as the most important constituent of the cell membrane, the lipid 2 as a pseudo- It is judged that it is appropriate to form the medium membrane (liposome) as usual, in other words, emulsified dispersion utilizing its self-emulsifying property, among which microemulsification or solubilization type prescription formulation. Further, it is easy to know which molecular species to introduce at the SN-2 position adjacent to the vinyl ether bond on the basis of the expression of a strong antioxidative activity in the molecular structure, and details thereof will be described in detail as a "bulk effect" For example, DHA. The other chemical effect of DHA is its antioxidant properties, and with the above physical and chemical action, DHA-conjugated PLs are modified into multiple self-stabilizing forms.

[Technique for regularly supplementing and maintaining the amount of PLs in the brain]

The core of the homeostasis of in vivo PLs is the peroxisome of the biosynthetic system, which is barely active. As described later, the synthesis of higher alcohols forming the core of the multistage biosynthetic system is identified with Far1 (fatty acyl-CoA reductase 1) as its biosynthesis rate-determining enzyme. As described later, it is reported that DHA phospholipids, among them DHA type PLs, exert an up-regulation of the rate-limiting enzyme, thereby promoting the production of Pls in peroxisome.

Poultry, especially scattering (also called clouding), is a main raw material for extraction of PLs (for example, Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4, etc.). In addition, recently, as a raw material for extraction, the interior of a sea urchin derived from a fish (Patent Document 5) and the endosperm of a scallop (for example, Patent Document 6) have started to be used. In cultured bivalves, the concerns about the podok, especially cadmium, accumulating from the environment are not completely eradicated. On the other hand, seawater-resistant PLs are characterized in that DNA and EPA are bound together at SN-2 position. EPA-binding PLs are not introduced into the brain because they are blocked in the blood-brain barrier, and only the DHA-binding type is attracting attention in the brain. In the method of breeding chickens with DHA feed according to the present invention, which will be described later, only DHA-conjugated PLs with high selectivity are produced, so that the efficiency is high and safe.

The presence form (binding molecule) of DHA in vivo is glycerophospholipid, especially ethanol amine type. DHA is mostly bound to the SN-2 position (the only optically active carbon in glycerol phospholipids). Of the fatty acids derived from living organisms, DHA has the highest structural specificity. DHA has a long chain, and therefore, the number of double bonds is very large as 6, and a plurality of bisallyl structures ((-CH = CHCH ₂ -) ₂ CH ₂ -) exist. The methylene carbon has a high oxidation sensitivity and is a major cause of the oxidation of DHA. However, when O / W emulsification (water-in-oil emulsification) is carried out, the permutation of the oxidation stability varies in the opposite manner (the numbers in the parentheses indicate the number of double bonds) (see, for example, Non-Patent Document 1).

* Normal stability permutation;

(2)> linolenic acid (3)> arachidonic acid (4)> EPA (eicosapentaenoic acid) (5)> DHA (6)

* Stability permutation of O / W emulsion type (underwater type);

DHA (6)> EPA (5)> Arachidonic acid (4)> Linolenic acid (3)> Linoleic acid (2)

It is strongly suggested that DHA is bound to glycerol phospholipids (which are amphipathic and have interfacial activity) in vivo, and that DHA is stabilized in a self-emulsifying state. In addition, it has been reported that DHA is highly selective in vivo, particularly in the brain, and is thus linked to the SN-2 position of PLs (for example, Patent Document 2), and the vinyl ether linkage at the SN- DHA binds to the SN-2 position, which is believed to be doubly stabilized by the following 1) to 2). In other words,

1) The bulk conformation of DHA manifests a steric hindrance effect and hinders access to the SN-1-position vinyl ether linkage of the oxidized active species.

2) Since the molecules are retained in the emulsified state by the self-emulsification function of the DHA-conjugated PLs, they are protected from further oxidization and hydration because they exist in the microcapsules in the microcapsule.

DHA and other polyunsaturated fatty acids (PUFAs) in the fish are the food chain. The animal, which eats phytoplankton containing a large amount of α-linolenic acid in the sea, calls it EPA and DHA and a small fish feeds it (See, for example, Non-Patent Document 3).

It is considered that the way to obtain safe and stable PLs is most reasonable to go through biometry. For example, as a living body, a scattering system having a practical use record of DHA eggs has been proposed, and in particular, a waste system of a scattering system (a scattering system caused by a decrease in scattering efficiency), more preferably a forced detoxification A two-way method for improving the efficiency). In addition, the laying hens are literally poultry for the purpose of scattering, and even the same chicken is a poultry that is different from the broiler for the purpose of harvesting. From the circumstances of distribution of the eggs, the laying hens are raised in the vicinity of the consuming area in addition to the scale of about 1/10 of the broiler (the size of the breeding is 10 million to tens of millions).

Generally, the annual amount of egg scatter per egg in this laying hens is 300 or more. When the ages are about 700 days, they are dismantled as waste streams, and the slaughterhouses are dismantled at the special waste disposal center (located in about 40 places nationwide and millions to millions of disposal capacity) . Although the processed product is provided for edible purposes, most of the processed product is sold in the form of minced meat as a raw material for cold meat processing. Laying hens were forced to sell cheaply in price competition with bulk imported frozen chickens. However, recently, due to the safety orientation of consumers, there is a tendency for prices to increase with added value as Japanese meat. However, laying hens can not compete economically with the vertical integrated poultry by tens of millions of specimens dedicated to the poultry, and the quality of the poultry farms can not stand up to the 50-day-old oyster taste. It continues.

In this situation, it should be noted that the annual average number of eggs produced in the scattering system is increased to 90 million, and the poultry delivery price is generally cheap, for example, 0 yen evaluation. In addition, since the degree of integration of the generation is high and the high-grade treated product such as a broiler can be obtained because it is brought into the waste system treatment center as a live chicken.

As a general rule chicken is an artificial breeding product, but at the genetic level it belongs to the bird. In addition, as an example of a dinosaur with a "gas-filled respiratory organ" ([Non-Patent Document 4]), a unique respiratory machine, and a "gas-filled respiratory organ" ([Non-Patent Document 5]). Its specificity is that the intake and exhaustion, which are the characteristic features of the air-bag, respectively, result in a much higher rate of metabolism, as much oxygen is introduced in comparison to mammals. This is the amount of feed required to obtain 1 kg of edible portion, which is sufficient for a typical livestock pig of 9.1 kg and beef cattle of 25.0 kg. Exceeding this is lacking palatability and versatility, but it is said that only 2.1 kg of cricket is produced (published in FAO 2013).

Many of the chicken tissues, organs and organs are unique to mammalian livestock. (Usually treated as industrial waste) or breast (distributed as edible mince such as "myocardium"), thigh-removed breasts Egg yolk ", egg yolk, bone marrow (contained in raw bone), and the like. DHA can be delivered to the tissues, sites and organs by administering DHA-containing feed to the laying hen for several weeks. As a form of DHA source and form to be added to the feed, fish oil and micro oil emulsification (preferably solubilized) are added to the feed.

It is important that a tissue or the like containing the DHA transition type PLs or the like be treated with a unique processing process that is important to obtain the object without reducing its specificity. As a treatment product thereof, for example, a complex lipid composition comprising a DHA-conjugated PLs-containing complex lipid retaining the above material-specific composition ratio, a lipid-soluble low molecular weight fraction (see below) added thereto, A complexing composition of protein and lipid in which the red protein fraction (see ** below) is restored, and various aqueous preparations in which they are microemulsified (solubilized).

* --- free amino acids, anserine or carnosine (reductive dipeptides such as [non-patent reference 19], coenzyme Q10 (involved in the transfer of electrons), carnitine It has lipid metabolism hyperactivity function and is effective in improving inhibition of [hyperlipidemia / hyperglycemia], which has a high risk factor activity of dementia, and can be an adjuvant of plasmarogens.

** --- For example, [myocardium] such as "breasts" or bone marrow collagen protein, skin collagen protein and so on.

As for the above-mentioned various compositions and aqueous formulations, it is a global universal incurable disease, and it is excommunicated in the conquest of dementia including AD, which is a global and troublesome problem held to the summit aiming at the root ([Non-Patent Document 6]) And the possibility of causing the disease is reported. In recent years, even in the case of acute brain injury such as AD, Parkinson's disease, amyotrophic lateral sclerosis (sometimes referred to as "ALS" hereinafter), chronic neurodegenerative diseases such as multiple sclerosis or stroke or head trauma, Brain, spinal cord, and the like). ≪ / RTI >

It is also conceivable that these diseases may be caused by central inflammation (Non-Patent Document 7). For example, it has been reported that central nervous system inflammation is likely to cause neurodegenerative diseases such as AD or to promote disease (see, for example, Non-Patent Document 7). In addition, an analysis of memory failure model rats produced by intraperitoneal administration of LPS (lipopolysaccharide), which is an inflammatory substance, revealed that accumulation of A _? Peptide in the brain, sulindac sulfide (Non-Patent Document 8). It has also become clear that the central nervous system inflammation is confirmed at a high rate in mental disorders such as depression and autism, developmental disorders, and normal aging processes.

In view of the above, prevention or treatment of central nervous system inflammation and related neuronal cell death (Non-Patent Document 9), inhibition of neuronal cell death (Patent Document 7), and accumulation of A _? It is expected to prevent neuropathy caused by damage or to treat neurodegenerative diseases such as AD and Parkinson's disease or to treat mental diseases or developmental disorders such as integrated ataxia, depression, autism (see Non-Patent Document 8 ]). Based on these findings, it is more desirable to treat central nervous system inflammation effectively and without side effects.

Under such circumstances, the present inventor succeeded in proving that it is possible to improve the cognitive function of an adult (dry box) before the onset of dementia using an innovative plasma composition derived from chicken breast by an innovative clinical test method, To complete it. The results of clinical trials have been published in the December issue of "Clinics and New Drugs", 53, which has been reviewed with titles of INPROVEMENT IN COGNITIVE FUNCTION BY SUPPLEMENT CONTAINED PLASMALOGEN FOR HEALTHY JAPANESE-A RAMDOMIZED, DOUBLE-BLIDED, and PLASEBO-CONTROLED STUDY Non-Patent Document 25). This innovative achievement is expected to contribute to the effective suppression of central nervous system inflammation and the like as a result of being able to hold a countermeasure for preventing and / or relieving central nervous system inflammation and the like in the future.

Japanese Patent No. 5847086 Japanese Patent No. 5062873 Japanese Patent No. 5774816 Japanese Patent No. 5430566 Japanese Patent Application Laid-Open No. 2007-262024 Japanese Patent Application Laid-Open No. 2006-121957 Japanese Patent No. 6016363 Japanese Patent No. 5540209 Japanese Patent No. 5360454 Japanese Patent No. 5704493 Japanese Patent No. 5784486 Japanese Patent Application Laid-Open No. 60-51104 Japanese Patent Application Laid-Open No. 57-59629 Japanese Patent Application Laid-Open No. 60-64919 Japanese Patent No. 6025568 Japanese Patent No. 4047354 [New Ravirintullah microorganism having high productivity of docosahexaenoic acid and its use] (Hokkaido University, etc.) Japanese Patent Application No. 2007-148398 [Process for producing phospholipids containing DHA by microbial fermentation] (Hokkaido University)

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The present invention is intended to provide a safe and stable PLs and a preparation thereof, a food containing them, a cosmetic product, a medicament or a feed, and a method for judging an incurable disease state of dementia.

The present inventors have surprisingly found that PLs can be safely stabilized not only by introducing DHA at the SN-2 position in the PLs molecule, but also by easily converting nano-emulsions (solubilizing) the PLs into shape, It was confirmed that the improvement effect was manifested, and that the integrated cost-effective effect was remarkably improved, and the research and development was repeated to complete the present invention.

That is, the present invention comprises the technical means described in the following paragraphs.

(1) a biological tissue-specific composition ratio comprising a purified fraction of a total lipid, which is extracted and extracted from a specific site or organ of a living body derived from a living body tissue and in which a by-product protein fraction and / or a water-soluble low- (Hereinafter referred to as " complex lipid "),

1) The specific part or organ derived from the living body tissue is a carcass derived from a living tissue of a chicken, a raw bone including a bone marrow, an egg yolk, a bowel, a sand bag, a brass including a ovary and a fallopian tube, At least one or more specific sites or organs selected from the group consisting of < RTI ID = 0.0 >

2) The plasmalogen-containing phospholipid is an ω-3 highly unsaturated fatty acid (hereinafter referred to as "ω-3HUFA") derivative (hereinafter collectively referred to as "ω-3HUFA derivative") containing docosahexaenoic acid (DHA) 3HUFA derivative in which the above-mentioned ω-3HUFA derivative is extracted from a specific site or organ of a living body in which the ω-3HUFA derivative has been transferred to the living tissue of a chicken raised with a feed containing the ω-3HUFA derivative Wherein the phospholipid is a plasma-containing phospholipid having a composition ratio of the plasma lipid.

(2) The complex lipid according to (1), wherein the? -3HUFA derivative is any one selected from the following 1) to 9).

1) ω-3HUFA derivative bound to SN-2 of glycerophosphatidyl phospholipid

2) ω-3HUFA derivative bound to SN-2 of 1-alkylglycerophosphatidyl phospholipid

3) ω-3HUFA derivative bound to SN-2 of 1-alkenyl glycerophosphatidyl phospholipid

4) ω-3HUFA derivative bound to SN-2 of 1-acylglycerophosphatidyl phospholipid

5) An omega-3HUFA derivative bound to SN-2 of the glycerophosphatidyl phospholipid described in any one of 1) to 4) above, which is contained in krill-peeled shrimp flesh and /

6) An omega-3 HUFA derivative bound to SN-2 of the glycerophosphatidyl phospholipid described in any one of 1) to 4) contained in the whole scallop and / or its processed residue or the mill (dried product)

7) An omega-3 HUFA derivative bound to SN-2 of the glycerophosphatidyl phospholipid described in any one of 1) to 4) contained in the whole seaweed and / or the processed residue thereof or the mill (dried product thereof)

8) An omega-3 HUFA derivative bound to SN-2 of the glycerophosphatidyl phospholipid according to any one of 1) to 4)

9) An omega-3 HUFA derivative bound to SN-2 of the glycerophosphatidyl phospholipid described in any one of 1) to 4) prepared by fermentation

(3) The complex lipid according to (1), wherein the specific region or organs is egg yolk, and the purified lipid is extracted from egg yolk containing DHA-PLs biosynthesized in the body of the chicken.

(4) A complex lipid comprising the total lipid purified from a specific part of a living body or an organ of a chicken raised in a feed containing an organic synthesized 1-alkylglycerophosphatidyl phospholipid.

(5) The complex lipid composition according to (1), wherein the complex lipid has the composition ratio of? -3HUFA bond type containing a water-soluble low-molecular fraction produced as a by-product in the above-mentioned (1).

(6) A lipid or lipid composite composition having an omega-3 HUFA binding-type composition according to any one of (1) to (5) above, which is nano-emulsified or solubilized in the presence of saponins in the aqueous phase. Aqueous preparation of a composite lipid composition having a composition ratio of a complex lipid or an? -3HUFA binding type.

(7) A method for producing a liposome comprising the steps of enzymatically treating the complex lipid according to any one of the above (1) to (4) with a phospholipase A1 (PLA1) to remove glycerol- Wherein the purity of the plasma is about 30 to 70%.

(8) A method for producing a plasma plasminogen or a high purity plasmaprogenic compound as described in (7), which comprises nano-emulsifying or solubilizing each of the prepared plasmalogen or high purity plasmalogen as a substrate in aqueous phase in the presence of saponins ≪ / RTI >

(9) A food comprising as an active ingredient at least one selected from the compound lipids, the complex lipid compositions, the plasma plasmids and aqueous formulations thereof according to any one of (1) to (8) , Cosmetics, medicines or feed.

(10) A pharmaceutical composition comprising, as an active ingredient, at least one selected from the group consisting of the complex lipid, the complex lipid composition, the plasma logen, and each of the aqueous preparations thereof according to any one of (1) to (8) And at least one kind of neurodegenerative disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, depression, and ataxia.

(11) A pharmaceutical composition comprising, as an active ingredient, at least one selected from the group consisting of the complex lipid, the complex lipid composition, the plasmarogens, and the respective aqueous preparations thereof according to any one of (1) to (8) Wherein the at least one neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, depression, and ataxia. Anti-central nervous system inflammatory agent.

(12) A pharmaceutical composition comprising, as an active ingredient, at least one selected from the group consisting of the complex lipid, the complex lipid composition, the plasma logen, and each of the aqueous preparations thereof according to any one of (1) to (8) Neuronal cell neoplasms.

(13) A pharmaceutical composition which comprises, as an active ingredient, at least one selected from the group consisting of the complex lipid, the complex lipid composition, the plasmarogens, and the aqueous preparations thereof according to any one of (1) to (8) An inhibitor of neuronal apoptosis.

(14) A pharmaceutical composition which comprises, as an active ingredient, at least one selected from the group consisting of the complex lipid, the complex lipid composition, the plasma logen, and the respective aqueous formulations thereof as described in any one of (1) to (8) A _{< RTI ID = 0.0 >} and / or &_lt; / _RTI >

(15) A pharmaceutical composition containing, as an active ingredient, at least one selected from the group consisting of the complex lipid, the complex lipid composition, each plasmarogens, and each of the aqueous preparations thereof according to any one of (1) to (8) And / or at least one action selected from the group consisting of anti-central nervous system inflammation, neuronal cell death, inhibition of neuronal cell death, and inhibition of accumulation of A _? Medicines for the improvement of mental illness or processed products as food.

