WO2005037848A2 - Glycerophospholipids containing omega-3 and omega-6 fatty acids - Google Patents
Glycerophospholipids containing omega-3 and omega-6 fatty acids Download PDFInfo
- Publication number
- WO2005037848A2 WO2005037848A2 PCT/IL2004/000957 IL2004000957W WO2005037848A2 WO 2005037848 A2 WO2005037848 A2 WO 2005037848A2 IL 2004000957 W IL2004000957 W IL 2004000957W WO 2005037848 A2 WO2005037848 A2 WO 2005037848A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- preparation
- omega
- pufa
- lipid
- disorders
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to phospholipids and polar lipids preparations which are enriched with omega-3 and/or omega-6 fatty acids covalently attached to the lipid backbone.
- the phospholipid preparations of the invention are particularly useful as nutraceuticals, food additives and/or pharmaceutical agents for the treatment of various conditions, in particular related to cognitive functions.
- Lipids and especially polar lipids, nitrogen containing lipids, and carbohydrate containing lipids (phospholipids, sphingosines, glycolipids, ceramides, sphingomyelins) are the major building blocks of cell membranes, tissues, etc. Additionally they play important roles in signal transduction processes and in a variety of biochemical and biosynthetic pathways.
- Glycerophospholipids lipids based on a glycerol backbone and containing a phosphate head group, are the main building blocks of cell membranes. Since most, if not all, biochemical processes involve cell membranes, the structural and physical properties of membranes in different tissues is crucial to the normal and efficient functioning of membranes in all biochemical processes.
- PUFA polyunsaturated fatty acids
- DHA Docosahexaenoic acid
- DHA DHA
- Other known benefits of DHA include: lower risk of arrhythmias, reduction in the risk of sudden cardiac death, lower plasma triglyceride levels and reduced blood clotting tendency.
- DHA may have importance in the field of brain functioning enhancement, baby formula fortification, diabetics and cancer.
- the human body does not adequately synthesize DHA. Therefore it is necessary to obtain it from the diet.
- Humans obtain DHA from their diets, initially through the placenta, then from breast milk, and later through dietary sources, such as fish, red meats, animal organ meats and eggs.
- Popular fish like tuna, salmon and sardines are rich sources.
- the primary source of DHA dietary supplements has been fish oils.
- the ability of enzymes to produce the omega-6 and omega-3 family of products of linoleic and alpha-linolenic acid declines with age. Because DHA synthesis declines with age, as we get older our need to acquire DHA directly from diet or supplements increases. In fact, several recent pubhcations suggested DHA to be considered as essential fatty acid [for example, Muskiet, F. et al. (2004) JNutr. 134(1): 183-6].
- DHA is important for signal transmission in the brain, eye and nervous system, many consumers concerned with maintaining mental acuity are searching for a pure, safe way to supplement their DHA levels.
- Polyunsaturated acids in particular long chain, such as omega-3 and 6, have been shown to confer many valuable health benefits on the population.
- long-chain PUFAs including the food segment, is rapidly growing.
- PS Phosphatidylserine
- PS is a natural phospholipid with bio- functionality that has made it one of the most promising dietary supplements in the field of brain nutrition.
- PS and its health benefits have been known to the scientific and nutrition communities since the 1970's. Numerous studies have been conducted in order to establish this efficacy in a variety of cognitive and mental functions. Those studies have shown that PS can improve memory, fight dementia, fight early stages of Alzheimer's disease, reduce stress and tension, improve attention span, enhance mood and fight depression, to name but few.
- PS is one of the most important building blocks of cell membranes in the brain. Hence, the level of PS in brain cell membranes ensures the fluidity and structure of these membranes. The normal level ensures normal and efficient signal transduction processes, efficient glucose consumption, and other biological pathways that result in normal cognitive and mental functions.
- PS Since PS is not abundant in human nutrition and since in many people, especially the elderly, the biosynthetic pathways responsible for the production of PS are malfunctioning, the levels of PS in the body and brain are low. This results in a variety of cognitive and mental disorders, such as depression, memory loss, short attention span, learning difficulties, etc.
- phospholipids are essential components of all cellular and sub-cellular membranes. Phosphatidylcholine and phosphatidylethanolamine predominate quantitatively, substantially constituting the typical bilayer configuration. Phospholipids belong to the amphipathic molecules with a water-soluble and a fat-soluble component. In the bilayer configuration the hydro hilic groups are arranged at the outer and inner side of the membrane toward the surrounding medium; the lipophilic groups, in contrast, face each other at the inner side of the bilayer configuration.
- lipid-protein complexes Other important constituents of biological membranes are cholesterol, glycolipids, and peripheral and integral proteins.
- the basic structure of biological membranes is thus a series of recurrent unities of lipid-protein complexes.
- the membrane is asymmetric.
- the function of the external (cellular) and internal (sub cellular) membrane systems depends on their composition and on the integrity of their phospholipid structure.
- phospholipids constitute structural and functional elements of the surface mono-layers of lipoproteins and of surfactants.
- membrane fluidity Of utmost importance for the function of biological membranes is their fluidity, which is decisively influenced by phospholipids. Besides the content in cholesterol and proteins and the nature and charge of the polar head groups of phospholipids in the system, membrane fluidity depends on the length of the chains of fatty acid residues in the phospholipid molecule, as well as on the number and type of pairing of their double bonds. Phospholipids containing poly-unsaturated fatty acids supply the organism with important building blocks which improves membrane fluidity.
- the polyunsaturated fatty acids contained in them are precursors of the cytoprotective prostaglandins and other eicosanoids.
- Phospholipids containing PUFA are theoretically of importance in all those diseases in which damaged membrane structures, reduced phospholipid levels, and/or decreased membrane fluidity are present. This hypothesis is supported by experimental and clinical investigations of various membrane-associated disorders and illnesses.
- liver diseases the hepatocyte structures are damaged by, for example, viruses, organic solvents, alcohol, medicaments, drugs, or fatty food.
- membrane fluidity and permeability may be disturbed, and membrane-dependent metabolic processes as well as membrane-associated enzyme activities may be impaired. This considerably inhibits the metabolism of the liver.
- hyperlipoproteinemia with or without atherosclerosis, hemorrheological disturbances with an elevated cholesterol/phospholipid ratio in the membranes of platelets and red blood cells, neurological diseases, gastro intestinal inflammations, kidney diseases, and in a variety of aging symptoms.
- HDL particles enriched with PUFA-containing-phosphatidylcholine are able to take up more cholesterol from low-density lipoprotein (LDL) and tissues. More cholesterol can be transported back to the liver. This action on the cholesterol reverse transport is unique. All other lipid-lowering agents reduce either the cholesterol absorption in the body or the cholesterol synthesis in the liver and its distribution to the periphery. These substances, however, do not physiologically mobilize the cholesterol already present in the periphery.
- LDL low-density lipoprotein
- the cholesterol/phospholipid ratio in membranes, platelets, and red blood cells decreases and membrane function is improved up to normalization.
- PUFA- containing-phosphatidylcholine solubilize fat and is used in reducing the risk and treatment of fat embolism.
- substitution with poly-unsaturated-fatty-acids and choline may have a cytoprotective effect in the brain and activate neuronal processes.
- Liposomes with polyunsaturated phosphatidylcholine molecules may act as drug carriers, such as of vitamin E.
- RNA and protein synthesis and of the liver cell glycogen content indicated a stimulation of the liver cells.
- the dosage of PUFA-containing-phosphatidylcholine ranged from 525 to 2,700 mg/day when administered orally, and from 500 to 3,000 mg/day in intravenous application.
- the duration of treatment lasted from a few weeks to up to 30 months.
- the main liver indications were acute hepatitis, chronic hepatitis, fatty liver, toxic liver damage, cirrhosis of the liver, and hepatic coma.
- mice lacking essential fatty acids i.e. linoleic acid (18:2 n-6) and ⁇ -linolenic acid (18:3 n— 3), which serve as the sole sources for LC-PUFA, were fed cerebral phospholipids and the quantity of phosphohpids in each part of the brain measured.
- linoleic acid 18:2 n-6
- ⁇ -linolenic acid 18:3 n— 3
- the utilization of phospholipids enriched with PUFA holds many potential advantages from a clinical point of view.
- the phospholipid may deliver the essential fatty acid to specific organs or body parts, such as the brain, and assist in the incorporation of these fatty acids in membranes.
- Other advantages may arise from the fact that phospholipids enriched with PUFA will not have odor problems such as found in the major current nutraceutical source, the fish oils.
- PUFA incorporated in phospholipids possess superior efficacy than PUFA carried by triglycerides. [Song et al. (2001) Atherosclerosis, 155, 9-18].
- DHA-rich phospholipid was different from that of DHA-rich triacylglycerol in spontaneously hypertensive rats [Irukayama-Tomobe et al. (2001) Journal of Oleo Science, 50(12), 945-950].
- Spontaneously hypersensitive rats (SHR) were fed test lipid diets for six weeks, which contained 30%-docosahexaenoic acid (DHA) phospholipid (DHA-PL) extracted from fish roe or 30%-DHA fish oil (DHA-TG).
- the control diet contained corn oil in the presence of test lipids. After feeding, blood pressure in the DHA-TG and DHA-PL diet groups was found significantly lower compared to the control.
- Serum fatty acid content of dihomo-linoleic acid (DHLnA) and Arachidonic acid (AA) of the DHA-PL diet group was significantly less than the control or DHA-TG diet group.
- Serum triacylglycerol, phospholipid and total cholesterol in the DHA-TG and DHA-PL diet groups were significantly less than in the control.
- Liver total cholesterol in DHA-PL was twice that in the DHA-TG diet group and control. The mechanism for cholesterol removal from blood by DH-PL would thus appear to differ from that by DHA-TG.
- Serum lipid peroxide (LPO) in the DHA-TG and DHA-PL diet groups was essentially the same as in the control.
- PUFA-containing agents suffer from stability and quality problems due to the high degree of oxidation of the polyunsaturated fatty acids. These problems require the incorporation of antioxidants as well as the utilization of special measures which attempts to reduce this oxidation.
- the utilization of phospholipids as carriers of PUFA may result in enhanced stability of such products due to the anti-oxidative properties of phospholipids.
- PUFAs are traditionally extracted from coldwater fish. Despite the healthy image, one of the problems of consumer acceptance has been the resulting strong, fishy taste. To address this, microencapsulated forms of omega-3 have been pioneered in the last 15 years. A further step was the development of egg-containing products such as DHA-enriched mayonnaise and pasta. DHA-enriched yogurts, baked goods and broilers were also envisaged.
- the composition of said preparation is such that it provides the preparation with the property of enhancing the bioavailability of PUFAs.
- the organism may, in the most efficient way, enjoy the benefits provided by said preparation, as will be described in detail below.
- the present invention provides a lipid preparation, wherein said lipid is selected from glycerophospholipids and their salts, conjugates, and derivatives and any mixture thereof, and poly- unsaturated fatty acid (PUFA) acyl groups, particularly long-chain polyunsaturated fatty acid (LC-PUFA) acyl groups, preferably omega-3 and/or omega-6 acyl groups, at a concentration of least 5% (w/w) of total fatty acids content of said preparation, preferably more than 10% (w/w), more preferably 20-50% (w/w), wherein said PUFA is covalently bound to said lipid.
- PUFA poly- unsaturated fatty acid
- LC-PUFA long-chain polyunsaturated fatty acid
- Said lipid may be a naturally occurring lipid, or a synthetic lipid.
- said lipid is a glycerophospholipid in which at least some of the sn-1 or sn-2 groups of the glycerol backbone are substituted with said polyunsaturated fatty acid (PUFA) acyl groups.
- PUFA polyunsaturated fatty acid
- said lipid is a glycerophosphlipid of formula I:
- R" represents a moiety selected from serine (PS), chohne (PC), ethanolamine (PE), inositol (PI), glycerol (PG) and hydrogen (phosphatidic acid - PA), and R and R', which may be identical or different, independently represent hydrogen or an acyl group, wherein said acyl group is selected from saturated, mono-unsaturated or poly-unsaturated acyl groups (PUFA), particularly long-chain poly-unsaturated fatty acids (LC-PUFA), more preferably omega-3 and/or omega-6 acyl groups, and salts thereof, with the proviso that R and R' cannot simultaneously represent hydrogen, and wherein said polyunsaturated acyl groups comprise at least 5% (w/w) of total lipid fatty acids, preferably more than 10% (w/w), and particularly 20-50% (w/w).
- PUFA mono-unsaturated or poly-unsaturated acyl groups
- LC-PUFA particularly long-chain poly-unsaturated
- R represents hydrogen and R' represents an acyl group.
- R' represents hydrogen and R represents an acyl group.
- said acyl group when said acyl group is preferably an omega-3 acyl group, it may be an eicosapentaenoyl (EPA), a docosahexaenoyl (DHA) group, or linolenic omega-3 group.
- said acyl group when said acyl group is preferably an omega-6 acyl group, it may be an arachidonoyl (ARA) group, or a linoleic omega-6 group.
- ARA arachidonoyl
- said acyl group may be a linolenoyl (18:3) group.
- R" may be any one of serine, choline, ethanolamine, inositol or glycerol.
- the identity and content of R and R' are predetermined.
- the preparation of the invention which comprises the compound of formula I in which R" is serine, mimics the composition of human brain PS.
- the invention also refers to preparations comprising the compound of formula I in which R" is serine, which are different from human brain PS, but still have an improved bioactivity, particularly as compared to soybean-PS.
- This improved bioactivity results in beneficial effects on both the learning and working memory in elderly population, in particularly in cholinergic impaired conditions like Alzheimer's disease.
- the invention also relates to preparation PS preparation which mimics the human brain PS, is effective at lower dosage (2-3 fold) compared to soybean-PS, while having similar or improved bioactivity compared to soybean-PS.
- the PS may be of plant, animal or microorganism source, and is enriched with PS of formula I, wherein R" represents a serine moiety.