(16) A pharmaceutical composition comprising a protein fraction as a by-product according to any one of (1) to (4) above, and a complex having a biom tissue-specific composition ratio containing a water-soluble low molecular fraction as a by- A lipid composition, and a lipid composition.

(17) The composite composition of the protein / lipid according to (16), wherein the complex protein / lipid composition comprising the mixture of the protein fraction and the complex lipid composition described in the preceding paragraph is derived from egg yolk.

(18) A pharmaceutical composition comprising the complexed composition of protein and lipid according to (16) or (17) as an active ingredient and is useful as an anti-central nervous system inflammatory agent for improving neurodegenerative diseases and mental disorders, And inhibiting the accumulation of A _{? In the} brain, as a medicament for the treatment of neurodegenerative diseases and / or mental disorders, or a processed product as a food.

(19) A liposome according to any one of (1) to (8), wherein the liposome comprises a complex lipid, a complex lipid composition, a plasma reactor or a high purity plasmalogen, (Gun box) before the onset of dementia in a state in which accumulation of physiologically harmless amounts of A _? And? In the brain is confirmed (hereinafter referred to as " dementia-infected state "),

(1) on the basis of the PET image SUVR values (scores) of A _β and by the rank of the accumulation in brain state of τ in order to examine the use of PET A _β and the τ accumulation in brain state determining mibyeong state or the subject certificate A step carried out by division,

1) Accumulation I period: 1.0 ± 0.2

2) Accumulation intermediate stage Ⅱ: 1.2 ± 0.2

3) Accumulation phase III: 1.4 ± 0.2

(2) a step of testing a dose response to a test subject of the plasma by the appropriate frequency over a long term of 3 to 10 months and setting an appropriate dose range or anticipated range by:

1) Subjects in phase I; &Quot; Increasing " range: 1.0 ± 0.15

2) subjects in stage Ⅱ; Expected range of "zero": 1.2 ± 0.15

3) Subjects in phase III; "Decrease" expected range: 1.4 ± 0.15

(3) a step of continuously administering to the subject of the adult (gun box) before the onset of the dementia, a supplement containing the plasma dose of the set daily dose as an active ingredient or a processed product as a food from the stage before the onset of dementia ,

(4) a step of periodically performing the PET diagnosis of the predetermined accumulation state of A _? And? At a suitable frequency during the long-term administration,

(5) a step of performing MRI diagnosis of the depression state of the hippocampus at an appropriate frequency during the long-term administration period in parallel with the periodic PET diagnosis,

(6) A method for judging a subject's cognitive impairment state, characterized by determining the cognitive impairment state of the subject by executing the steps (1) to (4) or the steps (1) to .

In addition, the present invention may include the following embodiments as specific matters of the invention according to the respective inventions described above.

(1) As an extractive fractionation method, three phases ("insoluble solids such as protein minerals" (sediment), "neutral lipids" (upper layer) and "functional ethanol Water-soluble low-molecular species, polar lipids) ").

(2) After the alcohol having a functional ethanol fraction, hexane is added thereto to separate and separate water-soluble low molecular weight components, and hexane is evaporated to obtain a polar lipid component (complex lipid).

(3) As the enzyme treatment process, the phospholipid obtained by evaporating and drying the separated ethanolic phase is subjected to PLA1 enzyme treatment to purify the plasma.

(4) Ethanolamine in each plasmalogen containing plasmalogen and choline plasmogen.

(5) Ethanolamine contained in each plasmalogen A plasma mass ratio of [1: 5] to [5: 0.01] in plasma and plasma.

(6) The oral dosage of DHA-containing plasmalogen is 0.01 mg to 10 mg, for example, 0.25 mg (preferably, less than or equal to 0.1 mg) per day.

(7) A PET used for diagnosis of accumulation of _β and τ in the brain is helmet-type PET dedicated to head.

(8) Plasma gonad has been administered from the 30s to the 40s more appropriately.

Hereinafter, the present invention will be described in detail. Biomaterials containing PLs have been heretofore used as edible phospholipids PLS. Therefore, the PLs extracted from the living body tissue according to the present invention are considered to have high safety because there is little concern about side effects and the like. However, once the PLs are extracted and separated from living tissue, the stability is lost momentarily, and the vinyl ether bond is exposed to the crisis of decomposition. That is, this means that the [strong-reducing] vinyl ether bond is a strong [disassociable] (= " biodegradable ") and it is necessary to take any appropriate defensive measures in order to utilize this effectively.

The inventor of the present invention has conducted intensive research on the above-mentioned countermeasures of rational overtaking of the " anti-rationality ", and found that three methods are effective. One is to rationally nanoise PLs and the second is to reasonably introduce DHA into the molecule of PLs, SN-2. The integration of these two, that is, the nano emulsification of DHA-conjugated PLs, is the strongest rational defense. The term "rational" as used here means that the overall cost-effectiveness ratio is significantly higher, which means realizing "safe and practical stabilization".

The third is to take the "ether phospholipids" with the molecular structure of [alkylphospholipid] as a feed to chickens in a "one and a half" manner in a natural way. This resulted in the remarkable increase in the alkylphospholipid and PLs in the serum by 1% by mass of the alkylphospholipid concentrate derived from the krill of the study results of HARA called HARA effect for 8 days in rats, -2 < / RTI > conjugated lipid class. That is, the present inventor has succeeded in making the present invention more rationalized and high-quality by utilizing the above-mentioned [HARA effect] as follows.

It has surprisingly been found that 1-alkenyl-2-docosahexenoyl-glycerophospholipid and 1-alkenyl-2-docosahexenoyl-glycerophospholipid in the egg yolk of scattering results from the administration of a suitable alkylphospholipid containing material, alkyl-2-docosahexenoyl-glyc-erophospholipid was produced with high selectivity, that is, it contained almost no EPA-conjugate.

In addition, administration of the egg yolk-enriched egg yolk oil to rats showed that 1-alkenyl-2-docosahexenoyl-2-docosahexenoyl-glycerophospholipid in serum was remarkably increased.

The significance / superiority of the above method in improving the [integrated cost-effectiveness ratio] of increasing PLs in vivo

(1) a selective and highly stable biosynthetic method of DHA-PLs and its precursor [DHA-ether phospholipid]

(2) a highly rational organic compound, such as an ether phospholipid, an alkyl glycerophospholipid or its DHA-linked [DHA-ether phospholipid] ] Can be put to practical use with a high [cost-effectiveness ratio]

(3) [Conversion to a living body type] As described above, chicken is a super artificial animal, and the rate of its metabolic rotation does not allow other followers, that is, ]] × [Safety is high, but productivity is low [Biosynthesis]], and safety and low-cost production can be achieved.

(Effects of the Invention)

The present invention exhibits the following special effects by employing the above configuration.

(1) In the present invention, an adult (dry box) before the onset of cognitive impairment in a state in which accumulation of physiologically harmless A _? And? In the brain is confirmed (cognitive impairment state) As shown in FIG.

(2) The present invention is useful as a supplement for alleviation and prevention of dementia or a processed product as food.

(3) A supplement for relieving and preventing neurodegenerative diseases (dementia, AD, Parkinson's disease, depression, and ataxia) containing the safe and stabilized PLs of the present invention as an active ingredient (Non-Patent Document 16) , wherein the central nervous system inflammatory agents (non-Patent Document 8 and Patent Document 1), neuron new formulation (Patent Document 7), apoptosis inhibiting agents of the nerve cells (non-Patent Document 9), and a _β ([Non-Patent Document 8]), it is possible to provide a supplement or preparation for preventing, alleviating, improving and treating the symptoms of general cognitive impairment / dysfunction.

(4) As one of the causes of inflammation of the central nervous system, it is thought that activated glial cells present in the central nervous system release inflammatory cytokines. However, the anti-central nervous system inflammatory agent of the present invention is effective in preventing inflammation of the central nervous system And has an increasing inhibitory action on glial cells which are increased and activated. It is possible to alleviate, prevent, improve, and treat central nervous system inflammation by the above action.

(5) chronic neurodegenerative diseases such as dementia (especially AD), Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, and diseases characterized by inflammation of the central nervous system, The anti-central nervous system inflammatory agent of the present invention may be suitably used for the treatment of mental disorders such as depression and autism.

(6) PLs are components contained in many tissues of living tissues. In addition, since biomolecules including PLs have been conventionally provided for food, safety has been demonstrated, and the brain of the present invention including PLs extracted from living tissue Suppression of functional impairment and prevention, anti-central nervous system inflammatory agent, neuronal neovascularization agent, neuronal apoptosis inhibitor agent, and inhibitor of accumulation of A _? And? In the brain are very safe because there is no worry about side effects.

Fig. 1 shows a three-step question for selection of subjects on cognitive function.
2 shows a sheet for MMSE.
Figure 3 shows a questionnaire for cognitive function diagnosis.
Figure 4 shows the test results of the MMSE.
Figure 5 shows the results of a UK test.

Hereinafter, the present invention will be described in more detail.

The present invention is a safe, stable PLs and their preparation, and cognitive function, relief of disturbance and supplement for the prevention, wherein the central nervous system inflammatory agents, neuron new formulation of neuronal apoptosis inhibiting agent and A _β and the accumulation in brain of τ inhibiting agents , And to a method for determining a dementia-free condition that contributes to inhibiting the onset of dementia through their oral ingestion.

Here, PLs is a type of ether phospholipid, and glycerophospholipid having a long-chain alkenyl group through vinyl ether bond in SN-1. In addition, PLs is a generic term for special phospholipids having general-purpose and strong reducing properties which occupy 18% by mass of phospholipids in vivo. This specificity is a cause of imparting significant oxidative decomposition and hydrolysis properties to PLs. For this reason, in the practical use of PLs, a rational breakthrough is required in the face of the classic idea of "half-nakedness". The present inventor has succeeded in achieving the above-mentioned " antipodality " idea rationally, that is, achieving stabilization at low cost and safe means while maximizing the original functionality of the PLs.

The PLs to be used in the present invention are preferably extracted and fractionated from a living tissue of a chicken. Biological tissue is a tissue containing PLs in living organisms. Here, as a general description, the organisms include, for example, animals and microorganisms. As the microorganism, anaerobic bacteria are suitable, and bacteria such as Acidaminococaceae of intestinal bacteria are particularly preferable. In the case of bacteria, "biological tissue" is the bacteria itself. As an animal, algae, mammals, fish, krill, shellfish and the like are suitable. In mammals, livestock is preferred from both aspects of its supply stability and safety, and examples include cattle, pigs, horses, sheep, and chlorine.

The main tissues of mammals for raw materials include skin, brain, intestines, heart, genitalia, muscle, vertebrae, and breast, and PLs can be extracted from these tissues (organs and parts). Examples of algae include chickens, ducks, quails, ducks, pheasants, ostriches, and turkeys. From the achievement, cost, and abundant eating experience, chicken, especially laying including breeder, is particularly suitable. The tissue to be used is not particularly limited, but it is preferable to use, for example, breast, chicken skin, viscera (especially a bowel, ovarian trough corium, sand bag, liver), egg, bone .

In the present invention, PLs extracted and separated from a chicken tissue are used as PLs extracted and extracted from a living tissue. Chickens, which have been regarded as edible in the past, are suitable because they are safe and stable. As a method for extracting and separating PLs from a living body tissue, there is no particular limitation as long as PLs can be extracted (and purified if necessary), but it is preferable to extract and purify them as described below from the standpoints of simplicity and cost. Further, according to the extraction and purification method described above, the phospholipid can be decomposed and removed with the diacyl-type glycer, which is preferable in that the purity of PLs can be further increased.

Specific examples of the step of extracting and purifying PLs include the following steps 1) to 5).

(1) A process of extracting and extracting total lipid fractions (including low molecular weight water soluble fractions) from biological tissues into three phases of protein fractions and neutral lipid fractions.

Specifically, the following processes are exemplified.

1) Process of slow freezing of raw tissue by minification

2) High-speed cooked and sterilized by forced degassing after freeze-thawing and squeeze-dewatering with a "superheated water" (aquagase ^RTM ; [Patent Document 8], [Patent Document 9], [Patent Document 10], [Patent Document 11] Vacuum High-speed cooling (cooling and dehydrating in an oxygen-free atmosphere)

3) A step of adding deaeration (deoxygenated) ethanol three times (V / W) after the dewatering treatment and performing the extraction by gentle stirring for 12 hours under sealed oxygen-

4) Repetition of the above steps

5) After the ethanol is coalesced, the ethanol fraction is distilled off in an oxygen-free atmosphere and centrifuged to separate the aqueous layer (water-soluble low molecular weight fraction) to obtain a total lipid fraction (water-soluble low molecular weight fraction is freeze-dried separately)

(2) a step of extracting a complex lipid 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 process and adding it to the complex lipid fraction to obtain a complex lipid composition.

(4) A step of fractionating the protein fractions from the above-mentioned steps and adding the complex lipid composition of the foregoing item to the resultant to obtain a protein / lipid composite composition.

(5) Hydrolysis of SN-1 binding fatty acid by adding enzyme to complex lipid fractions, conversion of diacylglycerol to phospholipids, and purification of PLs by extraction with hydrophilic solvent together with by-product fatty acids Process.

The extraction is preferably carried out with an organic solvent (for example, one having food suitability such as ethanol, acetone, hexane, etc., and a mixed solvent of at least two kinds selected from the group consisting of these) or a water-soluble organic solvent. Also, the chicken tissues provided for the extraction are suitably treated in the processes of (1) and (2) above. That is, in order to minimize the amount of ethanol used in the three-phase fractionation by ethanol in the subsequent step, it is required to perform degreasing and dehydration as far as possible from the raw tissue in an oxygen-free atmosphere at low temperature and in a short time.

What is crucial for the extraction treatment conditions is to perform a short-time agitation treatment at a low temperature in an oxygen-free atmosphere under a sealed condition in order to minimize the oxidative decomposition and hydrolysis of the contained PLs. As a suitable example, there is exemplified a method in which ethanol is added to the peeled meat of a scattering system which has been treated in the pretreatment (1) and (2) described above and the mixture is allowed to stand for at least 180 minutes at a temperature of not lower than 50 ° C . 2 to 4 L of ethanol having been subjected to deaeration (deoxygenation) treatment in advance is added to 1 kg of the breasts, and the mixture is sealed or gently stirred.

In the ethanol fraction, the water layer is separated by concentrating the ethanol by evaporation, and then the dephosphorylated hexane is added to extract the phospholipid fraction. The separated aqueous layer and the hexane insoluble layer were added together with deaeration water, and the mixture was allowed to stand at 4 ° C and then centrifuged at low temperature to remove the insoluble portion, followed by lyophilization to obtain 18 g of low-molecular water-soluble fraction. On the other hand, a hexane solution is evaporated and dried by a conventional method to obtain 7 g of a complex lipid fraction. The low-molecular water-soluble fraction is added to the phospholipid fraction to obtain 25 g of a composite lipid composition.

The phospholipid fraction may be subjected to an enzymatic hydrolysis treatment process and the diacyl phospholipid may be hydrolyzed to preferably concentrate the PLs. An example of such a hydrolysis treatment is an enzyme treatment with a phospholipase A1 (hereinafter referred to as "PLA1") (Patent Document 4). When treated with PLA1, phospholipids are decomposed into free fatty acids and lysophospholipids by mixed diacyl-type glycerol, and they can be purified by extracting and dispensing them with acetone and hexane. Removal of free fatty acids and lysophospholipids can be carried out, for example, by dispensing with acetone and hexane.

The origin of PLA1 is not particularly limited as long as the above effect can be obtained. For example, PLA1 derived from Aspergillus oryzae can be mentioned. The PLA1 can be purchased from, for example, Mitsubishi-Chemical Foods Corporation. The amount of use can be appropriately set in accordance with the amount of composite soil to be obtained. Preferably 0.2 to 200 units / 1 mg of complex lipid, and more preferably 2 to 200 units / 1 mg of complex lipid can be used. In addition, 1 unit is an amount that changes 1 mu mol substrate (complex lipid) per 1 minute, and it means 1 mu mol / min.

The buffer to be used can also be appropriately selected according to PLA1. For example, 1 g of a complex lipid may be dissolved in 1 to 30 ml, preferably 5 to 15 ml per 0.1 g of a 0.1 M citric acid-hydrochloric acid buffer (pH 4.5) per 1 g of the complex lipid, and a predetermined amount of PLA1 may be added . The reaction conditions are as follows. The enzyme reaction is carried out in a nitrogen gas atmosphere in a degassed buffer for as short a time as possible, preferably for 1 hour, and at a temperature as low as possible, preferably 50 ° C as an upper limit.

After the completion of the reaction, the reaction mixture was cooled to room temperature, and dehydrogenated hexane was added in an amount of 2 to 3 times the amount of the reaction solution. The hexane phase of the upper layer was recovered by centrifuging to remove the enzyme buffer and the enzyme protein Remove. The hexane solution is appropriately added with acetone and water to carry out the partitioning, and the solution is distributed with water or an aqueous solution to remove the lysophospholipid to purify the plasma lysogen. That is, neutral lipids other than the phospholipids are removed by acetone, and plasma and lysophospholipids are separated by plasma-based solution dispensing. The plasmogen derived from the living body tissue thus obtained is preferably used as a supplement for alleviating and preventing cognitive dysfunction of the present invention, an anti-central nervous system inflammatory agent, a neuronal neoplasia preparation, an apoptosis-inhibiting agent for neuronal cells, and / A _{< /} RTI _> brain accumulation inhibitory agent.

The phospholipids and their composition ratios of biologically derived complex lipids (including complex lipid compositions) and PLs have unique characteristics due to biotissues. The composition ratio in the case of the scattering system will be described below.

1. Shell

(1) PLs; [Ethanolamine type]: [Choline type] = [1 to 10]: 1

(2) diacylglycerol phospholipids; [Ethanolamine type]: [choline type] = 1: [1.5 to 15]

(3) [ether glycerophospholipid]: [diacylglycerophospholipid] = 1: [0.5 to 5]

(4) [Total glycerophospholipid]: [total sphingomyelin] = [1.5 to 10]: 1

2. Hitting conductor (peeling)

(1) PLs; [Ethanolamine type]: [Choline type] = [0.5 to 5]: 1

(2) diacylglycerol phospholipids; [Ethanolamine type]: [choline type] = 1: [2 ~ 15]

(3) [ether glycerophospholipid]: [diacylglycerophospholipid] = 1: [0.5 to 5]

(4) [total glycerophospholipid]: [total sphingomyelin] = [3 to 20]: 1

3. yolk

(1) PLs; [Ethanolamine type]: [choline type] = 1: [0.1 to 1.5]

(2) diacylglycerol phospholipids; [Ethanolamine type]: [choline type] = 1: [2 ~ 20]

(3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: [10-50]

(4) [total glycerophospholipid]: [total sphingomyelin] = [40 to 350]: 1

4. Sandbags

(1) PLs; [Ethanolamine type]: [Choline type] = [2 to 15]: 1

(2) diacylglycerol phospholipids; [Ethanolamine type]: [choline type] = 1: [1 to 10]

(3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: [0.5 to 6]

(4) [total glycerophospholipid]: [total sphingomyelin] = [1 to 10]: 1

Chapter 5

(1) PLs; [Ethanolamine type]: [Choline type] = [2 to 15]: 1

(2) diacylglycerol phospholipids; [Ethanolamine type]: [choline type] = 1: [2 ~ 20]

(3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: [1 to 12]

(4) [total glycerophospholipid]: [total sphingomyelin] = [1 to 10]: 1

6. Bone

(1) PLs; [Ethanolamine type]: [Choline type] = [1 to 10]: 1

(2) diacylglycerol phospholipids; [Ethanolamine type]: [choline type] = 1: [2 ~ 20]

(3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: [1 to 10]

(4) [total glycerophospholipid]: [total sphingomyelin] = [3 to 25]: 1

7. Brass (including ovaries)

(1) PLs; [Ethanolamine type]: [Choline type] = 1: [0.0001 to 0.1]

(2) diacylglycerol phospholipids; [Ethanolamine type]: [choline type] = 1: [1.5 to 15]

(3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: [15 to 130]

(4) [total glycerophospholipid]: [total sphingomyelin] = [20 to 200]: 1

8. Bone marrow

(1) PLs; [Ethanolamine type]: [Choline type] = 1: [0.0001 to 0.1]

(2) diacylglycerol phospholipids; [Ethanolamine type]: [choline type] = 1: [1 to 10]

(3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: [0.5 to 6]

(4) [total glycerophospholipid]: [total sphingomyelin] = [30 to 3]: 1

9. Breast

(1) PLs; [Ethanolamine type]: [choline type] = 1: [0.5 to 5]

(2) diacylglycerol phospholipids; [Ethanolamine type]: [choline type] = 1: [2-10]

(3) [ether glycerophospholipid]: [diacylglycerophospholipid] = 1: [0.5 to 5]

(4) [total glycerophospholipid]: [total sphingomyelin] = [5 ~ 50]: 1

High specificity is 1) to 4) below.

1) Breast ([PL-PE] <[PL-PC]), same as [myocardium]

2) The crown ([PL-PE] >>> [PL-PC]), and the [PL-PC]

3) The potential added value in the sense that the incidence of raw bone is high and the price is less than 0 in industrial waste handling and also the composition is close to [breasts] and also contains bone marrow (which contains the peripheral tissues of the brain) Function improvement function) is expected, and the integrated price performance ratio is considered to be remarkably high.

4) It is considered to be equivalent to [breast] + [bone marrow], which has a high [cost / performance ratio].

The complex lipids and PLs extracted from the biotissues used in the present invention have the contents of ethanolamine PLs and choline PLs in terms of dry mass as in 1) to 2) below.

1) The complex lipid has an upper limit of 50% by mass, more preferably 10% by mass or more, more preferably 20% by mass or more, more preferably 30% by mass or more, and still more preferably 40% by mass or more.

More preferably 70 mass% or more, more preferably 80 mass% or more, further preferably 90 mass% or more, and most preferably 90 mass% or more. Particularly preferably not less than 1% by mass.

The mass ratio and content of ethanolamine PLs and choline PLs can be determined by analyzing the complex lipids or plasmalogens extracted from living tissues by high performance liquid chromatography (HPLC). Specifically, in the HPLC, a chromatogram is obtained by an evaporation light scattering detector (ELSD), and the mass ratio is calculated by obtaining respective peak area ratios indicating ethanolamine PLs and choline PLs in the chromatogram . In addition, the content can be obtained by calculating how much the peak area representing the ethanolamine PLs and choline PLs corresponds to the percentage of the peak area of the entire chromatogram.

In the present invention, it is important to intentionally modify the living body of a chicken to be used. That is, in the present invention, by breeding chickens with feeds containing an ω-3HUFA derivative, lipids such as tissues and organs and parts, among them PLs, are highly selectively transferred to ω-3HUFA, -3HUFA is transesterified (Non-Patent Document 26), and ω-3HUFA-linked PLs-containing complex lipids and PLs are produced. There is an example that suggests that there is a relation with the cognitive function disorder for PLs of omega-3HUFA-binding type, and it is exemplified below.

1. Correlation between amount of DHA in the brain and amount of PLs

DHA in the brain exists as a glycerophospholipid, in particular PLs-coupled type (Non-Patent Document 26), and the fatty acid fattyacyl-CoA reductase 1 (Far1) of the biosynthesis system of PLs of peroxisome ) (See Non-Patent Document 10).

2. Correlation between the decrease in DHA and PLs concentrations in the brain and the onset of neurodegenerative diseases and mental disorders (Non-Patent Document 10).

1) When [ ³ H] DHA is added to the brain, DHA binds to the SN-2 of PLs existing between the membranes in the brain.

2) The combined DHA is greatly reduced in the cell line in which the PLs acid production is blocked.

3) When sir1-hexadecylglycerol is added to the culture system, the amount of PLs bound DHA and PLs are restored.

4) Decrease of DHA content in the brain and reduction of PLs production in the brain are related to the neurodegenerative diseases and the development of mental diseases in the following 1) to 7).

(1) Peroxisome ataxia

(2) AD

(3) Depression

(4) ADHD (Attention Deficit Hyperactivity Disorder)

(5) stroke

(6) Hyperactivity

(7) schizophrenia

5) The intake of DHA - enriched foods is related to the possibility of improving the information transfer related to the deterioration of mental condition and deterioration of learning ability and behavior abnormality peculiar to 1) to 7) above.

DHA is susceptible to oxidative decomposition from its structure and is usually sour and odorous, but it is not surprisingly known that DHA can be easily solved only by emulsification (nanoemulsifying). This will be exemplified below.

(1) When polyunsaturated fatty acids (HUFAs) and their esters (including glycerides) are dispersed (emulsified) in an aqueous solution, they are hardly oxidized as much as those having a high degree of unsaturation. In the case of an aqueous dispersion system, the oxidative degradability of DHA or EPA is very low (Non-Patent Document 1). The reason is that a steric structure such as emulsified DHA becomes a barrier against the approach of the oxidized active species and blocks the collision of the active species with the oxidation target site (bisallyl bonded carbon atom) by the "steric hindrance" effect, . At this time, it is considered that the presence of the water molecule is important, and indirectly protects the vicinity of the oxidation target site to cover (cover).

(2) In the O / W emulsion of the emulsification system, the finer the micelle particle size, the better the oxidative stability of the PUFA such as DHA, and thus the nano emulsification (solubilization) is preferable to the normal microemulsification. In addition, it is preferable to avoid the use of, for example, a high-pressure homogenizer or the like, which is likely to take a large load, and simple and gentle agitation. High-load emulsification impairs the oxidation stability of PUFAs.

(3) As a result of introducing linoleic acid (LA), arachidonic acid (AA) and DHA into the cell culture system and performing oxidation treatment, the amount of peroxide generation was increased in LA and AA addition systems, but the increase was not confirmed in DHA.

(4) When LA-PC (phosphatidylcholine), AA-PC, and DHA-PC were added to the culture cell system and subjected to oxidation treatment, the amount of peroxide generation specific to DHA was lower than control. As described above, the characteristic oxidation stability of DHA in cultured cells is completely different from that in air or solvent system, and DHA is not unstable in oxidation in vivo as conventionally thought.

(5) When fish oil is administered to rats, there is no change in lipid peroxidation level in vivo unless the dosage of fish oil is extremely high.

(6) This suggests that ingesting the proper amount of fish oil has little or no adverse effect on lipid peroxidation in the living body.

(7) From the above, it is expected that the direct stabilization effect in PLs molecules of the following 1) to 2) can be expected by reasonably binding DHA to SN-2 of PLs.

1) In vitro, the steric hindrance of the adjacent-bound DHA to the vinyl ether linkage of PLs effectively blocks the attack of the oxidizing active substance, and the DHA-binding molecule, that is, PLs itself, It is thought that the oxidation stability can be obtained through the molecular structure.

2) In vivo (coin cell culture system), especially in the brain (intracellular), DHA binds to phospholipids and, in particular, ethanolamine type PLs, and is locally localized in the membrane of PLs biosynthesis endoplasmicidal peroxidase "peroxisome" It is thought that promotes the production of PLs by accelerating the expression of the putative enzyme (restriction enzyme).

In addition to the above, correlation between PLs and brain dysfunction is summarized below.

1. Correlation with AD

1) PLs content in the brain of AD patients is significantly reduced (non-patent document 11 and non-patent document 12).

2) Serum PLs content in AD patients is significantly reduced (Non-Patent Document 13).

3) Red blood cell PLs content in AD patients is significantly reduced (Non-Patent Document 14).

4) In the central nervous system inflammatory model mice (cognitive dysfunction of inflammation caused by intraperitoneal injection of LPS), PLs in the brain decrease (non-patent document 8).

2. In vivo dynamics of PLs

1) Blood plasmogenicity of oral administration rats increases (Non-Patent Document 15).

2) PLs content in the brain of LPS-induced CNS inflammatory model mice increases (Non-Patent Document 8).

3) PLs Oral administration Ethanolamine PLs in the blood of patients with AD are increased (Non-Patent Document 16).

3. Prevention and alleviation of cognitive impairment and therapeutic effect

1) promotes neurogenesis of aging model rat (SAMP8) (Patent Document 7).

2) A _? Inhibiting the spatial recognition learning function impairment of both injection rats (Non-Patent Document 16).

3) relieves symptoms of LPS-induced central nervous system inflammatory mice (Non-Patent Document 8).

(1) inhibiting the activation of microglia.

(2) increase of intracerebral cytokine, TNFα-mRNA and inhibition of IL-2β expression in brain.

(3) inhibiting accumulation of A _? .

4) inhibition of central nervous system inflammation and A [ _beta] accumulation of CNS induced LPS (intraperitoneal injection) mice (Non-Patent Document 8).

(1) inhibition of activation of glial cells.

(2) Suppression of A _beta accumulation in the prefrontal and hippocampus.

Suppresses the reduction of PLs due to inflammation induced by intraperitoneal injection of LPS (Non-Patent Document 8).

5) In vitro inhibition of neuronal cell death (non-patent document 9).

6) Other related

(1) inhibition of hyperglycemia and hyperlipidemia of risk factors of onset of cognitive dysfunction (non-patent document 18).

(2) suppression of deterioration of cognitive function by carnosynthesis (Non-Patent Document 19).

In the above-mentioned effect of PLs, it is considered that the above-mentioned DHA-conjugated PLs exhibits a synergistic effect on the direct stabilization of the molecule, improvement and correction of cognitive dysfunction, and anti-cognitive dysfunction remarkably.

A method of breeding chickens with an omega-3 HUFA derivative-containing feed, and efficiently transferring omega-3 HUFA to the living tissue is described below.

1. Selection of Species

Chickens, particularly laying hens, are preferred, the clary system of the descendants is more preferred, and a scattering system comprising the " forced horn " laying system is particularly preferred. Examples thereof are shown below.

1) The only animal that inherits the "dinosaur-specific respiratory system" "air-bag" is a bird, which has remarkable specificity compared to animals.

(1) the intake of oxygen is two times (because intake and exhaust are different systems).

(2) the energy-related metabolic rate is doubled by the above.

(3) By the above, the feed required to produce 1 kg of edible portion is significantly higher than that of broiler (4.5 kg), livestock pig (9.1 kg) and beef cattle (25.0 kg), and edible animals do not have versatility. It is only 2.1 kg (FAO 2013 announcement).

2) It is remarkably superior in terms of achievement (integrated price performance ratio).

(1) Poultry is a global industry, the quality is uniform and the price is also very low due to low price settlement;

* The broiler is a vertically integrated industry

* The waste system of the spawning system (about 700 days old) (about 70 days per year is reduced to about 750 days) is the exclusive slaughterhouse disposal field " It is about 3 million per year and there are more than 10 million per year. ")

* Egg value stabilization by-products of national policy (Japan specific)

(2) the world's annual cumulative number of mares is 20 billion; Significant increase in China

(3) Respond to common global varieties; Broilers (meat) and laying eggs (eggs)

(4) Currently,

(5) Good sailing, slaughtering in a bow state

(6) It grows specifically in livestock; 50 days as a broiler, laying eggs as close to one every day through the year

(7) "Forced hunting" is an artificial means to reproduce a spawning cattle with a reduced spawning efficiency. It is a poultry style where breeding is carried out after a feather (wing) has fallen to become naked and consequently reared. Although animal abuse and paper are one sheet difference, they are tolerated as a first aid measure in the case of falling egg prices or sluggish sales volume. As a specific entity of biofunctional regeneration, it is interesting, for example, as a chicken for transfection of ω-3HUFA derivatives containing DHA. It is also one of the poultry 's peculiarities that this type of action can be realized on a large scale.

(8) Egg-derived egg yolk is PL-PC >> PL-PE (practically 0) in the specific gravity of the precursor, but PLs There is a phenomenon.

However, as a result of transfection of the ω-3HUFA derivative containing DHA, the egg yolk of the above-described laying hens surprisingly became as follows.

* PLs were detected

* Most of them were DHA-PLs

In addition, PL-PE >> PL-PC was the contrary to the precursor's crown

As described later, it is believed that the DHA enhances the expression of the rate-limiting enzyme Far1 in the biosynthetic pathway of the in vivo PLs neoplasia "peroxisome" as described later, resulting in the generation of PLs in the yolk. Further, it is interpreted that the PLs specifically supplemented DHA in egg yolk to generate DHA-PLs.

2. Selection of tissues suitable for extraction of PLs

The following are exemplified.

1) Yolk of laying hens (frozen)

2) Raw bone (Mins freeze)

3) Helm (Mins frozen)

4) Sand bag (Mine freeze)

5) Chang (freezing mins)

6) Peel (Mine freeze)

7) Brass (frozen)

8) Breast skin (Mins freeze)

3. Selection of published ω-3HUFA derivatives

Wheat derived from fish species, sardine, mackerel, saury, tuna, bonito, scallop, squid, krill, etc., and combinations of two or more of them, wheat by- By-product oil, microorganism fermentation medium, and the like.

4. ω-3HUFA-containing feed and breeding conditions

The following are exemplified.

1) Chicken species

Julia species and / or Boris Brown species

2) Feed

Cone 62%, omega-3HUFA containing feed 15%, vegetable oil 15%, animal basic feed 6% and other cereals 2%

3) Breeding conditions

(1) Breeding period is 1 to 5 weeks, preferably 1 to 3 weeks

(2) Chicken is about 40 weeks old

(3) The breeding place is Kyushu poultry house

(4) The number of mariners is about 50

4) Primary disposal

Kyushu's waste treatment center

The composite lipid derived from living body tissue and its composition and the details of nanoemulsification using PLs as a substrate are shown below.

1. Basic prescription

Suitable prescriptions are illustrated below.

A complex lipid or PLs-containing aqueous preparation is obtained which is characterized in that the complex lipid is solubilized as an aqueous phase or the PLs by nano-emulsification in the presence of saponins (Patent Document 12).

At this time, it is preferable to use saponin, preferably Kiraja saponin as an essential component and selected from a fatty acid monoglyceride, a fatty acid monoglyceride having 6 to 12 carbon atoms, a polyglycerol fatty acid ester, a polyhydroxy compound, One or more auxiliary components are suitably used.

2. Nano emulsification process

The complex lipid is degassed and added to an aqueous solution containing Kiraja saponin in a nitrogen gas atmosphere while stirring with a magnetic stirrer. When the solution is stirred until no turbidity is obtained, a solubilized solution having transparency is obtained.

3. Characteristics of nano emulsion

The prepared solution is diluted to 10, 100, and 1000 times, and the transparency is visually confirmed.

4. Stability test ([Patent Document 12])

The prepared solution was adjusted to pH 4 with citric acid in an aqueous solution having transparency, for example, diluted 500 times, and visually observed for change. After heating for 30 minutes at 95 ° C, the temperature was returned to room temperature, Check. Further, after the heating solution is evaporated to dryness, a hexane extract solution is obtained by a conventional method, and peak area comparison analysis is carried out on a HPLC / ELSD chart with the unheated solubilized solution as a control, and remaining plasma is assayed.

5. Average particle size measurement test (Patent document 12)

The average particle diameter of the oil-phase particles in the prepared solubilizing liquid is measured by a commercially available submicron analyzer.