- the preparation of the invention may be further enriched with PS of formula I, characterized in having reduced or absent of fish-related organoleptic effects.
- Such preparation may be particularly suitable for incorporation into chocolate-containing or dairy-based food articles (including concentrated milk).
- the preparation of the invention may be used in the improvement and treatment of cognitive and mental conditions and disorders as well as the maintenance of normal functions of brain-related systems and processes, preferably ADHD, aging, Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), dyslexia, depression, learning capabilities, intensity of brain waves, stress, anxiety, mental and psychiatric disorders, concentration and attention, mood, brain glucose utilization, general cognitive and mental well being, neurological disorders and hormonal disorders.
- ADHD aging
- Alzheimer's disease Parkinson's disease
- MS multiple sclerosis
- dyslexia depression
- learning capabilities intensity of brain waves
- stress anxiety, mental and psychiatric disorders
- concentration and attention mood
- mood brain glucose utilization
- general cognitive and mental well being neurological disorders and hormonal disorders.
- the preparation of the invention is particularly useful in enhancing the bioavailability of omega-3 and omega-6 fatty acids.
- the preparation of the invention may be used in combined improvement of cognitive and mental functions together with improvement of additional health disorders or conditions.
- additional health disorders or conditions may be at least high blood cholesterol levels, high triglycerides levels, high blood fibrinogen levels, HDL/LDL ratio, diabetes, metabolic syndrome, menopausal or post-menopausal conditions, hormone related disorders, vision disorders, inflammatory disorders, immune disorders, liver diseases, chronic hepatitis, steatosis, phospholipid deficiency, lipid peroxidation, dysrhythmia of cell regeneration, destabilization of cell membranes, coronary artery disease, high blood pressure, cancer, hypertension, aging, kidney disease, skin diseases, edema, gastrointestinal diseases, peripheral vascular system diseases, allergies, neurodegenerative and psychiatric diseases.
- the preparation of the invention may also be used in the reduction and/or prevention of serum oxidative stress leading to atherosclerosis, cardiovascular disorders and/or coronary heart disease.
- the invention further relates to nutraceutical compositions comprising a lipid preparation in accordance with the invention.
- the nutraceutical composition may be in the form of softgel capsules, tablets, syrups, or any other common dietary supplement delivery system.
- the invention relates to functional food article comprising the lipid preparation of the invention.
- Such functional food article may be selected from dairy products, dairy drinks, ice-creams, bakery products, confectionary products, biscuits, soy products, pastry and bread, sauces, condiments, oils and fats, margarines, spreads, cereals, drinks and shakes, oils and fats, infant formulas, infant foods (biscuits, mashed vegetables and fruits, cereals), bars, snacks, candies and chocolate products.
- the invention relates to pharmaceutical compositions comprising the lipid preparation of the invention, and optionally further comprising at least one pharmaceutically acceptable additive, diluent or excipient.
- the pharmaceutical composition of the invention may further optionally comprise at least one pharmaceutically active agent.
- Latency time to platform in the three days of acquisition (2 sessions per day) of aged rats supplemented for three months with various supplements as detailed below was analyzed using video camera, with
- Fig. 1A Rats supplemented with MCT, P ⁇ 0.007.
- Fig. IB Rats supplemented with PS- TO3, P ⁇ 0.07.
- Fig. 1C Rats supplemented with SB-PS, P ⁇ 0.02.
- Fig. ID Rats supplemented with LC-PUFA, P ⁇ 0.03.
- This graph represents percentage of time (T.) that aged rats, supplemented for three months with MCT (open bars), PS- t ⁇ 3 (solid bars), SB-PS (dotted bars) or LC-PUFA (striped bars), spent in different areas after the platform being removed, was analyzed using video camera, following pre-treatment of 1 mg/kg of scopolamine. Values represent mean ⁇ S.E.M of four to five rats per supplement. Significance compared to control group (MCT) * P ⁇ 0.02 and ** P ⁇ 0.08 Figure 3A-D: Performance of scopolamine-induced rats in locating the platform after its reposition.
- Fig. 3A Rats supplemented with MCT.
- Fig. 3B Rats supplemented with PS- ⁇ J3.
- Fig. 3C Rats supplemented with SB-PS.
- Fig. 3D Rats supplemented with LC-PUFA.
- Lat. T. latency time
- sec seconds
- tr. trials.
- Figure 4A-B Phospholipid levels in rat tissues as measured using 31 P-NMR.
- Lipids were extracted from tissues of aged rats that were supplemented for three months with MCT (open bars), PS- TO3 (solid bars), SB-PS (dotted bars) or LC-PUFA (striped bars). Phospholipids levels were analyzed using a 31 P-NMR machine and the relative levels of phosphatidylcholine of the different treatments are presented.
- Fig. 4A Analysis of lipids extracted from the liver.
- Fig. 4B Analysis of lipids extracted from the brain (cortex region).
- Values represent mean ⁇ S.D. of four to five rat tissues per supplement.
- Figure 5 Parental scores of ADHD children according to behavioral rating scales.
- the graph represents percentage of ADHD children that demonstrated improvement or lack of improvement in a parental view following two months of supplementation with canola oil (open bars), DHA (solid bars) or PS- ⁇ 3 (hatched bars). Rating includes remarks regarding behavioral tendencies at home, at school, with siblings or peers and teachers feedback. Values represent percentage of twenty to twenty-five ADHD children scores per supplement. Note that twelve parents decline to respond to the questioner and six children did not complete the supplementation period due to poor taste or severe discipline problems (mostly the control group).
- Improv. improvement
- Marg. Improve.
- n.c no change
- Deter. deterioration.
- Serum lipid peroxide (Ser. per.) levels were measured using a spectrophotometric assay. Values represent mean ⁇ S.D. of 5 mice per treatment.
- the present invention provides a lipid preparation, wherein said lipid is a glycerophospholipid, a salt, conjugate, and derivative thereof, and any mixture thereof, and poly-unsaturated fatty acid (PUFA) acyl groups, particularly long-chain poly-unsaturated fatty acid (LC-PUFA) acyl groups, preferably omega-3 and or omega-6 acyl groups, at a concentration of least 5% (w/w) of total fatty acids content of said preparation, preferably more than 10% (w/w), more preferably 20- 50% (w/w), wherein said PUFA is covalently bound to said glycerophospholipid.
- PUFA poly-unsaturated fatty acid
- LC-PUFA long-chain poly-unsaturated fatty acid
- Said lipid may be a naturally occurring lipid, or a synthetic lipid.
- said lipid is a glycerophospholipid in which at least some of the sn-1 or sn-2 groups of the glycerol backbone are substituted with said polyunsaturated fatty acid (PUFA) acyl groups.
- PUFA polyunsaturated fatty acid
- said lipid is a glycerophosphlipid of formula I:
- R" represents a moiety selected from serine (PS), choline (PC), ethanolamine (PE), inositol (PI), glycerol (PG) and hydrogen (phosphatidic acid - PA), and R and R', which may be identical or different, independently represent hydrogen or an acyl group, wherein said acyl group is selected from saturated, mono-unsaturated or poly-unsaturated acyl groups (PUFA), particularly long-chain poly-unsaturated fatty acids (LC-PUFA), more preferably omega-3 and/or omega-6 acyl groups, and salts thereof, with the proviso that R and R' cannot simultaneously represent hydrogen, and wherein said polyunsaturated acyl groups comprise at least 5% (w/w) of total lipid fatty acids, preferably more than 10% (w/w), and particularly 20-50% (w/w).