6. Preparation test of powder formulation and residual property of component (Patent document 14)

After the starch hydrolyzate of the excipient is dissolved in the solubilized solution, spray drying is performed using a tabletting mini spray dryer. The transparency of the solution of the powder preparation is visually determined by, for example, diluting the solution 100 times with water to confirm its solubilization.

Further, as described above, peak area comparison analysis is carried out on the HPLC / ELSD chart with the unheated solubilized liquid as a control, and the remaining amount of PLs is confirmed.

7. Preparation test of solubilized jelly (Patent Document 13)

1) dissolve casein sodium in glycerin by heating, and add 1% of a mixed lipid δ tocopherol solution, for example, with stirring to obtain a jelly-like solubilized product having transparency. After evaporation, the residue is extracted with hexane after extraction and analyzed by HPLC / ELSD from the contrast analysis of the peak area ratio as in the previous section. Further, a diluted water of, for example, a 100-fold dilution of the jelly is prepared, and the average particle size distribution is measured with a commercial submicron analyzer.

2) For example, 2 g of dried egg white is dissolved in 8 g of water, and an equivalent white sugar is dissolved therein. To this solution is added, for example, a 0.5% delta tocopherol solution of PLs in an appropriate amount with stirring in a nitrogen gas atmosphere to obtain a jelly-like solubles having a transparency.

Composite lipids according to the present invention, compositions thereof, PLs and their aqueous preparations, protein / lipid complex compositions, complex lipids containing omega-3 HUFA-binding PLs and compositions thereof, PLs and aqueous preparations thereof, (Hereinafter sometimes referred to as &quot; various PLs &quot;) may be used as a therapeutic agent for central nervous system inflammation, neuronal cell neoplasia, apoptosis of neurons and accumulation of A _? And? Cosmetics, medicines or feedstuffs as an active ingredient for the purpose of alleviating, preventing, improving, and treating cancer.

When the PLs preparation according to the present invention is used as a supplement and / or a general food (hereinafter sometimes referred to as &quot; various foods &quot;), the various foods may be various PLs preparations, , A carrier, an additive, and other ingredients or materials that can be used as other foods may be appropriately blended. In addition, examples of such various food forms include, but are not limited to, liquid foods, powdery foods, flaky foods, granular foods and pasty foods.

When the PLs preparation according to the present invention is used as a food or drink, the above-mentioned preparation should be appropriately blended with PLs and ingredients or materials that can be used as foods, carriers, additives or other foods acceptable in food hygiene (that is, &Lt; / RTI &gt; For example, processed foods, beverages, health foods (nutritional functional foods, foods for specified health use, etc.) and sick food (hospital foods, patient foods, nursing foods, etc.) including various PLs preparations can be exemplified.

The types of supplements and foods are not particularly limited. For example, health foods containing processed foods such as hamburgers, meatballs, Vienna sausages, chopped chicken, chicken skin chips, and processed meat foods containing various PLs preparations (Nutritional functional food, specific health food, etc.), supplement, sick food, and the like. In addition, various PLs preparations can be used in the form of powder, for example, beverages (such as juice), confections (e.g., gum, chocolate, candy, biscuits, cookies, rice confectionery, rice crackers, puddings, Etc.), breads, soups (including powdered soups), processed foods, and the like.

When foods and drinks related to the present invention are prepared as health foods (nutritionally functional foods, foods for specified health use, etc.) and supplementary substances, it is preferable to use, for example, granules, capsules, tablets ), Beverage (such as a drink), and the like. Among them, capsules, tablets, tablets, jellies and the like are more preferable from the viewpoint of ease of ingestion. Granules, capsules, tablets, jellies and the like can be appropriately prepared in accordance with a conventional method using pharmaceutical and / or food hygienically acceptable carriers and the like.

The blending amount of PLs in the food and drink according to the present invention is preferably 0.00005 to 100% by mass, more preferably 0.0005 to 75% by mass, and more preferably 0.005 to 50% by mass. The food according to the present invention can be used for preventing, alleviating, and improving cognitive dysfunction. It is preferable that the measurement of the amount of intake, the subject to be ingested, the amount of contained PLs, and the like are the same as those of the medicament according to the present invention described later, for example.

In addition, the hospital diet is a meal provided when the patient is admitted to the hospital, the patient diet is a meal for the patient, and the nursing diet is a meal for the nursing person. The food according to the present invention can be used as a hospital type, a patient type, or a nursing type, particularly for a patient who is admitted to the above-mentioned example, who is receiving home care or receiving nursing care. In addition, a person who is likely to suffer from the above-mentioned diseases, such as the elderly, may be ingested prophylactically.

When the anti-cognitive dysfunction of the present invention is used in the medical field, the preparation may be composed of only PLs, or may be blended with other components (i.e., pharmaceuticals containing PLs). For example, in the case of pharmaceuticals according to the present invention, various kinds of PLs, which are effective ingredients, may be added to a pharmaceutically acceptable base, carrier, additives (for example, excipients, binders, disintegrators, lubricants, A coloring agent, a flavoring agent, a surfactant, a moisturizing agent, a preservative, a pH adjuster, a tackifier, etc.). In addition, it can be prepared by a conventional method such as tablets, coated tablets, powders, granules, fine granules, capsules, pills, solutions, suspensions, emulsions, jellies, chewables and soft tablets. Particularly, it may be prepared as a liquid preparation, a suspension, an emulsion or the like and may be used as an injection or a drip agent, or as an oral preparation.

The compounding amount of PLs in the medicament according to the present invention is not particularly limited as long as the anti-cognitive function is exerted, and it can be suitably set according to the desired amount of PLs per day. The blending amount thereof is preferably 0.0005 to 100 mass%, more preferably 0.005 to 90 mass%, and still more preferably 0.05 to 80 mass%. The subject to which the drug according to the present invention is administered is preferably a subject suffering from cognitive dysfunction. Examples of such diseases include neurodegenerative diseases and psychiatric diseases. Examples of neurodegenerative diseases include AD, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, and the like.

Specific examples of mental disorders include depression, mania, bipolar disorder, integrated ataxia, autism, and contact disorder. In addition, the drug of the present invention may be administered to a subject who is likely to have such a disease in the future. For example, it can be prophylactically administered to a subject who is genetically susceptible to the above-mentioned example disease or to an elderly person (particularly, those aged 60 years or older). The subject to which the drug according to the present invention is administered may be not only humans but also other mammals for feed use. Examples of such mammals include, but are not limited to, dogs, cats, cows, horses, pigs, sheep, goats, monkeys, rabbits, mice, rats and hamsters have.

The administration time of the anti-cognitive function deprivation according to the present invention is required to be preferably 5 years, more preferably 10 years, more preferably 15 years before the onset of cognitive dysfunction. It is clear that the donor is waiting for donation at the time of diagnosis (Non-Patent Document 20). A suitable dosage form is preferably oral in view of its long-term administration period. The dose of the anti-cognitive dysfunctional release according to the present invention is suitably selected according to the age of the patient, the degree of symptoms of the patient, other conditions, and the like. In general, the amount of PLs in the preparation is preferably in the range of 0.001 to 1000 mg, more preferably 0.01 to 100 mg per adult, per day. It may be administered once or twice a day (preferably 2 to 3 times).

The present invention also provides a method for treating cognitive dysfunction comprising administering an effective amount of the anti-cognitive dysfunction of the present invention (particularly, oral administration or light-vein administration) to a subject suffering from cognitive dysfunction. In addition, the present invention relates to a method for treating or preventing neurodegenerative diseases or psychiatric disorders, which comprises administering an effective amount of the anti-cognitive dysfunction of the present invention (particularly, oral administration or light blood vessel administration) &Lt; / RTI &gt; The method is specifically carried out by administering the above-described anti-cognitive dysfunction of the present invention. In addition, the respective conditions such as the control and the intake amount in the above method are as described above.

Examples of the independent clinical test methods for predetermined effects (prevention and treatment of neurodegenerative diseases and mental disorders) of PLs and preparations according to the present invention include the following 1) to 7).

1) person is physiologically is characterized in that it is harmless amount of A _β and if in the state where the accumulation in brain confirmation of τ adult before increasing onset (dry box). Among them, the "dementia mibyeong state" subject in.

In recent research results in the United States (non-patent document 20), accumulation of A [ _beta] and [tau] proteins accumulate in the brain for at least 10 years, usually 15 to 20 years, A kind of "paradigm shift" is happening. Early prevention is the crucial method of inhibiting the onset of the disease, and it is a benign symptom of the above-mentioned manifestation of efficacy in an adult (dry case) to an uncontaminated state before the onset of dementia.

2) use of safe and stable PLs and / or preparations thereof.

As described above, components for prevention, alleviation, improvement and treatment of neurodegenerative diseases and mental disorders require safety and stability, and inexpensive plasmogen is required for a longer period of time than conventional ones.

3) more suitably safe, stable omega-3HUFA coupled PLs and / or preparations thereof.

4) The safe and stable omega-3HUFA-binding PLs are safely extracted from safely raised chickens containing feeds containing a safe omega-3-HUFA source.

5) It is safe and easy oral administration.

6) The administration period is shorter than 2 years, preferably 18 months, more preferably 12 months, preferably 6 months or less and 1 month or more, longer than 1 year or more of the clinical trial period of the usual disease subjects, So that the burden on the user can be reduced.

7) The method for determining the preventive and therapeutic efficacy of an innovative neurodegenerative disease and a mental disorder, characterized in that the essential essential measurement efficacy includes at least 3 items selected from the group of the following markers.

* Uchida / Coplelin inspection

* MMSE

* Functional MRI (rs-fMRI) image analysis during stabilization (Non-Patent Document 17)

* Measurement of PLs content in erythrocytes (Non-Patent Document 24)

* PSOL "Cognitive function self-diagnostic test"

* RBANS ([Non-Patent Document 21])

* Cognitrax ([Non-Patent Document 21])

* Wexler memory test ([Non-Patent Document 22])

In addition, the rs-fMRI image is useful for analysis and evaluation of the brain's default mode network (DMN). In other words, it has been thought that the brain is also resting when the conscious activity is not performed conventionally. However, recent surveys of brain function imaging have revealed remarkable facts, and important activities are carried out even in the stable state. The energy consumed reaches 20 times the brain energy used for the conscious reaction (Non-Patent Document 17). The heart of this brain activity is a network composed of multiple brain regions called DMN, which synchronize with various neural activities in the brain. It should be noted that the brain area where significant atrophy is confirmed in the AD patients is mostly overlapped with the main brain area constituting the DMN, and thus it is expected that the interpretation of the fMRI image at the time of stabilization will lead to the understanding of the new neurological disease.

In recent years, it has become clear that the small-world nature and modularity of the stabilized brain function network are degraded depending on, for example, their functional changes are generally preceded by anatomical changes such as brain atrophy. It has been reported that it is possible to become a useful marker (Non-Patent Document 17).

A clinical trial meeting the following requirements for the determination of the cognitive function improving effect of the latest PLs based on the above-described basic concept by the present inventors;

* JACTA (Tokyo) of the professional organization of the implementation of entrustment

* Randomized, double blind, placebo-controlled

* Innovative PLs composition using cognitive function improving food

* Selected healthy subjects (135 applicants for institutional registrants ⇒ 81 candidates for cognitive function 3-rd party examination ⇒ 75 candidates for screening of examiners ⇒ 71 for non-competitors discovered during testing)

* Very low daily doses of 0.25 mg and 0.5 mg,

* Within a very short period of 12 weeks, and at only 6 weeks significant improvement in cognitive function and an immediate improvement (Non-Patent Document 25) are evaluated as a remarkable achievement.

The method of conducting the [Phase II clinical trial] related to conventional dementia is sometimes referred to as brain, making it difficult to objectify the test results to a reasonable degree. The direct image analysis method has never been able to obtain an academic sense such as an excessively high amount of apparatus, lack of rationality in image analysis, problem in reproducibility, and the like.

For the dynamics of the brain A _β and τ protein to test directly, but is necessary to "lumbar puncture", there is a very high versatility invasive.

According to a recent report, PET (Positoron Emission Tomography) was developed and miniaturized, and tofu-exclusive PET was developed by the Institute of Radiological Medicine and Research Institute of Quantum Science and Technology to reduce the cost of the device by 1/3 , And that it has also succeeded in improving the sensitivity in the vicinity of the seahorse (Non-Patent Document 28).

In addition, and in the same place that allows observation in Fig PET [τ proteins; with A _β succeeded in the development of test drug [PBB3] to observe the [τ protein] as PET.

The present inventor has obtained very interesting results by using the above-mentioned [amyloid PET-PIB] and evaluating the efficacy (clinical test) of [DHA-PLs] vs [PLs] in improving cognitive function of the present invention.

Example

Hereinafter, the present invention will be described concretely with reference to verification examples, preparation examples and examples, but the present invention is not limited to the following examples.

Preparation Example 1 [Preparation of phospholipids containing PLs for biomolecule extraction]

[Production of phospholipids containing PLS of living tissue]

1. Preparation of complex lipid from the peeling helmet of the pulmonary system

A complex lipid was prepared from a fresh thin stripping helper of a scattering system of chicken (a conductor from which a "crotch" was removed from a "quick removal conductor").

The peeling helmet was procured from the waste system treatment center, and 1 kg of mins of about 8 mm was prepared. The mins were stored by gentle freezing. In use, it was forcibly thawed with warm water and then squeezed to perform dehydration and deaeration. This was cooked for 5 minutes in an "oxygen-free atmosphere" (oxygen content of 0.5% or less) with "Superheated water" (Aqua gas; registered trademark), followed by rapid cooling and dehydration by a vacuum cooling method. The obtained dehydrated, deaerated, cooked and sterilized breasts were subjected to low-temperature pulverization and then subjected to an ethanol three-phase separation process.

[Three-Phase Separation Process]

The cooked and sterilized pulverized sheath was put in a container and degassed. 800 ml of deaerated ethanol was added to the container, and the container was sealed with gentle agitation at 35 ° C for 10 hours, and the container was left under ice-cooling , The upper layer of chicken fat and the solid precipitated protein fraction were separated to obtain a functional ethanol fraction (sealed refrigerated storage). And 800 ml of deaerated ethanol was added to protein and the like, and the same extraction operation was repeated. The ethanol phase was separated by centrifugation, and the resulting mixture was ice-cooled under a sealed condition, followed by concentration under reduced pressure. The solids of the water-soluble low-molecular fraction were separated by filtration, evaporated under reduced pressure, and dried to obtain 7 g of PLs-containing phospholipid (complex lipid).

1) Fractionation of total lipid

The total lipid extracted, distributed and separated by Folch method was 26.5 mass%.

2) Phospholipid profile assay

It was measured by HPLC / ELSD method such as NADACHI of Commercial Law.

3) List of the above results [mg / 100g Peak Helmet]

TL (total lipid): 26.5 mass%, TPL (total phospholipid): 0.6 mass%

(Phosphatidylethanolamine): 43, PL-PC (choline type PLs): 49, PC (phosphatidylcholine): 327, SM (sphingomyelin): 74

4) The composition ratio of the specific phospholipid

(1) PLs; [Ethanolamine type]: [Choline type] = 2.1: 1

(2) diacylglycerol phospholipids; [Ethanolamine type]: [Choline type] = 1: 7.6

(3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: 2.4

(4) [total glycerophospholipid]: [total sphingomyelin] = 7: 1

2. Preparation of complex lipids from raw bone of the lungs

It was handled according to the pitch.

1) Fractionation of lipids

The total lipid separated and extracted by Folch method was 14 mass%.

2) Phospholipid profile assay

It was measured by HPLC / ELSD method such as NADACHI of Commercial Law.

3) List of the above [㎎ / 100g raw bone]

TL (total lipid): 14 mass%, TPL (total phospholipid): 0.73%

PL-PE (ethanolamine type PLs): 149, PE (phosphatidylethanolamine): 119, PL-PC (choline type PLs): 42, PC (phosphatidylcholine): 283, SM

4) Composition ratio of specific phospholipids in raw bone

(1) PLs; [Ethanolamine type]: [Choline type] = 3.5: 1

(2) Acylglycerol phospholipids; [Ethanolamine type]: [Choline type] = 1: 2.4

(3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: 2.1

(4) [total glycerol phospholipids]: [total sphingomyelin] = 10: 1

3. Preparation of complex lipids from the intestinal tract

It was handled according to the pitch.

1) Fractionation of lipids

The total lipid extracted and separated by Folch method was 32 mass%.

2) Phospholipid profile assay

It was measured by HPLC / ELSD method such as NADACHI of Commercial Law.

3) List of the above [㎎ / 100g raw bone]

TL (total lipid): 32 mass%, TPL (total phospholipid): 1 mass%

(Phos- phatidylethanolamine): 88, PL-PC (choline type PLs): 14, PC (phosphatidylcholine): 379, SM (sphingomyelin): 86

4) Total specific lipid composition ratio

(1) PLs; [Ethanolamine type]: [Choline type] = 12: 1

(2) diacylglycerol phospholipids; [Ethanolamine type]: [Choline type] = 1: 4.3

(3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: 2.6

(4) [total glycerophospholipid]: [total sphingomyelin] = 7.6: 1

4. Preparation of complex lipid from the sand bag of the scavenging system

It was handled according to the pitch.

1) Fractionation of lipids

The total lipid separated and extracted by Folch method was 7.9 mass%.

2) Phospholipid profile assay

It was measured by HPLC / ELSD method such as NADACHI of Commercial Law.