- PUFA mono-unsaturated or poly-unsaturated acyl groups
- LC-PUFA particularly long-chain poly-unsaturated
- R represents hydrogen and R' represents an acyl group.
- R' represents hydrogen and R represents an acyl group.
- said acyl group when said acyl group is preferably an omega-3 acyl group, it may be an eicosapentaenoyl (EPA), a docosahexaenoyl (DHA) group, or linolenic omega-3 group.
- said acyl group when said acyl group is preferably an omega-6 acyl group, it may be an arachidonoyl (ARA) group, or a linoleic omega-6 group.
- ARA arachidonoyl
- said acyl group may be a linolenoyl (18:3) group.
- R" may be any one of serine, choline, ethanolamine, inositol or glycerol.
- the identity and content of R and R' are predetermined.
- the preparation of the invention which comprises the compound of formula I in which R" is serine, mimics the composition of human brain PS.
- the invention also refers to preparations comprising the compound of formula I in which R" is serine, which are different from human brain PS, but still have an improved bioactivity, particularly as compared to soybean-PS.
- PS active ingredients used as dietary supplements were produced by the extraction of animal brains, particularly bovine brains.
- the PS extracted from animal brain tissues, similarly to human brain PS, has a fatty acid composition which is characterized by relatively higher levels of omega-3 moieties, compared to the levels of omega-3 found in plant phospholipids.
- PS has the following structure:
- Human brain PS is characterized by over 20-30% PS containing omega-3 fatty acyls, preferably at the sn-2 position of the glycerol moiety, and mainly DHA or EPA.
- omega-3 fatty acyls preferably at the sn-2 position of the glycerol moiety, and mainly DHA or EPA.
- phospholipids, and PS are responsible for membrane structure and physical properties.
- One of the major physical properties governed by phospholipids is the fluidity of these membranes.
- Omega-3 fatty acids, DHA and EPA in particular also have a crucial role in membrane fluidity in light of their unique 3D structure. Therefore, PS with omega-3 fatty acyl moieties, DHA and EPA in particular, has unique bio-functionality which cannot stem from just the basic phospholipid skeleton of this phospholipid.
- PS supplements are usually prepared using PS originating from soybean lecithin.
- This lecithin is enriched, usually enzymatically, with PS.
- This method of production results in PS with a fatty acid profile of soybean phospholipids, which is characterized by low level of omega-3 fatty acids, and almost no DHA and EPA.
- This PS active ingredient is also known as soybean-PS.
- soybean-PS Although the bio-functionality of soybean-PS in the improvement of cognitive function has been shown to be similar to that of bovine-PS, it is still different from human brain PS. It is a purpose of the present invention to provide a PS ingredient with a predetermined fatty acid composition that mimics the fatty acid composition of the human brain PS.
- This improved PS ingredient has a predetermined fatty acid composition.
- the PS ingredient of the present invention is enriched with omega-3 fatty acyls, preferably DHA, EPA or linolenic omega-3. Furthermore, the PS of this invention is enriched with omega-3 fatty acyls covalently bonded to either or both of the sn-1 or sn-2 positions of the glycerol moiety in the PS backbone.
- the present invention is also related and describes other phospholipids, such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidyl-inositol (PI), phosphatidylglycerol (PG) and phosphatidic acid (PA), enriched with omega-3 fatty acids, preferably DHA, EPA, or linolenic acid which are covalently bonded at either or both of the sn- 1 or sn-2 positions of the glycerol moiety of the phospholipid.
- the phosphohpids of the invention are enriched with omega-6 fatty acids.
- PS when referring to PS in the present description, it should be taken to mean also any other lipid, such as, but not limited to, the polar lipids listed above.
- the amount of omega-3 (particularly EPA, DHA or linolenic acid) or omega-6 (particularly ARA and linoleic acid) fatty acids in the PS ingredient of the invention is greater than 10% at either or both of the sn-1 or sn-2 positions, preferably at the sn-2 position, preferably over 20% and most preferably above 40%.
- the desired omega-3/omega-6 fatty acyls can be bonded at both or only one of the sn-1 and sn-2 positions.
- the fatty acid composition of the PS preparation of this invention can have a predetermined fatty acid composition similar to or different from the fatty acid composition found in normal healthy human brain, provided it has enhanced activity, particularly compared to the activity of plant PS, for example soybean-PS.
- the preparation of the omega-3/omega-6-enriched PS preparation of this invention can be enzymatic, chemical or by molecular biology methods.
- the PS can be enriched with omega-3 or omega-6 moieties by enzymatic processes, e.g. enrichment of a natural phospholipid/lecithin with omega-3 fatty acids by enzymatic transesterification/esterification followed by transformation of the head group to serine (using PLD enzymes) to obtain a PS-omega-3/omega-6 conjugate.
- Another enzymatic pathway is to obtain a lecithin or phospholipid source which is naturally rich in omega-3 acids, such as krill phospholipids, and transform their head groups to serine.
- the fatty acid composition of the PS obtained by this method has an omega-3 composition which is predetermined by the source of choice (fish, krill, algae, etc.).
- fish, krill, algae, etc. Such methods have been thoroughly described in Applicant's co-pending PCT Application claiming priority from IL158553.
- the PS-omega-3/omega-6 ingredient of the present invention can also be prepared by chemical transesterification/esterification methods that will enrich the S7i-1 and 2 positions with omega-3 or omega-6 acyl residues. Such methods of preparation of PS-omega-3 and PS-omega-6 have been described in Applicant's co-pending PCT Application claiming priority from IL158553.
- the PS ingredient of the present invention can be prepared by GMO (genetically modified organis ⁇ hs)/biotechnology methods, for example, providing phospholipids-producing organisms with omega-3 or omega-6 fatty acids to obtain phospholipids enriched with omega-3 or omega-6 PS. It may be preferred to use genetically engineered plants or microorganisms, to avoid use of animal sources.
- GMO genetically modified organis ⁇ hs
- the PS of this invention can have the omega-3 or omega-6 fatty acid composition of a specific lecithin raw material, relatively rich with omega- 3 or omega-6 fatty acids, enriched with PS to yield a PS ingredient with elevated omega-3 or omega-6 fatty acids levels, compared to soybean-PS.
- a specific lecithin raw material relatively rich with omega- 3 or omega-6 fatty acids
- enriched with PS to yield a PS ingredient with elevated omega-3 or omega-6 fatty acids levels, compared to soybean-PS.
- Such is the case, for example, when phospholipids from krill are used as the starting material, as described above.
- the PS enriched with omega-3 or omega-6 can be soybean-PS or any other PS, from plant, animal, for example krill, or microorganism source.
- the omega-3 or omega-6 enrichment can be performed on a lecithin, which in turn is enriched with PS by transphosphatidylation.