3) List of the above results in [mg / 100g sand bags]

TL (total lipid): 7.9 mass%, TPL (total phospholipid): 0.88 mass%

(Phos- phatidylethanolamine): 91, PL-PC (choline type PLs): 23, PC (phosphatidylcholine): 255, SM (sphingomyelin): 118

4) Sand bag Specific composition ratio

(1) PLs; [Ethanolamine type]: [Choline type] = 4.8: 1

(2) diacylglycerol phospholipids; [Ethanolamine type]: [Choline type] = 1: 2.8

(3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: 2.6

(4) Total Glycerophospholipid: Total Sphingomyelin = 4.1: 1

5. Preparation of composite lipids from brass

1) The brass of scattering system

It was handled according to the pitch.

(1) Fractionation of lipids

The total lipid extracted and fractionated by Folch method was 31 mass%.

(2) Phospholipid profile assay

It was measured by HPLC / ELSD method such as NADACHI of Commercial Law.

(3) List of the above results in [㎎ / 100 g brass]

TL (total lipid): 31 mass%, TPL (total phospholipid): 9.5 mass%

(Phos- phatidylethanolamine): 1,574, PL-PC (choline type PLs): 0, PC (phosphatidylcholine): 7,542, SM (sphingomyelin): 145

(4) Composition ratio of brass-specific phospholipids

1) PLs; [Ethanolamine type]: [Choline type] = 200: 0

2) diacylglycerol phospholipids; [Ethanolamine type]: [Choline type] = 1: 4.8

3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: 45

4) [total glycerophospholipid]: [total sphingomyelin] = 64: 1

2) The female brass of the descendant female

(1) Fractionation of lipids

The total lipid extracted and fractionated by Folch method was 39.3 mass%.

(2) Phospholipid profile assay

It was measured by HPLC / ELSD method such as NADACHI of Commercial Law.

(3) List of the above results in [㎎ / 100 g brass]

TL (total lipid): 39.3 mass%, TPL (total phospholipid): 12.2 mass%

(Phosphatidylethanolamine): 2,236, PL-PC (choline type PLs): 0, PC (phosphatidylcholine): 10,592, SM (sphingomyelin): 339

(4) Composition ratio of brass-specific phospholipids

1) PLs; [Ethanolamine type]: [Choline type] = 551: 0

2) diacylglycerol phospholipids; [Ethanolamine type]: [Choline type] = 1: 4.7

3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: 23.3

4) Total Glycerophospholipid: Total Sphingomyelin = 40: 1

6. Preparation of complex lipids from the epidermis of the pulmonary system

It was handled according to the pitch.

1) Fractionation of lipids

The total lipid separated and extracted by Folch method was 46 mass%.

2) Phospholipid profile assay

It was measured by HPLC / ELSD method such as NADACHI of Commercial Law.

3) List of the above results in [mg / 100g bark]

TL (total lipid): 46 mass%, TPL (total phospholipid): 0.72 mass%

(Phosphatidylethanolamine): 21, PL-PC (choline type PLs): 17, PC (phosphatidylcholine): 95, SM (sphingomyelin): 55

4) Composition of shell-specific phospholipids

(1) PLs; [Ethanolamine type]: [Choline type] = 3.4: 1

(2) diacylglycerol phospholipids; [Ethanolamine type]: [Choline type] = 1: 4.5

(3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: 1.5

(4) Total Glycerophospholipid: Total Sphingomyelin = 3.5: 1

7. Preparation of complex lipids from the lungs of the respiratory system

A fresh skinny breasts of the chicken egg scattering system was procured from the waste system treatment center and 1 kg of mins of about 8 mm was prepared. The mins were stored by gentle freezing. In use, it was forcibly thawed with warm water and then squeezed to perform dehydration and deaeration. This was cooked for 5 minutes in an "anaerobic atmosphere" (oxygen content of 0.5% or less) with [superheated water] (aqua gas; RTM), followed by rapid cooling and dehydration by a vacuum cooling method. The obtained dehydrated, deaerated, cooked and sterilized breasts were subjected to low-temperature pulverization and then subjected to an ethanol three-phase separation process.

[Three-Phase Separation Process]

The milled breasts thus obtained were put in a container and degassed. 800 ml of ethanol, which had been completely deaerated, was added to the container. The container was kept under ice cooling for 10 hours at 35 占 폚 under sealed condition. Of chicken fat and solid precipitated protein were fractionated to obtain a functional ethanol fraction (sealed refrigerated storage). To the protein component, 800 ml of deaerated ethanol was added, and the same extraction operation was repeated. The ethanol phase was separated by centrifugation, and the mixture was ice-cooled under a sealed condition, followed by concentration under reduced pressure. The solids of the water-soluble low-molecular fraction were separated by filtration, evaporated under reduced pressure, and dried to obtain 7 g of PLs-containing phospholipid (complex lipid).

(1) Discrimination of total lipid

The total lipid extracted, distributed and separated by the Folch method was 1.8% by mass.

(2) Phospholipid profile assay

And it was measured by HPLC / ELSD method such as NADACHI of Commercial Law [Patent Document 1].

(3) List of the above results [㎎ / 100g Breast]

TL (total lipid): 1.8 mass%, TPL (total phospholipid): 0.7 mass%

(Phosphatidylethanolamine): 44, PL-PC (choline type PLs): 124, PC (phosphatidylcholine): 276, SM (sphingomyelin): 32

(4) Composition of breast-specific phospholipids

1) PLs; [Ethanolamine type]: [Choline type] = 1: 2

2) diacylglycerol phospholipids; [Ethanolamine type]: [Choline type] = 1: 6.3

3) [ether glycerol phospholipid]: [diacyl glycerophospholipid] = 1: 1.7

4) Total Glycerophospholipid: Total Sphingomyelin = 16: 1

Preparation example 2

[Preparation of purified PLs from complex lipids]

1. Preparation of purified PLs from complex lipids of the pulp head

20 g of the PLs-containing phospholipid (complex lipid) was dispersed in 400 ml of a Mitsubishi-CHEMICAL FOODS CORPORATION solution (10 mg / mL of 0.1 M citric acid-hydrochloric acid buffer) and stirred at 50 DEG C for 2 hours in a nitrogen gas atmosphere . The mixture was stirred under ice cooling and twice the volume of hexane. The mixture was stirred and distributed twice, and the upper layer was recovered and concentrated. Further, 60 ml of acetone was added to the dry solid, and the operation of stirring, centrifuging, and collecting the precipitate was repeated twice.

Further, 60 ml of hexane / acetone (7: 3) was added to the precipitate, followed by stirring and centrifugation, and the liquid layer was recovered. This liquid layer was concentrated to dryness, and then 240 ml of hexane / acetone (1: 1) was added to the separating lot. 36 ml of water was added thereto, followed by stirring and dispensing. The lower layer was discarded, and 96 ml of acetone / water (5: 3) was added to the upper layer, followed by stirring and dispensing. The upper layer was recovered and rapidly dried under reduced pressure to obtain purified PLs derived from a helmet-derived helmet shell.

[Determination of purity of tablets PLs derived from pulp-based peeling helmet]

Purity determination was carried out according to the method of NADACHI et al. (Patent Document 1). The purity was 93.6 mass%.

2. Preparation of purified PLs from complex lipids of the lungs

20 g of the phospholipid containing phospholipid was dispersed in 400 mL of a Mitsubishi-CHEMICAL FOODS CORPORATION solution (10 mg / mL of 0.1 M citric acid-hydrochloric acid buffer) and stirred at 50 DEG C for 2 hours in a nitrogen gas atmosphere. The mixture was stirred under ice cooling and twice the volume of hexane. The mixture was stirred and distributed twice, and the upper layer was recovered and concentrated. Further, 60 ml of acetone was added to the dry solid, and the operation of stirring, centrifuging, and collecting the precipitate was repeated twice. Further, 60 ml of hexane / acetone (7: 3) was added to the precipitate, followed by stirring and centrifugation, and the liquid layer was recovered.

This liquid layer was concentrated to dryness, and then 240 ml of hexane / acetone (1: 1) was added to the separating lot. 36 ml of water was added thereto, followed by stirring and dispensing. The lower layer was discarded, and 96 ml of acetone / water (5: 3) was added to the upper layer, followed by stirring and dispensing. The upper layer was recovered and rapidly dried under reduced pressure to obtain tablets PLs derived from the obesity raw bone.

[Determination of Purity of Purified PLs Derived from Bovine Bone Marrow]

The purity test was conducted according to the method of NADACHI et al. The purity was 94.3 mass%.

3. Preparation of purified PLs from complex lipids in the waste field

20 g of the phospholipids containing PLs was dispersed in 400 ml of a Mitsubishi-CHEMICAL FOODS CORPORATION solution (10 mg / mL of 0.1 M citric acid-hydrochloric acid buffer) and stirred at 50 ° C for 2 hours under nitrogen gas. The mixture was stirred under ice cooling and twice the volume of hexane. The mixture was stirred and distributed twice, and the upper layer was recovered and concentrated. Further, 60 ml of acetone was added to the dry solid, and the operation of stirring, centrifuging, and collecting the precipitate was repeated twice. Further, 60 ml of hexane / acetone (7: 3) was added to the precipitate, followed by stirring and centrifugation, and the liquid layer was recovered.

This liquid layer was concentrated to dryness, and then 240 ml of hexane / acetone (1: 1) was added to the separating lot. 36 ml of water was added thereto, followed by stirring and dispensing. The lower layer was discarded, and 96 ml of acetone / water (5: 3) was added to the upper layer, followed by stirring and dispensing. The upper layer was recovered and rapidly dried under reduced pressure to obtain purified PLs derived from the pulmonary instrument.

[Purification of purified purity of plasma from the intestinal tract of the lungs]

The purity test was conducted according to the method of NADACHI et al. The purity was 91 mass%.

4. Preparation of Purified Plasma Lactogen from Complex Lipids of Waste Sand Pouch

20 g of the phospholipids containing PLs was dispersed in 400 ml of a Mitsubishi-CHEMICAL FOODS CORPORATION solution (10 mg / mL of 0.1 M citric acid-hydrochloric acid buffer) and stirred at 50 ° C for 2 hours under nitrogen gas. The mixture was stirred under ice cooling and twice the volume of hexane. The mixture was stirred and distributed twice, and the upper layer was recovered and concentrated. Further, 60 ml of acetone was added to the dry solid, and the operation of stirring, centrifuging, and collecting the precipitate was repeated twice. Further, 60 ml of hexane / acetone (7: 3) was added to the precipitate, followed by stirring and centrifugation, and the liquid layer was recovered.

This liquid layer was concentrated to dryness, and then 240 ml of hexane / acetone (1: 1) was added to the separating lot. 36 ml of water was added thereto, followed by stirring and dispensing. The lower layer was discarded, and 96 ml of acetone / water (5: 3) was added to the upper layer, followed by stirring and dispensing. The upper layer was recovered and rapidly dried under reduced pressure to obtain 3 g of purified plasma derived from the waste sand bag.

[Blackness of Purity of Tablets PLs Derived from Chicken Sand Bag]

The purity test was conducted according to the method of NADACHI et al. The purity was 95.4 mass%.

5. Preparation of purified PLs from complex lipids of chicken brass

1) The brass-derived brass

20 g of the phospholipids containing PLs was dispersed in 400 ml of a Mitsubishi-CHEMICAL FOODS CORPORATION solution (10 mg / mL of 0.1 M citric acid-hydrochloric acid buffer) and stirred at 50 ° C for 2 hours under nitrogen gas. The mixture was stirred under ice cooling and twice the volume of hexane. The mixture was stirred and distributed twice, and the upper layer was recovered and concentrated. Further, 60 ml of acetone was added to the dry solid, and the operation of stirring, centrifuging, and collecting the precipitate was repeated twice. Further, 60 ml of hexane / acetone (7: 3) was added to the precipitate, followed by stirring and centrifugation, and the liquid layer was recovered.

This liquid layer was concentrated to dryness, and then 240 ml of hexane / acetone (1: 1) was added to the separating lot. 36 ml of water was added thereto, followed by stirring and dispensing. The lower layer was discarded, and 96 ml of acetone / water (5: 3) was added to the upper layer, followed by stirring and dispensing. The upper layer was recovered and rapidly dried under reduced pressure to obtain purified PLs derived from the waste type brass.

[Purification of Purification Plasma R Genes Derived from Waste System Brass]

The purity test was conducted according to the method of NADACHI et al. The purity was 95.6 mass%.

2) The female brass of the descendant female

Tablets PLs derived from the female crown of the genus were prepared on the basis of the above.

[Determination of Purity of Purified PLs Derived from Waste System Brass]

The purity test was conducted according to the method of NADACHI et al. The purity was 96.7% by mass.

6. Preparation of purified PLs from complex lipids of the pulp shell

20 g of the phospholipids containing PLs was dispersed in 400 ml of a Mitsubishi-CHEMICAL FOODS CORPORATION solution (10 mg / mL of 0.1 M citric acid-hydrochloric acid buffer) and stirred at 50 ° C for 2 hours under nitrogen gas. The mixture was stirred under ice cooling and twice the volume of hexane. The mixture was stirred and distributed twice, and the upper layer was recovered and concentrated. Further, 60 ml of acetone was added to the dry solid, and the operation of stirring, centrifuging, and collecting the precipitate was repeated twice. Further, 60 ml of hexane / acetone (7: 3) was added to the precipitate, followed by stirring and centrifugation, and the liquid layer was recovered.

This liquid layer was concentrated to dryness, and then 240 ml of hexane / acetone (1: 1) was added to the separating lot. 36 ml of water was added thereto, followed by stirring and dispensing. The lower layer was discarded, and 96 ml of acetone / water (5: 3) was added to the upper layer, followed by stirring and dispensing. The upper layer was recovered and rapidly dried under reduced pressure to obtain tablets PLs derived from the pulp shell.

[Determination of the purity of the purified PLs derived from the pulp shell]

The purity test was conducted according to the method of NADACHI et al. The purity was 96.7% by mass.

7. Preparation of purified PLs from complex lipids of the pulmonary trunk

20 g of the PLs-containing phospholipid (complex lipid) was dispersed in 400 ml of a Mitsubishi-CHEMICAL FOODS CORPORATION solution (10 mg / mL of 0.1 M citric acid-hydrochloric acid buffer) and stirred at 50 DEG C for 2 hours in a nitrogen gas atmosphere . The mixture was stirred under ice cooling and twice the volume of hexane. The mixture was stirred and distributed twice, and the upper layer was recovered and concentrated. Further, 60 ml of acetone was added to the dry solid, and the operation of stirring, centrifuging, and collecting the precipitate was repeated twice.

Further, 60 ml of hexane / acetone (7: 3) was added to the precipitate, followed by stirring and centrifugation, and the liquid layer was recovered. This liquid layer was concentrated to dryness, and then 240 ml of hexane / acetone (1: 1) was added to the separating lot. 36 ml of water was added thereto, followed by stirring and dispensing. The lower layer was discarded, and 96 ml of acetone / water (5: 3) was added to the upper layer, followed by stirring and dispensing. The upper layer was recovered and rapidly dried under reduced pressure to obtain purified PLs derived from chicken breasts.

[Blackness of purity of purified plasma from lungs of breasts]

Purity determination was carried out according to the method of NADACHI et al. (Patent Document 1). The purity was 94 mass%.

Preparation Example 3

[Preparation of a phospholipid (complex lipid) containing omega-3HUFA-conjugated PLs with the production of the egg-laying catfish fed with the omega-3HUFA derivative-containing feed and the site-specific composition ratio thereof]

~ Breeding conditions ~

a. Laying hens and breeding marigolds; Julia 30

b. The age of the statue (Id.); 700 days

c. Mean weight of statues; 1.8 kg

d. feed containing ω-3HUFA derivatives; Feed for commercial laying hens (cone 62%, vegetable oil 20%, basic animal feed 6%, other 12%) with 5% of bonito oil containing DHA-TG25% (EPA-TG6%

e. Bronchial administration period; 4 weeks

f. Breeding environment; Cage breeding

g. Slaughter; 735 days

h. Results after termination of breeding;

[Analysis of phospholipid profile of complex lipids in ω-3HUFA transduction tissues and regions and its purification:

1. Peeling Helmet

1) classification of each lipid; Total lipid: 26.5 mass% Total phospholipid: 0.6 mass%

2) Profile of phospholipids

(1) HPLC / ELSD method.

(2) The profile is shown below as mg / 100g (pitch).

PL-PE: 114, PE: 43, PL-PC: 54, PC: 276, SM: 74

3) Verification of the binding DHA of PLs of the peeling helmet

(1) Preparation of PLs

The purity of PLs prepared by the method of NADACHI et al. Was 94.6 mass% (breakdown, PL-PC: 30.4%, PL-PE: 64.2%).

(2) Analysis of fatty acid composition of PLs

The above-mentioned PLs were subjected to methyl esterification by a conventional method to analyze fatty acid composition. The composition ratio of DHA in the SN-2 binding fatty acids of PLs was 64%.

2. raw bone

1) classification of each lipid; Total lipid: 14 mass% total phospholipid: 0.73 mass%

2) Profile of phospholipids

(1) HPLC / ELSD method.

(2) The profile is shown below as mg / 100 g (raw bone).

PL-PE: 164, PE: 119, PL-PC: 46, PC: 283, SM: 60

3) Assay of bound DHA of PLs of raw bone

(1) Preparation of plasmalogens

The purity of PLs prepared by the method of NADACHI et al. Was 94.4 mass% (breakdown, PL-PC: 20.8%, PL-PE: 73.6%).

(2) Analysis of fatty acid composition of PLs

The above-mentioned PLs were subjected to methyl esterification by a conventional method to analyze fatty acid composition. The composition ratio of DHA in SN-2 binding fatty acids of PLs was 69%.

Chapter 3

1) classification of each lipid; TL: 32% TPL: 1%

2) Profile of phospholipids

(1) HPLC / ELSD method.

(2) The profile is described below as mg / 100 g (sheet).

PL-PE: 186, PE: 88, PL-PC: 16, PC: 379, SM: 86

3) Confirmation of binding DHA of PLs of intestine

(1) Preparation of PLs

The purity of PLs prepared by the method of NADACHI et al. Was 92.4 mass% (breakdown, PL-PC: 7.3%, PL-PE: 85.1%).

(2) Analysis of fatty acid composition of PLs

The above-mentioned PLs were subjected to methyl esterification by a conventional method to analyze fatty acid composition. The composition ratio of DHA in SN-2 binding fatty acids of PLs was 70%.

4. Sandbags

1) classification of each lipid; Total lipid: 7.9 mass% total phospholipid: 0.9 mass%

2) Profile of phospholipids

(1) HPLC / ELSD method.

(2) The profile is described below as mg / 100g (sand bag).

PL-PE: 122, PE: 91, PL-PC: 25, PC: 255, SM: 118

3) Verification of binding DHA of PLs of sandbags

(1) Preparation of plasmalogens

The purity of the PLs prepared by the method of NADACHI et al. Was 95 mass% (breakdown, PL-PC: 16.2%, PL-PE: 78.8%).

(2) Analysis of fatty acid composition of PLs

The above-mentioned PLs were subjected to methyl esterification by a conventional method to analyze fatty acid composition. The composition ratio of DHA in SN-2 binding fatty acids of PLs was 69%.

5. Brass

[Egg production]

1) classification of each lipid; Total lipid: 31 mass% Total phospholipid: 9.5 mass%

2) Profile of phospholipids

(1) HPLC / ELSD method.

(2) The profile is described below as ㎎ / 100 g (brass).

PL-PE: 220, PE: 1574, PL-PC: 0, PC: 7,542, SM: 145

3) Verification of binding DHA of PLs of crown

(1) Preparation of PLs

The purity of PLs prepared by the method of NADACHI et al. Was 96 mass% (breakdown, PL-PC: 0%, PL-PE: 96%).

(2) Analysis of fatty acid composition of PLs

The above-mentioned PLs were subjected to methyl esterification by a conventional method to analyze fatty acid composition. The composition ratio of DHA in SN-2 binding fatty acids of PLs was 69%.

[Bred female]

1) classification of each lipid; Total lipid: 39 mass% total phospholipid: 12.2 mass%

2) Profile of phospholipids

(1) HPLC / ELSD method.

(2) The profile is described below as ㎎ / 100 g (brass).

PL-PE: 551, PE: 2, 238, PL-PC: 0, PC: 10,592, SM: 339

3) Verification of binding DHA of PLs of crown

(1) Preparation of PLs

The purity of the PLs prepared by the method of NADACHI et al. Was 97 mass% (breakdown, PL-PC: 0%, PL-PE: 97%).

(2) Analysis of fatty acid composition of PLs

The above-mentioned PLs were subjected to methyl esterification by a conventional method to analyze fatty acid composition. The composition ratio of DHA in SN-2 binding fatty acids of PLs was 70%.

6. Skin (epidermis)

1) classification of each lipid; Total lipid: 31 mass% Total phospholipid: 9.5 mass%

2) Profile of phospholipids

(1) HPLC / ELSD method.

(2) The profile is shown below as mg / 100g (shell).

PL-PE: 58, PE: 21, PL-PC: 17, PC: 95, SM: 55

3) Assay of binding DHA of PLs of the bark

(1) Preparation of PLs

The purity of the PLs prepared by the method of NADACHI et al. Was 96 mass% (breakdown, PL-PC: 21.8%, PL-PE: 74.2%).

(2) Analysis of fatty acid composition of PLs

The above-mentioned PLs were subjected to methyl esterification by a conventional method to analyze fatty acid composition. The composition ratio of DHA in SN-2 binding fatty acids of PLs was 67%.

7. Breast

(1) classification of each lipid; TL: 1.9%, TPL: 0.8%

(2) Profile of phospholipids

1) HPLC / ELSD method.

2) The profile is described below as mg / 100g (breast).

PL-PE: 67, PE: 44, PL-PC: 136, PC: 276, SM: 32

(3) Verification of binding DHA of PLs of breasts

1) Preparation of purified PLs

The purity of the PLs prepared by the method of NADACHI et al. Was 95.4 mass% (breakdown, PL-PC: 36.8%, PL-PE: 58.6%).

2) Analysis of fatty acid composition of PLs

The above-mentioned PLs were subjected to methyl esterification by a conventional method to analyze fatty acid composition. The composition ratio of DHA in SN-2 binding fatty acids of PLs was 65%.

8. Egg yolk

1) classification of each lipid; Total lipid: 32.1 mass% total phospholipid: 9.8 mass%

2) Profile of phospholipids

(1) HPLC / ELSD method.

(2) The profile is described below as ㎎ / 100 g (brass).

PL-PE: 100, PE: 1,624, PL-PC: 5, PC: 7,942, SM: 133

3) Verification of binding DHA of PLs of crown

(1) Preparation of PLs

The purity of the PLs prepared by the method of NADACHI et al. Was 97 mass% (breakdown, PL-PC: 5%, PL-PE: 92%).

(2) Analysis of fatty acid composition of PLs

The above-mentioned PLs were subjected to methyl esterification by a conventional method to analyze fatty acid composition. The composition ratio of DHA in SN-2 binding fatty acids of PLs was 75%.

Preparation Example 4

[Extraction and isolation of phospholipid-containing phospholipids (complex lipids) derived from egg yolk]

20 g of ethanol was mixed with 100 g of raw egg yolk and allowed to stand at room temperature for 10 minutes, and then 120 g of 20% aqueous ethanol was further added and stirred. When centrifuged at 2000 rpm for 5 minutes, it is separated from the upper layer into a yellow transparent egg yolk oil phase, a yellowish white complex lipid oil image, and a mostly white egg yolk protein precipitate. The egg yolk oil phase and the oil phase were separated and the precipitated phase was extracted with 50 g of 20% hydrous ethanol. Similarly, the supernatant was centrifuged and the filtrate was concentrated under reduced pressure together with the oil phase to obtain 11.5 g of yellowish egg yolk complex lipid (acetone insoluble portion: 80% lost.

1) Fractionation of lipids

Total lipid separated by extraction and separation by Folch method was 33.5 mass%.

2) Phospholipid profile assay

And measured by HPLC / ELSD method of NADACHI method of commercial law.

3) List of the above results in [mg / 100 g egg yolk]

TL (total lipid): 33.5%

TPL (total phospholipid): 9.5%

PLs ([PL-PE] + [PL-PC] (ethanolamine type PLs + choline type PLs)): 0

PE (phosphatidylethanolamine): 1,574

PC (phosphatidylcholine): 7,542

SM (Sphingomyelin): 145

4) The composition ratio of phospholipids specific to complex lipid of egg yolk

(1) PLs; [Ethanolamine type]: [Choline type] = -

(2) diacylglycerol phospholipids; [Ethanolamine type]: [Choline type] = 1: 4.8

(3) [ether glycerophospholipid]: [diacylglycerophospholipid] = -

(4) [total glycerophospholipid]: [total sphingomyelin] = 62.9: 1

[Extraction and isolation of PLs-containing phospholipids

20 g of ethanol was mixed with 100 g of the brass, and the mixture was allowed to stand at room temperature for 10 minutes, and then 120 g of 20% ethanol was further added thereto and stirred. When centrifuged at 2000 rpm for 5 minutes, it is separated from the upper layer into three phases of a yellowish transparent pearl-like oil phase, a yellowish white composite lipid oil image, and a mostly white egg yolk protein precipitate. The brine oil phase and the oil phase were separated, and the precipitated phase was extracted with 50 g of 20% aqueous ethanol. Similarly, centrifugal separation was carried out to concentrate the supernatant under reduced pressure together with the oil phase to obtain 12.2 g of a yellow brass complex lipid (acetone insoluble portion: 80% lost.

1) Fractionation of lipids

The total lipid extracted and fractionated by Folch method was 39.3 mass%.

2) Phospholipid profile assay

And measured by HPLC / ELSD method of NADACHI method of commercial law.

3) List of the above results in [mg / 100 g egg yolk]

TL (total lipid): 39.3%

TPL (total phospholipid): 12.2%

PLs ([PL-PE] + [PL-PC] (ethanolamine type PLs + choline type PLs)): 551

PE (phosphatidylethanolamine): 2,233

PC (phosphatidylcholine): 10,592

SM (sphingomyelin): 339

4) The composition ratio of phospholipids specific to the complex lipid of the crown

(1) PLs; [Ethanolamine type]: [choline type] = 1: [~ 0.1]

(2) diacylglycerol phospholipids; [Ethanolamine type]: [Choline type] = 1: 4.7

(3) [ether glycerophospholipid]: [diacyl glycerophospholipid] = 1: 23

(4) Total Glycerophospholipid: Total Sphingomyelin = 40: 1

Preparation Example 5

[Composition of two kinds of products using raw materials of the waste breeding stock]

1. Compositional lipid compositions; Mg / g

PLs type 6 to 60, nonplasma phosphorous phospholipid 9.6 to 84.3, anserine 0.4 to 3.6, carnosine 0.07 to 0.6, free amino acid 0.24 to 2.4, vitamin E 0.12 to 1.2, carnitine 0.3 to 3, coenzyme Q10 0.12 to 1.2

2. Protein / lipid complex composition

Protein fraction 87.1, complex lipid fraction 1.4, low-molecular water-soluble fraction 3.2

Verification Example 1

1. Measurement of the effects of chicken-derived PLs on cognitive function and related thinking (black) Example

The PLs for the measurement test were prepared as follows.

[Chicken species and parts thereof]

I procured the peeled breast skin of the scattering system from the waste treatment center.

[Total lipid preparation]

The above-mentioned mins was lyophilized outdoors, and this was extracted gently with ethanol in accordance with the conventional method to prepare total lipids derived from breasts.

[Preparation of complex lipid]

The complex lipid was degassed (de-neutralized lipid) by appropriately adding to the ethanol solution of the total lipid to prepare a complex.

[Preparation of glycerol phospholipids]

The complex lipid was treated with hexane / acetone (7: 3) according to the conventional method to prepare a phospholipid from the desalting myelin and purified glycerol.

[Preparation of high purity PLs]

PLS having a purity of about 90% by mass was prepared by converting a phospholipid into a lithia by diacylglycerol with PLA1 enzyme according to the conventional method.

2. Verification of digestion and absorption of orally administered pneumoconiosis PLs

(1) The effectiveness of oral administration was confirmed by the increase in PLs in blood of rats (Non-Patent Document 15).

(2) Increased PLs concentration in the brain of LPS-induced central nervous system inflammatory model mice confirmed intracerebral absorption from orally administered PLs from the cerebral blood gates (Non-Patent Document 8).

(3) The increase in plasma PLs concentration in AD patients proved the effectiveness of oral administration to humans, among them AD patients (Non-Patent Document 16).

3. Verification of the inhibition (prevention) and mitigation and therapeutic effects of the cesarean section PLs cognitive impairment

(1) The neuronal cell of senescence model rat (SAMP8) is newly born, and the possibility of the cognitive dysfunctional alleviation due to the pulmonary hemorrhage PLs and the therapeutic effect thereof is verified (Patent Document 7).

(2) Expression of the inhibitory action of the spatial cognitive learning function impairment by the pulmonary system breast plasma plasma for bilateral injection model rats of A _? Proves the possibility of the therapeutic effect of the cognitive function impairment of the pulmonary system thoracic PLs (Non-Patent Document 16 ).

4. Verification Example of Mitigation of Inflammatory Symptoms of LPS-Induced Central Nervous System Inflammatory Model Mice (Non-Patent Document 8)

1) Inhibition of microglia activation by pulmonary hemorrhage PLs demonstrates the possibility of mitigation and treatment of cognitive dysfunction through its central nervous system inflammation.

2) The increase of mRNA of TNFα in brain and the suppression of IL-2β expression in brain by pulmonary hemorrhage PLs demonstrate the possibility of cognitive dysfunction mitigation and treatment through central nervous system inflammation caused by pulmonary hemisphere PLs will be.

3) accumulation of inhibitory activity in the brain caused by A _β pyegye breast PLs is to demonstrate the potential of the relief and treatment of cognitive impairment through the central nervous system inflammation.

5. Test for inhibition of central nervous system inflammation and A _? Accumulation of intraperitoneal injection LPS-induced central nervous system inflammatory model mice (Non-Patent Document 8)

1) Central nervous system inflammation of the central nervous system through inhibition of central nervous system glial cell activation by pulmonary thrombosis PLs demonstrates the possibility of preventing and alleviating the cognitive dysfunction of the thoracic PLs.

2) inhibition of A _β accumulation by pyegye breast PLs to the hippocampus and frontal Eve is to demonstrate the possibility of inhibiting the effect of cognitive dysfunction by the inhibition of A _β accumulation of pyegye breast PLs.

3) The pulmonary gland PLs demonstrate the possibility of inhibiting the cognitive dysfunction by inhibiting the reduction of PLs caused by inflammation induced by intraperitoneal injection of LPS.

4) Tumor-bearing breast cells PLs demonstrate the ability to directly treat cognitive dysfunctions associated with neuronal cell death through inhibition of neuronal cell death in neuronal cell culture systems (Non-Patent Document 9).

5) Other

(1) The composite lipid fraction derived from the lungs of the lungs demonstrates the possibility of delaying the onset of the cognitive dysfunction by inhibiting hyperglycemia and hyperlipidemia of the risk factors for the cognitive dysfunction (Non-Patent Document 18).

(2) The composite lipid composition derived from the pulmonary system breast is to prove the possibility of preventing the cognitive function disorder or suppressing the cognitive function by inhibiting the deterioration of the cognitive function by the carnosynthesis (Non-Patent Document 19).

Verification Example 2

1. Verification of whether or not the inhibitory effect of DHA-conjugated PLs derived from chickens corresponding to the cognitive dysfunction inhibitory effect of the lungs of the pneumoconiosis PLs is remarkably increased

1) Verification of binding suitability of PLs with DHA

PLs are the main phospholipids storing DHA (Non-Patent Document 26).

2) Verification of biochemical and physiological specificity of DHA-PLs

(1) In a single molecule (glass), the aqueous system (emulsion) is more stable (Non-Patent Document 1).

(2) In the complex system (lipid bilayer), it is more stabilized than monomolecular system because it is the main membrane constituent.

(3) It is believed that DHA-PLs stabilize as a result of the adherence to vinyl ether bonding sites such as radicals and active acidic compounds by DHA, which is a bulk fatty acid bound adjacent to an unstable vinyl ether bond, (Non-Patent Document 1).

(4) Fatty acid residues bound to the SN-2 position of the glycerophospholipid are hardly hydrolyzed, and digestion and absorption systems are well absorbed without being decomposed, and PLs are also introduced into the blood, and DHA-PLs Is effectively transferred to the blood.

(5) In terms of the transitivity in the brain from the cerebral blood gates, DHA can not migrate into the brain in the glyceride structure, and the phospholipid structure is considered to be essential. PLs have a high selectivity for DHA binding (described above) It is not an exaggeration to say that the structure of PLs is the optimal molecular species of passage through the blood-brain barrier.

(6) After transfection into the brain, it is approached to the endoplasmic reticulum peroxisome of neurons of the PLs acidic living body, and DHA promotes PLs production by promoting the expression of the rate-limiting enzyme Far1 (fattyacyl-CoA reductase 1) in the PLs biosynthetic system Patent Document 10]).

(7) Increased concentration of PLs in the brain promotes suppression of cognitive dysfunction and its mitigation and treatment mainly through inhibition of central nervous system inflammation (Non-Patent Document 7, Non-Patent Document 8, Non-Patent Document 10, One).

In addition to the direct stabilization in the molecule and the synergistic effect on the improvement and correction of cognitive dysfunction, DHA-PLs can be said to be the most suitable molecular species for improving, maintaining and improving cognitive function.

Verification Example 3

(1) Prevention is needed from adulthood

1) having the In "end state" at the time of diagnosis it is obvious made result, dementia onset, which occurs in brain accumulation of a dramatic performance of the DIAN ^* Research projects comprehensively, the Washington representative Morris, professor of the United States from the 40-generation A _β and τ protein It is clear that there is not much cure for the dementia patient.

Dominantly Inherited Alzheimer's Network: Whether or not families can detect changes to AD by tracking long-term family members (100 persons) who are likely to have a causative gene for AD, The aim is to find a change in the brain some time before the symptoms appear, and this breakthrough was achieved in 2012, seven years after the start in 2005 (Morris, JC et al. [Non-Patent Document 20] [Repair Alzheimer's Disease!] NHK Special Report Group (SHUFU TO SEIKATSU SHA (National Institute of Advanced Industrial Science and Technology (AIST)) 2014))

2) The first is that pre-defined to suppress the accumulation of A _β precursor symptoms of AD onset, neurons within the aggregation ([entanglement of τ] in the τ protein that occurs in conjunction with the [accumulation of A _β]; induced neuronal four ).

3) Symptoms of the above symptoms are activation of microglial cells to "combat mode", resulting in attack of released strong oxidizing factors or cytokines, resulting in death of neurons, thus inhibiting "microglial activation" Is required.

(2) Various actions of scattering chicken breasts PLs (hereinafter referred to as &quot; breasts PLs &quot;) contributing to visibility in the brain

1) Breast PLs suppress [accumulation of A _{? In} the brain] (Patent Document 1).