- the improved PS preparation of this invention exhibits enhanced activity in the improvement and treatment of cognitive and mental conditions and disorders as well as the maintenance of normal functions of brain related systems and processes. These include, but are not limited to ADHD, multiple sclerosis (MS), dyslexia, depression, learning capabilities, intensity of brain waves, stress, mental and psychiatric disorders, neurological disorders, hormonal disorders, concentration and attention, mood, brain glucose utihzation, and general cognitive and mental well being.
- ADHD multiple sclerosis
- MS multiple sclerosis
- dyslexia depression
- learning capabilities intensity of brain waves
- stress mental and psychiatric disorders
- neurological disorders include, hormonal disorders, concentration and attention, mood, brain glucose utihzation, and general cognitive and mental well being.
- the novel lipid preparation of this invention exhibits enhanced activity in the improvement of cognitive functions, as detailed hereunder, over omega-3 or omega-6 lipids per se or soybean-PS. Furthermore, under certain conditions or for all or specific disorders, the lipid preparation of the invention is effective at a dosage of less than 100 mg/day. This is lower that the current recommended daily dosage of soybean-PS (100- 300mg/day) or omega-3 lipids (approx. l-2g/day or more) currently available in the market. Nonetheless, dosages of 100-600mg/day are preferred for enhanced efficacy of the lipid preparation of the invention.
- An important advantage of the PS preparation of the invention is that it exhibits multifunctional activity. This multi-functionality is exhibited by improvement in cognitive and mental functions, together with improvement of other health disorders or conditions.
- the enhanced activity of this PS ingredient may arise from the unique structure of this ingredient and its influence on the physical and chemical properties of cell membranes in brain tissues as well as other organs and tissues.
- the enhanced activity of this PS ingredient may also be attributed to the enhanced bioavailability of the omega-3 fatty acids, due to their incorporation in the PS skeleton.
- the omega-3 fatty acids can be delivered to the brain across the blood- brain barrier, being a part of the PS molecule, which readily passes this barrier.
- the PS functions as a delivery platform for the fatty acids bound thereto, to various organs and tissues, thereby enhancing their bioavailability.
- the additional health disorders or conditions which are affected by the multifunctional PS preparation of the invention include, but are not limited to high blood cholesterol levels, high triglycerides levels, high blood fibrinogen levels, HDL/LDL ratio, diabetes, metabolic syndrome, menopausal or post-menopausal conditions, hormone related disorders, vision disorders, inflammatory disorders, immune disorders, liver diseases, chronic hepatitis, steatosis, phospholipid deficiency, lipid peroxidation, dysrhythmia of cell regeneration, destabilization of cell membranes, coronary artery disease, high blood pressure, cancer, hypertension, aging, kidney disease, skin diseases, edema, gastrointestinal diseases, peripheral vascular system diseases, allergies, airways diseases, neurodegenerative and psychiatric diseases.
- the new ingredients of the invention can be delivered and utilized in a variety of products.
- Such products include dietary supplements, functional foods, pharmaceutical delivery systems, etc.
- the preparations of the invention may be used in the form of soft gel capsules, tablets, syrups, and other common dietary supplements delivery systems.
- the preparations of the invention can be incorporated and used in a variety of foods, such as dairy products, ice-creams, biscuits, soy products, pastry and bread, sauces, condiments, oils and fats, margarines, spreads, cereals, drinks and shakes, infant formulas, infant foods (biscuits, mashed vegetables and fruits, cereals), bars, snacks, candies, chocolate products.
- the preparations of the invention can be delivered orally, intravenously, or by any other conventional or special route of administration.
- the new preparations of the invention may be in the form of fluid oil, powder, granules, wax, paste, oil or aqueous emulsion, and any other form that will enable its use in the target applications.
- compositions comprising the PS preparation of the invention may include physiologically acceptable free flowing agents, other additives, excipients, dessicants and diluents, colorants, aroma and taste ingredients, and any ingredients that control physical, organoleptic, and other properties, as well as additional active ingredients, for example minerals, vitamins, other nutritional additives.
- omega-3 lipids in a variety of applications, and especially as ingredient of functional foods, is hindered due to their distinct fish odor.
- omega-3 enriched phospholipids ingredients of the invention are that they have reduced odor or taste of omega-3 acyl moieties, due to the covalent binding of these groups to the PS backbone. This increases the vapor pressure of these materials, hence reducing their distinct aroma.
- the covalent binding of the omega-3 fatty acids to the phospholipid backbone, especially PS alters and improves their taste properties.
- the PS ingredient of the invention also offers enhanced stability to the oxidation sensitive omega-3 fatty acids.
- Phospholipids in general, and PS in particular, are known to act as anti-oxidants and stabilizers.
- novel ingredients can be formulated with additional lipids for an even enhanced bio-functionality and efficacy.
- the polar lipids derivatives of PUFA such as the PS-PUFA derivatives have exhibited high stability as a preparation and additionally in several food applications, used in the chnical trials of the present invention.
- the stability of these sensitive compounds is emerging from the covalent combination of phospholipids, known in the past to be used as preservatives and of the un-stable PUFA moieties.
- the new ingredients of the invention can be delivered and utilized in a variety of products.
- Such products include dietary supplements, functional foods, pharmaceutical delivery systems, etc.
- mice Male Wistar rats originated from the same colonies were obtained from Harlen. Fifty rats were randomly divided into five dietary supplemented groups, in addition to their normal diet: (i) a group fed O.lg medium-chain triglycerides (MCT)/lml supplement matrix (MCT group); (ii) a group fed O.lg DHA/EPA (20/30% of total fatty acids composition, diluted with MCT to generate 30% (w/w) LC-PUFA compound) triglycerides/lml supplement matrix (LC-PUFA group); (hi) a group fed O.lg soybean lecithin-derived PS (20% SB-PS w/w)/l ml supplement matrix (SB-PS group); and (iv) a group fed O.lg PS- w3 (20% PS w/w, and total LC-PUFA composition of 30%)/l ml supplement matrix (PS group).
- MCT medium-chain triglycerides
- MCT group MCT group
- the supplement matrices were stored at -20°C, and fresh portions were fed to the rats every day. All supplements were handled so as to minimize oxidation of the fatty acids. Rats consumed the diet and water ad libitum. All rats were housed in a standard environment, in which temperature was maintained at 24 ⁇ 0.5°C, and the relative humidity was kept at 65 ⁇ 5% with 12-h periods of hght and dark. Body weight was measured at the beginning and the end of the treatment period.
- the PS- TO3 compound used in this study mimics the fatty acids composition of the mammalian brain PS, with respect to its DHA content (20%).
- the fatty acid composition of PS varies from tissue to tissue, but does not appear to resemble the precursor phosphohpids, either because of selective utihzation of specific molecular species for biosynthesis or because or re -modeling of the lipid via deacylation-reacylation reactions.