2) Breast PLs inhibit microglia activation in the brain (Non-Patent Document 8).

3) Breast PLs inhibit neuronal apoptosis (Non-Patent Document 9).

4) Breast PLs inhibit the damage of neurons by inhibiting TNFα-mRNA hyperactivation and IL-2β expression of intracerebral cytokines (Non-Patent Document 8).

5) Breast PLs promote neuronal neogenesis (Patent Document 7).

Long-term PPLs ingestion from age 40 through each of the above actions of the breasts PLs [inhibiting the accumulation of A [ _beta ] and enhancing by neuronal innervation of neuronal aggregation [tau protein] induced cell death may be an effective preventive measure have.

(3) about the "4 eyes ^* " of the breasts PLs; * Safety, security, stability,

1) Rest assured

i) The experience of breasts by mankind has been long, and its consumption is also remarkable.

ii) Breasts that require long-term activity during an emergency are considered equivalent to mammalian myocardium.

Therefore, since it is an energy-consuming institution, there are many biosynthetic substances, so it is necessary to build an antioxidant system that adequately protects them. It is believed that the core is the strongly reducing PLs of cell membrane constituents and therefore the content is high.

iii) By the above, PLs is a "universal" phospholipid that is an important component of the cell membrane composition in vivo and occupies 18% of the total human phospholipid.

iv) Although PLs are usually produced by intracellular endoplasmic reticulum [peroxisome], their biosynthesis performance deteriorates together with, for example, the spread of PLs.

2) Safety

i) In the production of breasts PLs, the chemical treatment is excluded, and the safe and mild extraction treatment and decomposition of phospholipids belonging to the same species contained in the purification are carried out into natural-derived enzymes.

ii) The raw breasts are separated from the removing conductor in the fresh egg-laying system, and are edible meat produced by peeling. The records of the breed, the house, the feed, the day, the pesticide residues, antibiotics and heavy metals are recorded.

iii) Spawning stocks are made in Japan.

3) Stable

i) Dissolve in tocopherol of edible grade to stabilize, antioxidize,

ii) Soft capsule-encapsulating this into a shell plate,

iii) It is nano-emulsified with mild natural ingredients only,

iv)

(i) soft encapsulation,

(ii) adding a predetermined amount to existing foods,

(iii) an excipient is added and spray-dried to be granulated and pulverized,

(iv) refining it, or

(v) Dry blend with solid foods.

4) Not going

i) Since the daily dose is 0.5 mg, it can be provided at a reasonable cost

ii) With the above stabilization, the storage stability is good and no swelling is required at the unit level

iii) Raw spawning stocks (Japanese) are the lowest in poultry

iv) Breast meat is the most inexpensive chicken meat, usually processed into bulk mins,

v) The breasts are excellent in achieving the highest rate among the chicken meat parts

Verification Example 4

[Productivity of DHA phospholipid in microorganism of ravirin tulle]

1) Ravirin tullah microbes isolated from microalgae collected from mangrove watershed in Okinawa 12B The amount of DHA contained in the main DHA is as high as 21g (total DHA) / 100g (see fish data below) Of the total amount of DHA was clarified by Professor Okuyama of Hokkaido University (Patent Document 16, Patent Document 17).

(1) DHA contained in fish (g / edible portion 100 g) (Non-Patent Document 29)

1) bluefin tuna and tuna; 3.2

2) mackerel (from the Atlantic Ocean); 2.3

3) Salmon and salmon roe; 2.0

4) defense; 1.6

5) saury; 1.6

(2) The new technology "glucose starvation fermentation method" dramatically improved the phospholipid, the DHA content is further increased

Ravirin tullah microbes 12B accumulate large amounts of fat when fermented in the presence of glucose. As a result of glucose starvation, accumulated fat is converted into phospholipids (13% ⇒ 67%), resulting in an increase in DHA content.

2) Objective of practical use of DHA phospholipid

(1) development (bench level) DHA phospholipids; 11% of the dry weight of the culture (1 g / L)

(2) target DHA phospholipid; 20% of the dry weight of the culture (5-10 g / L)

3) The fermentation broth and / or the dried product thereof are highly suitable as omega-3HUFA derivatives

(1) activation of peroxisome in the in vivo plasma genogens livestock

(2) easy transition from brain blood gate into brain

(3) Reconstructed structure of DHA in brain

EXAMPLES Next, the present invention will be described in detail with reference to Examples.

Example 1

[Preparation of Purified Plasma Genogens Derived from Egg Yolk of Scattering System]

(PLs) having a purity of 95.6% by mass was prepared in accordance with the method of NADACHI et al. (Patent Document 4).

[Preparation of tablets PLs derived from egg yolk of female females]

PLS having a purity of 96.7% by mass was prepared in accordance with the method of NADACHI et al. (Patent Document 4).

Example 2

[Nano emulsification of tabular PLs derived from egg yolk and its stability]

5 g of a 10 mass% δ tocopherol solution of 95.6 mass% PLs was added dropwise to 95 g of an aqueous solution containing 15 g of Kiraja saponin while stirring with a magnetic stirrer, and stirring was continued until the turbidity was eliminated, thereby obtaining a nano emulsion. The average particle size of the oil-phase particles in the nano emulsion was measured with a submicron analyzer to find that it was 58 nm. The nano emulsion was diluted 500 times with water, and it was transparent. No change was observed even at pH 4 using citric acid. After heating at 95 占 폚 for 30 minutes, the nano emulsion was returned to room temperature and there was no turbidity and no change in transparency. The nano-emulsified diluted solution was evaporated to dryness at a low temperature, and the purity of the PLs was determined by the method of the patent (HPLC / ELSD). The result was 94% by mass.

Example 3

[Shape Transformation and Stability of Nano Emulsion of Tablet PLs from Egg Yolk]

1) Spray drying of 0.5 mass% nano emulsion of 92 mass% PLs prepared in Example 1 30 g of starch hydrolyzate (for example, AMYCOL 6H made by NIPPON STARCH CHEMICAL CO., LTD.) Was dissolved in 100 g of the above nano emulsion Spray-drying was performed at a hot air inlet temperature of 110 DEG C and an outlet temperature of 60 DEG C by using a tabletop mini spray drier (for example, manufactured by Yamato Scientific Co., Ltd.) to prepare a powdery phase containing 92% by mass of PL- The formulation was obtained. The 100-fold dilution of this powdered formulation showed a somewhat blue appearance, but was transparent. The particle size of the oil-based particles in the water diluted solution was measured and found to be 61 nm. Further, the water diluted solution did not change at all even when it was adjusted to pH 4 using citric acid, and there was no change such as turbidity even after heating at 95 캜 for 30 minutes and then returning to room temperature. The nano-emulsified diluted solution was evaporated to dryness at a low temperature, and the purity of PLs was determined by the method of the patent (HPLC / ELSD). As a result, it was confirmed that 90% by mass.

2) Preparation and properties of PL-PE-containing jelly from egg yolk

The dried white powder was dissolved in 8 g of water, and 14 g of an equivalent white sugar was added thereto and dissolved. To this solution was added 120 g of a 10 mass% delta tocopherol solution of 95% PLs and homogenized with stirring to obtain a translucent jelly-like solubilized product. When this was put in water, a roughly transparent aqueous solution was obtained.

Example 4

[Extraction and purification of DHA-conjugated PLs of PLs from DHA transitional yolk obtained from eggs produced by the egg yolk prepared in Preparation Example 3]

An egg yolk complex lipid transited with DHA was prepared in the same manner as in Preparation Example 3.

Example 5

[Preparation of tablets PLs derived from egg yolk transited by DHA]

PLs containing DHA-bound PLs of 96% purity were prepared according to the HPLC / ELSD method (Patent Document 4) of NADACHI et al.

Example 6

[Measurement of DHA binding ratio of PLs in the preceding paragraph]

The fatty acid composition of the PLs was methylesterified according to the conventional method. As a result, it was found that the DHA binding ratio (mol%) in SN-2 binding fatty acids of PLs was 75%.

Example 7

[Nano emulsion of 96% purity DHA-bound (75%) type PLs and its stability)

The procedure of Example 2 was repeated to obtain a nano emulsion. The average particle diameter of the oil phase particles in the nano emulsion was measured with a submicron analyzer, and it was found to be 37 nm.

The nano emulsion was diluted 500 times with water, and it was transparent. No change was observed even at pH 4 using citric acid. After heating at 95 캜 for 30 minutes, the nano emulsion was returned to room temperature and no turbidity occurred and no change in transparency was observed. The nano-emulsified diluted solution was evaporated to dryness at a low temperature, and the purity of PLs was determined by the method of the patent (HPLC / ELSD). As a result, it was confirmed that 95% by mass.

Example 8

[Shape Conversion and Stability of Nano Emulsion]

Was carried out as follows according to Example 3.

1) Spray drying of a 0.5 mass% nano emulsion of 96 mass% PLs prepared in Example 1

30 g of a starch hydrolyzate (for example, AMYCOL6H manufactured by NIPPON STARCH CHEMICAL CO., LTD.) Was dissolved in 100 g of the nano emulsion, and then a tabletted mini spray drier (for example, manufactured by Yamato Scientific Co., Ltd.) And spray-dried at an inlet hot air temperature of 110 캜 and an outlet temperature of 60 캜 to obtain a powdery preparation containing 96 mass% PLs at 1 mass%. The 100-fold dilution of this powdered formulation showed a somewhat blue appearance, but was transparent. The particle size of the oil phase particles in this water dilution was measured and found to be 40 nm. Further, the water diluted solution did not change at all even when it was adjusted to pH 4 using citric acid, and there was no change such as turbidity even after heating at 95 캜 for 30 minutes and then returning to room temperature. The nano-emulsified diluted solution was evaporated to dryness at a low temperature, and the purity of PLs was determined by the method of the patent (HPLC / ELSD). As a result, it was confirmed to be 94% by mass.

2) Preparation and properties of jelly containing DHA-binding PLs

The dried white powder was dissolved in 8 g of water, and 14 g of an equivalent white sugar was added thereto and dissolved. To this solution was added 120 g of a 10 mass% delta tocopherol solution of 96% PLs and homogenized with stirring to obtain a translucent jelly-like solvate. Its 100-fold dilution of water was approximately transparent, and no change was observed even at pH 4 using citric acid, and no change such as turbidity was observed even after heating to 95 ° C for 30 minutes and then returning to room temperature. The nano-emulsified diluted solution was evaporated to dryness at a low temperature, and the purity of PLs was verified by the method of the patent (HPLC / ELSD). As a result, it was confirmed that it was 95% by mass.

Example 9

[Stability comparison test of 96 mass% PLs of 92 mass% PLs and 75 mole% DHA binding ratio]

1) 50% test in a sealed state under 10% by mass of δ tocopherol solution under light shielding

In comparison of the half-life of contents, 92 mass% PLs were halved to an average of 1 week, while 96 mass% PLs of DHA binding did not decrease even for 4 weeks.

2) 60% test of standing at 60 占 폚 in sealed under light shielding of 0.1 mass% nano emulsion of 10 mass% delta tocopherol solution

The 92% by mass PLs were halved to an average of 5 days, while the 96% by mass PLa of DHA binding was decreased for 4 weeks.

Example 10

[Examination of the egg yolk reforming effect of the threshing krill mill]

~ Test conditions ~

· Laying species; Boris Brown 42 wks 56 wks, 28 wards / wards

· Examination area; Control

·feed; Commercial feed (2,850 kcal / kg, CP 17.0%)

85% by mass in the test plate feedstuff + 15%

· Breeding period; 1 week

~ Sample processing and assay ~

· Treatment of egg production; The egg yolk was separated from the halan, and this was freeze-dried. And extracted with ethanol to separate lipid fractions.

· Lipid assay of lipid fractions; Gas Chromatography and HPLC / ELSD

Black items; EPA, DHA, PLs

~ Test result ~

Table 1 shows the results of the review.

Effect of Addition of Threshing Kill Mill; Contrast contrast ~

(1) EPA; 0

(2) DHA; 3.3 Back-up

(3) PLs; 2.5 times up

The remarkable effect of modifying egg yolk by threshing krill was confirmed above.

Example 11

[Clinical Trial on the Improvement of Cognitive Function of PLs Derived from the Tumors of the Breast]

[Production of PLs-containing phospholipids extracted from pulp-based pea breast]

1. Preparation of complex lipids from the skin of the skin

An edible [complex lipid] derived from breast was prepared according to Preparation Example 1-7.

[Preparation of purified PLs from complex lipids]

2. Preparation of purified PLs from edible [complex lipids]

Tablet PLs were prepared according to Preparation Example 2-7.

[Preparation of edible [PLs sample] for clinical trial]

[Composite lipids] and [Tablets PLs] of the above preparation were appropriately mixed to prepare an edible [PLs sample] for public use.

[Clinical Trial]

The study of the effect of randomized, double-blind, placebo-controlled trials (see non-patent document 21 for details) on the improvement of cognitive function by the administration of supplements made by adding edible PLs specimens with the selected healthy Japanese as subjects.

This test was conducted by the Japan Foundation Clinical Trials Association (JACTA) (Japan Clical Trial Association Tokyo), a specialized institution in the field of clinical trials. The implementation period was 12 weeks from April 5, 2016 to June 29, 2016, and was conducted in compliance with ethical principles based on the Helsinki Declaration. 135 consecutive male and female healthy women aged 40-79 years were selected as candidates and the consent form was obtained from the entire sample.

I. Preparation of Disclosed Samples

1) Formulation of published samples [PLs]

The same as above.

2) An undiluted solution for soft capsules containing PLS 0.25 mg (hereinafter referred to as "Plasmarogen EX") and soft capsules containing PLs 0.50 mg (hereinafter referred to as "Plasmarogen ES") by addition of edible [PLs sample] Preparation of

Based on the prescriptions shown in Table 1, the undiluted solution for plasma encapsulation of Plasmarogen EX and Plasmagogen ES was prepared.

3) Preparation of placebo for soft capsule of placebo

Based on the prescription described in Table 1, the edible [PLs sample] was removed from the plasma broth EX stock solution, and starch was added thereto to adjust the weight to prepare a placebo soft capsule solution.

4) Soft encapsulation of each stock solution

Two types of test and soft capsules for placebo were prepared by external professional makers to manufacture oval spherical soft capsules made of caramel colored food grade gelatin which is indistinguishable from each appearance. Table 2 shows the specifications of the disclosure capsule.

Ⅱ. Selection of subjects

135 people were screened by volunteer registrants from March to April 2016 of CROee Inc. (Tokyo) of Monitor Bank.

1) selection criteria;

(1) Japanese general men and women aged 40 to 79 years

(2) Although it can not be said that it is completely normal due to the cognitive function, the person who has not experienced a proper medication in the past has been clarified by the cognitive function questionnaire of FIG. 1

2) exclusion criteria; Exclude 54

(1) the person being treated for cognitive dysfunction

(2) Those taking medicines containing herbal medicine

(3) Pregnant women and women who may become pregnant during the test period

(4) Person who is not qualified as the subject of the test and judged by the person in charge of the test execution

As a result of the above, 54 subjects were excluded from 135 persons, resulting in 81 subjects.

As a result, three groups were randomly assigned to group A (n = 26), group B (n = 28), and group C (n = 27) At this time, gender and age were considered not to be deviated.

* Group A is a placebo

* Group B consisted of test-1 (0.25 mg)

* Group C consisted of test-2 (0.5 mg) spheres

The subjects were divided into two groups as described above. The subjects consumed 2 capsules (1 capsule each morning and evening) for 12 weeks while avoiding binge eating and drinking, and recorded the status of physical and forgetfulness The diary was submitted to the supervisor of the test.

Ⅲ. Exam Overview

1) Schedule of examination

Table 3 shows the schedule of the tests.

2) MMSE

See FIG. The top score is 30.

3) Uchida, crane test (hereafter referred to as "U-K test")

The addition of a simple one-digit sequence is performed continuously for a predetermined period of time, and a check is made of the calculation power to determine "ability when a person calculates" and "characteristic when the calculation power is exercised" by a curve indicated by the amount of calculation. Normally, two sets of 1 minute x 15 times are used.

4) PSOL cognitive function self-diagnostic test

See Figure 3 in the form of answering high quality surveys of cognitive functionality independently designed. A four-step evaluation from 0 to 4, with a 2-point reference point (baseline). If it exceeds 2, it is evaluated favorably.

5) Safety evaluation of public samples (3 kinds of soft capsules)

And it was described in the work report from the subject and evaluated.

6) Data interpretation method

In this test, the number of samples was not matched and all analysis results were used. All statistical values were expressed as mean ± SD.

The differences in the measured values of 0, 6, and 12 weeks were statistically used for pair t test. A comparative evaluation of the measurements of the MMSE, U-K test, and PSOL cognitive function self-diagnostic test within the same group was performed using a pair t test.

Student's t-test was used to compare the differences between the measurements at 0, 6, and 12 weeks and the baseline values from the baseline (0-6 weeks and 0-12 weeks). Background comparisons of subjects in the group were performed using unidirectional square deviation analysis.

We did not adjust this for fluctuations depending on the time of implementation. Subjects who were present were excluded from statistics processing completely. Statistical analysis was performed using statistic 4 and Excel statistics. 2 Statistical analysis between samples The statistical results were judged to be <5%.

IV. Test result

1) Statistical information of subjects

We started the intake test by dividing 81 people into three groups, but six people were eliminated. The reason for the breakdown was 2 bad body condition, sudden work condition 3, housework 1 and eventually 75 people completed the test. Test 1; 27, test 2; 23, placebo; 25, but there was no significant difference in age, sex and U-K test (Table 3).

Table 4 shows the contents of statistical processing on subjects.

2) MMSE

The results are shown in FIG. 1 and Table 4.

A significant difference was found in the comparison between the test-1 and test-2 groups at 12 weeks. Also, at 6 weeks, there was a significant difference in the comparison between groups of placebo groups. However, there was no significant difference in test-1 versus placebo versus test-2 versus placebo.

3) U-K test

The results are shown in FIG. 2 and Table 4. There was no significant difference in all three groups. However, there was a significant difference between the test - 1 and the placebo at 6 weeks.

4) Cognitive function self-diagnosis

The results are shown in Table 5.

In Table 5, a significant difference was found between the test-1 and the placebo, and the test-2 and the placebo in the interpretation of the change amount between the groups, as follows:

# 1 (Test-1, Test-2), # 5 (Test-1), # 1), # 13 (Test-1), # 17 (Test-1, Test-2), # 18 (Test-1, Test-2), # 4 (Test-1, Test-2) and # 5 (Test 1, Test 2), # 8 (Test 1, Test 2), # 12 (Test 1), # 15 (Test 2) # 2 (Test-2), # 21 (Test-2), # 23 (Test-1, Test-2).

In the test-1 vs. placebo, the number of significant items of the 6th week decreased from 12 weeks to 6 items, but in the test-2 placebo, the number of significant items of 4 at the 6th week was significantly increased to 14 at the 12th week .

5) Cognitive function self-diagnosis result and its interpretation

The results are shown in Tables 6 to 9.

6) Safety evaluation

There was no sign of any significance to the safety of a publicly available sample from the daily report, and there was no problem with safety.

V. Evaluation of Test Results

1) Overall

Was effective in improving cognitive function related to the language and the situation of the subjects who had been taking the plasma-containing supplement for 12 weeks. Also, the disclosed soft capsules did not cause any safety problems during the 12-week trial period.

There was no significant difference in the results of the U-K test, but there was a significant difference between the high-dose group at 6 weeks and the placebo group. Dose - dependency between high - dose and low - dose groups and significant trends between them and placebo group were obtained.

It is a "micron" order, which is considered to be less than or equal to the oral medicines, because it has a very low capacity as a food, especially as a supplement. Moreover, it is a dry box object with not more than 0.5 mg per aliquot, and the administration period is as short as 3 months. It is a surprising discovery that the result of suggesting an immediate improvement of.

2) Topics

(1) MMSE

Significant differences were found in the group at 0.5 and 12.5 weeks in each group. However, a significant difference was found in the placebo group at 6 weeks.

(2) U-K test

It was worth noting that there was a significant difference in the tendency between the high - dose group and the placebo group at 6 weeks, and the dose dependency trend was confirmed between the high - dose group and the low - dose group.

(3) PSOL cognitive function self-diagnostic test

There was a significant difference in both the high and low dose groups and between the placebo and placebo groups at 12 weeks and immediately after 6 weeks. A congested significant difference was observed between the high and low dose groups, but the dose dependence was lacking.

3) Overall evaluation

* Randomized, double-blind, placebo-controlled trial,

* Innovative edible plasma using a genetic composition

* Selected candidates (135 applicants for institutional registrants ⇒ 81 candidates for cognitive function 3-layer interviews ⇒ 75 candidates for exam candidates ⇒ 71 candidates excluded during testing)

* Very low daily doses of 0.25 mg and 0.5 mg, and

Within a very short 12-week period

At just 6 weeks, significant and immediate improvement of cognitive function was identified and evaluated as a remarkable achievement.

Example 12

[open-end blind trial trials of ω-3HUFA derivative proceeds breeders breast origin of the origin of the crown -PLs and scattering pyegye PLs in contrast, the placebo and old settings "A _β and accumulation in brain trend clarification of τ" of the female;

1) Specimen

(1) DHA-PLs; 96.7% purity, the DHA binding rate was 75 mol%

[DHA transition female gold brass] according to Preparation Example 25.2

(2) PLs; 92% by mass [derived from breast tissue]

2) Target and n number

The subjects were divided into 5 groups of 15 persons (DHA-PLs 3 × [0.25 mg and 0.5 mg], PLs 3 × [0.25 mg and 0.5 mg] and 3 placebo) . Men and women are composed of 5 males and 10 females.

3) Conditions

(1) daily dose; 0.25 mg (morning) and 0.5 mg (0.25 mg × twice in the morning and evening)

(2) Formulation; Soft capsule

(3) the period; 40 weeks

(4) Inspection interval; 0, 20 weeks, 40 weeks

4) Evaluation method

A _{&lt; /} RTI _&gt; protein. PIB (Non-Patent Document 31) was used for the test of A _? PET.

The accumulation amount is the SUVR (Standardized Uptake Value Ratio) of the PET image corresponding to the progress of the cognitive function disorder. Tables 10 to 11 show SUVR scores of PET images.

5) Results

&Lt;

(1) Overview of the PET image at the start

[A _beta image]

Since the subject is a dementia patient, the blue color was not confirmed, and the development of "yellow + rust" including a slight "enemy" in the background of "blue" was confirmed.

(4) Overall evaluation

1) [DHA-PLs] and [PLs] has been suggested that both inhibitory activity on the accumulation of A _β of the low ilryang subjects of dementia mibyeong state to the oral intake of. The reduction effect in all 40 weeks for reducing the accumulation of A _β was suggested.

2) [PLs], [DHA-PLs] showed the same tendency in the above.

&Lt; 0.5 mg /

(1) Overview of the PET image at the start

[A _beta image]

Since the subject was MCI, the blue color was not confirmed, and the development of "yellow + rust" including a little "enemy" in the background of "blue" was confirmed.

(2) Evaluation

1) [PLs] and [DHA-PLs] has been suggested that accumulation of A and suppressing the effect of reducing the accumulation of _β increased US Sick whether oral intake of the low ilryang.

2) In [PLs] contrast, [DHA-PLs] was suggested to have a high efficacy in the above.

(3) Overall evaluation

In [PLs] and [DHA-PLs], among others by more than [DHA-PLs] has been suggested to have an effect of reducing the accumulation and inhibit the accumulation of A _β even dementia US sick for oral pole low work capacity 0.25㎎.

Example 13

[Clinical trials of single-blind, open-label clinical trials of "clarification of the hippocampal gradient of the hippocampus" in comparison with the PLs and the placebo regimens derived from the breasts of the -PLs and the scattering system from the brim of the ω-3HUFA derivative-

1) Specimen

(1) DHA-PLs; 96.7% purity, the DHA binding rate was 75 mol%

[Diamond brine of DHA transition female] According to Preparation Example 25.2

(2) PLs; 92% by mass [derived from breast tissue]

2) Target and n number

The subjects were divided into 5 groups of 15 (DHA-PLs 3 × [0.25 mg, 0.5 mg], PLs 3 × [0.25 mg, 0.5 mg] and 3 placebo) I was selected at the age of five. Men and women are composed of 5 males and 10 females.

3) Conditions

(1) daily dose; 0.25 mg (morning) and 0.5 mg (0.25 mg x twice in the morning and evening)

(2) Formulation; Soft capsule

(3) the period; 40 weeks

(4) Inspection interval; 0, 20 weeks, 40 weeks

4) Evaluation method

And examined the depressed state of the "hippocampus" in the brain MRI image of the subject.

5) Results

The results are shown in Tables 12 to 13.

(1) 0.25 mg

1) Both [PLs] and [DHA-PLs] were shown to have a low inhibitory effect on the sedation of hippocampus in subjects with dementia due to low daily oral intake.

(2) Evaluation results of 0.5 mg or less

1) Both [PLs] and [DHA-PLs] showed a tendency to inhibit hippocampal depression in brain MRI of subjects with dementia due to 40-week oral ingestion of low-dose dose.

(3) Overall evaluation

Both [PLs] and [DHA-PLs] showed a tendency to inhibit hippocampal depression in brain MRI of subjects with demented condition due to 40-day oral ingestion of low-dose dose.

(Industrial applicability)

As described above, the present invention relates to a safe and stable plasma geng, a preparation thereof and a use thereof. According to the present invention, 1) a safe and stable plasma genome derived from a safe biological material, more specifically, (2) providing a stable, stable plasma-containing complex lipid made by combining DHA (docosahexaenoic acid) with SN-2 of Gen-2; (2) providing plasma lipid complex lipids with a nano- (3) a complex lipid having an organism-specific composition ratio on the aqueous phase in the presence of saponins, and (3) a combination of ω-3HUFA bond type complex Lipids and complex lipids in which their complex lipid compositions are nano-emulsified or solubilized, and ω-3HUFA-linked complex lipids and their complex lipid compositions 4) providing their aqueous preparations, 5) preparing various types of omega-3HUFA-binding form, or a variety of agents for the prevention or treatment of neurodegenerative diseases and / or mental disorders comprising, as an active ingredient, The present invention has industrial applicability in that specific effects such as providing a processed product, a supplement, a preventive or therapeutic agent, and 6) a method for determining a dementia-free state can be obtained.

Claims (19)

A plasma having a biom tissue-specific composition ratio composed of a purified fraction of a total lipid extracted and fractionated from a specific region or organ originating from a living tissue and in which a byproduct and / or a water-soluble low molecular fraction is purified (Hereinafter referred to as &quot; complex lipid &quot;),
1) The specific site or organ derived from the living body tissue is selected from the group consisting of a helminth conductor derived from a living tissue of a chicken, a raw bone including bone marrow, an egg yolk, a bowel, a sand bag, a brass tube including ovaries and fallopian tubes, At least one or more specific regions or organs,
2) The plasmalogen-containing phospholipid is an ω-3 highly unsaturated fatty acid (hereinafter referred to as "ω-3HUFA") derivative (hereinafter collectively referred to as "ω-3HUFA derivative") containing docosahexaenoic acid (DHA) 3HUFA derivative in which the above-mentioned ω-3HUFA derivative is extracted from a specific site or organ of a living body transited from the above-mentioned ω-3HUFA derivative transited to a living tissue of a chicken raised with a feed containing the ω-3HUFA derivative Wherein the phospholipid is a plasma-containing phospholipid having a composition ratio of the plasma lipid. The method according to claim 1,
wherein the? - 3HUFA derivative is any one selected from the following 1) to 9).
1) ω-3HUFA derivative bound to SN-2 of glycerophosphatidyl phospholipid
2) ω-3HUFA derivative bound to SN-2 of 1-alkylglycerophosphatidyl phospholipid
3) ω-3HUFA derivative bound to SN-2 of 1-alkenyl glycerophosphatidyl phospholipid
4) ω-3HUFA derivative bound to SN-2 of 1-acylglycerophosphatidyl phospholipid
5) An omega-3HUFA derivative bound to SN-2 of the glycerophosphatidyl phospholipid described in any one of 1) to 4) above, which is contained in krill-peeled shrimp flesh and /
6) An omega-3 HUFA derivative bound to SN-2 of the glycerophosphatidyl phospholipid described in any one of 1) to 4) contained in the whole scallop and / or its processed residue or the mill (dried product)
7) An omega-3 HUFA derivative bound to SN-2 of the glycerophosphatidyl phospholipid described in any one of 1) to 4) contained in the whole seaweed and / or the processed residue thereof or the mill (dried product thereof)
8) An omega-3 HUFA derivative bound to SN-2 of the glycerophosphatidyl phospholipid according to any one of 1) to 4)
9) An omega-3 HUFA derivative bound to SN-2 of the glycerophosphatidyl phospholipid described in any one of 1) to 4) prepared by fermentation The method according to claim 1,
Wherein the specific region or organs is egg yolk and the total lipid purified from egg yolk containing DHA-PLs biosynthesized in the body of the chicken. The method according to claim 1,
Alkylglycerophosphatidyl phospholipid, or a purified lipid of total lipid extracted and fractionated from a specific part of a living body or an organ of a chicken raised with a feed containing an organic synthesized 1-alkylglycerophosphatidyl phospholipid. The complex lipid composition according to claim 1, wherein the complex lipid has the composition ratio of? -3HUFA binding type containing the water-soluble low molecular fraction as a by-product of the fractionation according to claim 1. Wherein the complex lipid or complex lipid composition having the composition ratio of? -3HUFA bond type according to any one of claims 1 to 5 is nano-emulsified or solubilized in the presence of saponins in the presence of saponin a water-soluble preparation of a complex lipid composition having a composition ratio of? - 3HUFA bond type. A process for producing a liposome comprising the steps of enzymatically treating the complex lipid according to any one of claims 1 to 4 with a phospholipase A1 (PLA1) to remove phospholipids from glycerol containing a lysomer and further extracting and removing sphingomyelin Characterized in that it has a purity of 30 to 70%. A process for preparing an aqueous preparation of the above-mentioned prepared plasma halogenated or high purity plasmalogen, which comprises nano-emulsifying or solubilizing each of the prepared plasma halogen or high purity plasmonogen according to claim 7 as a substrate in the aqueous phase in the presence of saponins Way. A food, a cosmetic, a cosmetic, a cosmetic, a cosmetic, a cosmetic, a cosmetic, a cosmetic, a cosmetic, a cosmetic, a cosmetic, a cosmetic, a cosmetic, Drug or feed. A pharmaceutical composition comprising at least one compound selected from the group consisting of the complex lipid according to any one of claims 1 to 8, the complex lipid composition, each plasmalogen, and each aqueous preparation thereof as an active ingredient, , Mitigating and preventing at least one neurodegenerative disease selected from the group of Alzheimer's disease, Parkinson's disease, depression, and integrated ataxia. A pharmaceutical composition comprising at least one compound selected from the group consisting of the complex lipid according to any one of claims 1 to 8, the complex lipid composition, each plasmalogen, and each aqueous preparation thereof as an active ingredient, , At least one kind of neurodegenerative disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, depression, and ataxia, and an agent for alleviating, preventing or treating said neurodegenerative disease Central nervous system inflammatory agent. A neurocyte nephropathy comprising at least one selected from the group consisting of the complex lipid according to any one of claims 1 to 8, the complex lipid composition, each plasmalogen, and each aqueous preparation thereof as an active ingredient My. A pharmaceutical composition for treating a nerve cell, which comprises as an active ingredient at least one member selected from the group consisting of the compound lipid according to any one of claims 1 to 8, the lipid composition, each plasmalogen, Apoptosis inhibitor. The A _β, and that at least one member selected from 1) to (a complex lipid, complex lipid composition according to any one of claim 8, wherein each plasma gen, and their respective aqueous formulation into, characterized in that it contains as an active ingredient / Or &lt; RTI ID = 0.0 &gt; tau. &Lt; / RTI &gt; 9. A pharmaceutical composition comprising, as an active ingredient, at least one selected from the group consisting of the complex lipid according to any one of claims 1 to 8, the complex lipid composition, each plasmalogen, and each aqueous preparation thereof, A neurodegenerative disease and / or a psychiatric disorder, characterized by having at least one action selected from the group consisting of anti-central nervous system inflammation, nerve cell neoplasia, inhibition of neuronal cell death, and inhibition of accumulation of A _? Pharmaceutical products or processed products as food. A mixture of a lipid composition having a biochemical specific composition ratio containing the protein fraction as a by-product according to any one of claims 1 to 4 and the water-soluble low-molecular fraction as a by- Wherein the protein / lipid complex composition is a mixture of proteins and lipids. 17. The method of claim 16,
Wherein the complex composition of protein / lipid comprising a mixture of the protein fraction and the complex lipid composition is derived from egg yolk. Claim 16 or contains, as an active ingredient a hybrid composition of protein, lipids as described in 17, wherein the neurodegenerative diseases and psychiatric diseases improvement wherein the central nervous system inflammation of the action of nerve cells neovascularization, suppression of neuronal cell death, and A _β brain And / or a pharmaceutical product for the treatment of neurodegenerative diseases and / or psychiatric disorders, or a processed product thereof as a food product. Use of a complex lipid according to any one of claims 1 to 8, a complex lipid composition, a complex lipid composition, a prepared plasma gum or a high purity plasmalogen, and one selected from the respective aqueous preparations thereof An adult (gun box) before the onset of dementia in a state in which accumulation of physiologically harmless amounts of A _? And? In the brain (hereinafter referred to as &quot; dementia-infected state &quot;
(1) on the basis of the PET image SUVR values (scores) of A _β and by the rank of the accumulation in brain state of τ in order to examine the use of PET A _β and the τ accumulation in brain state determining mibyeong state or the subject certificate A step carried out by division,
1) Accelerated I period: 1.0 ± 0,2
2) Accumulation intermediate stage Ⅱ: 1.2 ± 0.2
3) Accumulation phase III: 1.4 ± 0.2
(2) a step of testing a dose response to a test subject of the plasma by the appropriate frequency over a long term of 3 to 10 months and setting an appropriate dose range or anticipated range by:
1) Subjects in phase I; &Quot; Increasing &quot; range: 1.0 ± 0.15
2) subjects in stage Ⅱ; "0 increase" expected range: 1.2 ± 0.15
3) Subjects in phase III; "Decrease" expected range: 1.4 ± 0.15
(3) a step of continuously administering to the subject of the adult (gun box) before the onset of the dementia, a supplement containing the plasma dose of the set daily dose as an active ingredient or a processed product as a food from the stage before the onset of dementia ,
(4) a step of periodically performing the PET diagnosis of the predetermined accumulation state of A _? And? At a suitable frequency during the long-term administration,
(5) a step of performing MRI diagnosis of the depression state of the hippocampus at an appropriate frequency during the long-term administration period in parallel with the periodic PET diagnosis,
(6) A method for judging a subject's cognitive impairment state according to any one of (1) to (4) or the steps (1) to (5) .

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