- the distance swum to the platform and the time taken in doing so should decrease over testing sessions (days) as the rat learns the location of the platform. Moreover, it is expected that if the rat has learned the location of the platform in relation to the extra- maze cues, its initial response on the probe trial will be to swim directly to the quadrant in which it expects to find the platform. Thus the distance swum (and time spent) in the target quadrant should be greater than that in the other two quadrants (excluding the start quadrant). The distance swum to the platform as well as the latency to reach the platform were monitored using the video-based tracking system. The behavioral testing was conducted during the dark cycle, when rats are normally most active.
- the pool was located in a test room in which there were many extra-maze spatial cues.
- the rats were required to locate the hidden platform (15.5 cm x 15.5 cm) situated 1 cm below the surface of the water.
- the rat was placed, facing the wall, in one of the four quadrants in the tank, and allowed to swim for a maximum of 60 seconds. Once the rat found the platform, it remained there for 5 seconds before being returned to the holding cage, which was kept warm on a heating pad. If the rat failed to find the platform in that time, it was placed on it for 5 seconds before being returned to the holding cage.
- Each of the eight trials conducted each day was started from a different quadrant, with the order determined pseudorandomly (not twice from the same quadrant) and varying from day to day.
- the intertrial interval (ITI) was 120 seconds, counted from the end of one trial to the beginning of the next.
- ITI intertrial interval
- the platform was removed from the tank, and a probe trial was conducted by placing the rat in the quadrant opposite to that of the platform and then allowing it to swim for 60 seconds.
- the day following the probe trial the rats were tested with a session in which the maze was set up as previously described, followed by a session in which the platform was repositioned to the center of the opposite quadrant. The latency to find the platform on each trial was recorded.
- Scopolamine (lmg/Kg) was intraperitoneally (i.p.) administered 30 minutes before the indicated trials.
- the rats were anesthetized with Halothane and then decapitated. Liver and brain tissues were quickly removed and stored (at -80°C). The lipid fraction of the rat tissues were extracted using a modified version of the technique described by Bligh and Dyer 1959 [Bligh and Dyer, (1959) Can. J. Biochem. Physiol. 37, 911-917]. Briefly, 500-700 mg and 300-1200 mg of liver and brain tissues, respectively, were homogenized in a solution of CDC13, methanol and CS- EDTA (1:2:2 v:v:v). The homogenates were further agitated using ultrasonic bath (10 in, 80°C), followed by additional vigorous shaking (20 min). The relative ratio of the phospholipids in the homogenates was measured using high-resolution 31 P-NMR at 121.MHZ using a 7.06 Tesla General Electric spectrometer.
- lipids extracts were desalted by reverse-phase chromatography using an RP-18 column [Williams et al. (1980) J. Neurochem.; 35, 266-269]; diheptadecanoyl phosphatidylcholine was added as internal standard before the loading on the column.
- Phospholipids were separated from neutral lipids, such as cholesterol, on silica gel plates (Merck 60) developed in isohexane: ether: formic acid 80:20:2 (v:v:v). The phospholipids spot was visualized by spraying primulin solution and compared with authentic phosphohpids standards.
- Henicasonoic methyl ester (C21:0) was added as a 2nd internal standard and the phospholipids were converted to methyl esters by mild acid hydrolysis with 1% methanolic H2S04 overnight at 50°C.
- the fatty acids profile of the different samples was determined by gas-liquid chromatography.
- BC-PS bovine brain cortex-derived PS
- SB-PS soybean lecithin transphosphatidylated PS
- BC-PS treated mice demonstrated a nonsignificant but clear tendency to be less adventurous in the open field behavior trial, by spending less time in the center area.
- the rats that were treated with PS- -013 it is interesting to compare their performance in the Morris water maze task in the spatial probe test to the one obtained by the SB-PS treated animals by Suzuki et al [Suzuki et al (2001) id ibid.].
- the percent of time spent in the quadrant where the platform was located is similar ( ⁇ 45%), it is remarkable that the dosage in the current study was merely one third of the administration levels in Suzuki et al 2001 (20mg/kg vs. 60mg/kg, respectively).
- Fig. 4A shows that in rats supplemented with . PS for three months (SB-PS and PS- ⁇ J3) there was a notable increase in the levels of the primer phospholipids, i.e. phosphatidylcholine (PC).
- PC phosphatidylcholine
- the improved performance in the Morris water maze test of the PS- t ⁇ 3 treated rats under scopolamine sedation strongly supports the potency of PS- ⁇ 3 as an anti-dementia and age-associated memory impairment effects.
- This cognitive enhancement is further supported by the biochemical evidence of the elevated phospholipids levels in the liver and brain tissues (Fig. 4A-4B), and with elevated levels of DHA attached to the phospholipids from the cortex of the PS- ⁇ 3 fed rats.
- Table 1 summarizes the effect of dietary LC-PUFA from different sources on the fatty acids profile in cerebral phospholipids from elderly Wistar rats. Fatty acids from the purified phospholipids fraction were analyzed by gas-hquid chromatography. The major fatty acids are expressed as % of total fatty acids in the phospholipids. Values represent mean ⁇ S.D. of four different rats per treatment. Statistical significant between different supplements and MCT group is presented as followed: * P ⁇ 0.05; ** PO.01.
- ADHD Attention-deficit/hyperactivity disorder
- ADHD Attention-deficit hyperactivity disorder: a handbook for diagnosis and treatment. New York: Guilford Press].
- Children with ADHD often have trouble performing academically and paying attention, and may be disorganized, have poor self-discipline, and have low self-esteem. A conservative estimate is that 3-5% of the school-age population has ADHD [American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. (DSM-IV) Washington, DC: American Psychiatric Association, 1994].
- Treatments for ADHD include behavior therapy and medications, mainly methylphenidate (RitalinTM).
- Psychostimulant drugs and antidepressants are often used to calm children with ADHD, with an effectiveness rate of -75% (Swanson et al. Except Child 1993; 60:154-61).
- the advantages of using these medications include rapid response, ease of use, effectiveness, and relative safety. Disadvantages include possible side effects, including decreased appetite and growth, insomnia, increased irritability, and rebound hyperactivity when the drug wears off [Ahmann et al. (1993) Pediatrics; 91:1101-6].
- these medications do not address the underlying causes of ADHD. Thus, studies to elucidate the potential contributors to the behavior problems in ADHD may lead to more effective treatment strategies for some children.
- Omega-3 fatty acids are specifically implicated in maintaining central nervous system function. Deficiency of n-3 fatty acids in rats and monkeys has been associated with behavioral, sensory, and neurological dysfunction [Yehuda et al. (1993) Proc. Natl. Acad. Sci. USA; 90:10345-9; Reisbick et al. (1994) Physiol. Behav. 55:231-9; Enslen et al. (1991) Lipids; 26:203-8].
- Several studies have focused on essential fatty acid metabolism in children with ADHD [Colquhoun et al. (1981) Med Hypotheses; 7:673- 679].
- ADHD children were scored according to parental behavioural rating scales (Connors' Rating scale).
- complementary therapies are particularly common among patients with chronic, incurable, or frequently relapsing conditions.
- use of complementary and alternative medical therapies is common in children with cancer, asthma, and cystic fibrosis.
- Parents or subjects who seek CAM typically do so because such therapies are more consistent with their values, are more empowering, and are perceived as more natural and less risky than conventional treatments.
- the majority of these patients do not abandon mainstream therapies but use herbs and other forms of CAM as adjunctive treatments. Only a minority ( ⁇ 40%) talk with their pediatricians about their use of CAM. Because of the stigma and side effects that accompany use of stimulant medications, many families turn to CAM to treat ADHD.
- PS- ⁇ u3 had a marked higher rate of substantial improvement (47% versus 35%, respectively) with the lowest rats of lack or deteriorating effects (21% & 11% versus 26% and 17%, respectively).
- Apolipoprotein E deficient mice [Hayek T. et al. (1994) Biochem.
- mice at 8 weeks of age, were assigned randomly (5 mice each) to LC-PUFA enriched lecithin (30% omega-3 of total fatty acids composition; PC-DHA group) or placebo.
- the mice were fed, besides the regular chow diet, once every three days with either 25 ⁇ l PC-DHA or PBS, via oral gavage, during 10 weeks.
- Each mouse consumed approximately 5 mL of water/day, and 5 g of chow/day.
- Serum was diluted 1:4 in PBS. Serum susceptibility to oxidation was determined by incubating serum sample with lOOmM of the free radical generating compound, 2'-2'-azobis 2'-amidinopropane hydrochloride (AAPH), which is an aqueous soluble azo compound that thermally decomposes to produce peroxyl radicals at a constant rate. The formation of thiobarbituric reactive substances (TBARS) and of lipid peroxides was measured and compared to serum that was incubated under similar conditions, but without AAPH.
- AAPH 2'-2'-azobis 2'-amidinopropane hydrochloride
- ApoE 0 mice are widely used as an animal model for atherosclerosis as they develop severe hypercholesterolemia and atherosclerotic lesions on a chow diet. Moreover, accelerated atherosclerosis is associated with increased lipid peroxidation of plasma lipoproteins and arterial cells in these mice [Hayek T. et al. (1994) id ibid.; Keidar S. (1998) Life Sci. 63:1-11].
- Figure 6 shows how prolonged PC-DHA consumption by ApoE 0 mice resulted in a clear tendency (P ⁇ 0.10) to reduce the serum susceptibility to AAPH-induced oxidation by 16% (in comparison to placebo).
- omega-3 lipids in a variety of applications, and especially as ingredient of functional foods, is hindered due to their distinct fish odor.
- omega-3 enriched phospholipids ingredients of the invention are that they have reduced odor or taste of omega-3 acyl moieties, due to the covalent binding of these groups to the PS backbone. This increases the vapor pressure of these materials, hence reducing their distinct aroma.
- the covalent binding of the omega-3 fatty acids to the phospholipid backbone, especially PS alters and improves their taste properties.
- the PS ingredient of the invention also offers enhanced stability to the oxidation sensitive omega-3 fatty acids.
- Phospholipids in general, and PS in particular, are known to act as anti-oxidants and stabilizers.
- novel ingredients can be formulated with additional lipids for an even enhanced bio-functionality and efficacy.
- the starting compound used for the above-mentioned clinical trial in ADHD patients was LC-PUFA enriched PS mixed with fish oil.
- this product and the control fish oil were formulated in food products like energy bars; however the responses from expert panels were categorically devastating, pointing at severe organoleptic problems.
- the PS- ⁇ 3 product of the invention was de-oiled.
- the end-product of this process was a paste that when reformulated with either inert or dominant - organoleptic saturated fats could be easily formulated in chocolate bars, chocolate spread, chocolate coated cornflakes, low-fat dairy products or concentrated milk. Each one of these formulations had an evidently reduced organoleptic objection from both the expert panels and the trial volunteers.
- the polar lipids derivatives of PUFA such as the PS-PUFA derivatives have exhibited high stability as a preparation and additionally in several food applications, used in the clinical trials of this invention. This stability, of these sensitive compounds is emerging from the covalent combination of phospholipids, known in the past to be used as preservatives and of the un-stable PUFA moieties.
- PS- ⁇ u3 containing products utilized for the clinical studies were tested for their shelf-life and stability in room temperature.
- the enriched PS- ⁇ 3 formulated in condensed milk (1 g product per 10 ml milk) was analyzed by 31 P-NMR for stabihty in cycles of freeze -thawing for a week, and was found to be stable.
- PS- u3 in a chocolate paste matrix (0.75 g product per 20 g chocolate spread) was tested for stability after two weeks storage in room temperature.
- This formulation also presented a stable percentage of PS, in 31 P-NMR analysis.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Reproductive Health (AREA)
- Rheumatology (AREA)
- Ophthalmology & Optometry (AREA)
- Pulmonology (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Vascular Medicine (AREA)
Abstract
Description
Claims
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006536258A JP2007509131A (en) | 2003-10-22 | 2004-10-21 | Glycerophospholipids containing omega-3 and omega-6 fatty acids |
CA2542504A CA2542504C (en) | 2003-10-22 | 2004-10-21 | Lipids containing omega-3 and omega-6 fatty acids |
BRPI0415744A BRPI0415744B8 (en) | 2003-10-22 | 2004-10-21 | use of a lipid preparation containing omega-3 and omega-6 fatty acids, this preparation, use of glycerophospholipids, nutraceutical composition and functional food item |
KR1020067007683A KR101331658B1 (en) | 2003-10-22 | 2004-10-21 | Glycerophospholipids containing omega-3 and omega-6 fatty acids |
AU2004282006A AU2004282006C1 (en) | 2003-10-22 | 2004-10-21 | Glycerophospholipids containing omega-3 and omega-6 fatty acids |
EP10180547.1A EP2258377B1 (en) | 2003-10-22 | 2004-10-21 | Glycerophospholipids containing omega-3 and omega-6 fatty acids |
EP04791827A EP1689413A2 (en) | 2003-10-22 | 2004-10-21 | Glycerophospholipids containing omega-3 and omega-6 fatty acids |
US10/994,175 US20050130937A1 (en) | 2003-10-22 | 2004-11-19 | Lipids containing omega-3 and omega-6 fatty acids |
IL174925A IL174925A (en) | 2003-10-22 | 2006-04-11 | Glycerophospholipids containing omega-3 and omega-6 fatty acids |
US11/414,150 US8052992B2 (en) | 2003-10-22 | 2006-04-28 | Glycerophospholipids containing omega-3 and omega-6 fatty acids and their use in the treatment and improvement of cognitive functions |
US11/872,440 US7968112B2 (en) | 2003-10-22 | 2007-10-15 | Lipids containing omega-3 and omega-6 fatty acids |
US11/872,258 US20080085319A1 (en) | 2003-10-22 | 2007-10-15 | Lipids containing omega-3 and omega-6 fatty acids |
US12/215,080 US7935365B2 (en) | 2003-10-22 | 2008-06-24 | Glycerophospholipids for the improvement of cognitive functions |
US12/590,893 US8470345B2 (en) | 2003-10-22 | 2009-11-16 | Lipids containing omega-3 and omega-6 fatty acids |
IL224977A IL224977A (en) | 2003-10-22 | 2013-02-28 | Glycerophospholipids containing omega -3 and omega-6 fatty acids |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL15855203A IL158552A0 (en) | 2003-10-22 | 2003-10-22 | Lipids containing omega-3 fatty acids |
IL158552 | 2003-10-22 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/994,175 Continuation US20050130937A1 (en) | 2003-10-22 | 2004-11-19 | Lipids containing omega-3 and omega-6 fatty acids |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005037848A2 true WO2005037848A2 (en) | 2005-04-28 |
WO2005037848A3 WO2005037848A3 (en) | 2005-05-26 |
Family
ID=34044222
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IL2004/000957 WO2005037848A2 (en) | 2003-10-22 | 2004-10-21 | Glycerophospholipids containing omega-3 and omega-6 fatty acids |
Country Status (10)
Country | Link |
---|---|
EP (2) | EP2258377B1 (en) |
JP (2) | JP2007509131A (en) |
KR (2) | KR101331658B1 (en) |
CN (2) | CN103381172A (en) |
AU (1) | AU2004282006C1 (en) |
BR (1) | BRPI0415744B8 (en) |
CA (1) | CA2542504C (en) |
IL (3) | IL158552A0 (en) |
RU (1) | RU2362566C2 (en) |
WO (1) | WO2005037848A2 (en) |
Cited By (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005038037A2 (en) * | 2003-10-22 | 2005-04-28 | Enzymotec Ltd. | Methods for preparing phospholipids containing omega-3 and omega-6 moieties |
WO2007004685A2 (en) * | 2005-06-30 | 2007-01-11 | Suntory Limited | Compositions for ameliorating a reduced higher brain function resulting from organic brain lesions |
WO2007100566A2 (en) * | 2006-02-28 | 2007-09-07 | Bristol-Myers Squibb Company | Use of dha and ara in the preparation of a composition for regulating gene expression |
JP2008260743A (en) * | 2006-08-03 | 2008-10-30 | Nagase Chemtex Corp | Nqo1 expression promoter |
KR20100094490A (en) * | 2007-11-01 | 2010-08-26 | 엔지모테크 리미티드 | Lipid mixture for infant nutrition |
WO2011050474A1 (en) | 2009-10-29 | 2011-05-05 | Acasti Pharma, Inc. | Concentrated therapeutic phospholipid compositions |
WO2011137160A3 (en) * | 2010-04-30 | 2012-01-19 | U.S. Nutraceuticals, Llc D/B/A Valensa International | Composition and method to improve blood lipid profiles and optionally reduce low density lipoprotein (ldl) per-oxidation in humans |
US8202907B2 (en) | 2004-09-17 | 2012-06-19 | Suntory Holdings Limited | Composition with preventive or improvement effect on symptoms or diseases associated with stress-induced behavior disorders |
WO2012148926A2 (en) | 2011-04-26 | 2012-11-01 | Retrotope, Inc. | Neurodegenerative disorders and muscle diseases implicating pufas |
US8372812B2 (en) | 2009-02-26 | 2013-02-12 | Aker Biomarine Asa | Phospholipid and protein tablets |
US8383677B2 (en) | 2006-12-28 | 2013-02-26 | Suntory Holdings Limited | Nerve-regenerating agent |
WO2013136183A2 (en) | 2012-03-12 | 2013-09-19 | Innolipid, As | Oxidixable fatty acid composition delivery form |
WO2014045127A2 (en) | 2012-09-19 | 2014-03-27 | Aker Biomarine As | Omega-3 phospholipid supplements for females |
US8697138B2 (en) | 2007-03-28 | 2014-04-15 | Aker Biomarine As | Methods of using krill oil to treat risk factors for cardiovascular, metabolic, and inflammatory disorders |
US8728531B2 (en) | 2010-04-30 | 2014-05-20 | U.S. Nutraceuticals, LLC | Composition and method to improve blood lipid profiles and optionally reduce low density lipoprotein (LDL) per-oxidation in humans |
WO2014140873A2 (en) | 2013-03-14 | 2014-09-18 | Aker Biomarine As | Omega- 3 phospholipid supplements for improved brain maturity |
US8846604B2 (en) | 2011-09-02 | 2014-09-30 | Artic Nutrition AS | Lipid compositions with high DHA content |
US9168241B2 (en) | 2005-06-30 | 2015-10-27 | Suntory Holdings Limited | Compositions ameliorating a reduced diurnal activity and/or depressive symptoms |
WO2015181640A1 (en) * | 2014-04-30 | 2015-12-03 | Enzymotec Ltd. | Krill oil preparations and their uses |
WO2016079595A2 (en) | 2014-11-20 | 2016-05-26 | Enzymotec Ltd. | Phospholipid preparations for the improvement of communication skills |
US9351982B2 (en) | 2009-07-23 | 2016-05-31 | U.S. Nutraceuticals, LLC | Krill oil and reacted astaxanthin composition and associated method |
US9644170B2 (en) | 2007-03-28 | 2017-05-09 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
WO2017153841A1 (en) | 2016-03-10 | 2017-09-14 | Enzymotec Ltd. | Phospholipid preparations for the improvement of brain plasticity |
US9763897B2 (en) | 2010-04-30 | 2017-09-19 | U.S. Nutraceuticals, LLC | Therapeutic astaxanthin and phospholipid composition and associated method |
US9789122B2 (en) | 2012-02-29 | 2017-10-17 | B. Braun Melsungen AS | Hormone containing emulsion |
US9867856B2 (en) | 2014-01-10 | 2018-01-16 | Aker Biomarine Antarctic As | Phospholipid compositions and their preparation |
ES2663392R1 (en) * | 2016-05-17 | 2018-05-10 | Universidad De La Laguna | Nutritional supplement for the protection of neurons against the risk of Alzheimer's and Parkinson's in women combining isoflavones and docosahexaenoic acid. |
US10052299B2 (en) | 2009-10-30 | 2018-08-21 | Retrotope, Inc. | Alleviating oxidative stress disorders with PUFA derivatives |
US10058612B2 (en) | 2011-04-26 | 2018-08-28 | Retrotope, Inc. | Impaired energy processing disorders and mitochondrial deficiency |
US10058522B2 (en) | 2011-04-26 | 2018-08-28 | Retrotope, Inc. | Oxidative retinal diseases |
US10154978B2 (en) | 2011-04-26 | 2018-12-18 | Retrotope, Inc. | Disorders implicating PUFA oxidation |
CN109689041A (en) * | 2016-09-29 | 2019-04-26 | 雀巢产品技术援助有限公司 | Omega-3 fatty acid and choline as the neuroprotective agent for being not suffering from dementia patients |
US10456412B2 (en) | 2015-02-11 | 2019-10-29 | Aker Biomarine Antarctic As | Lipid extraction processes |
US10688070B2 (en) | 2013-12-05 | 2020-06-23 | Enzymotec Ltd. | Serine glycerophospholipid preparation and method for treatment of seizures |
US10704011B2 (en) | 2013-06-14 | 2020-07-07 | Aker Biomarine Antarctic As | Lipid extraction processes |
US10744146B2 (en) | 2001-08-02 | 2020-08-18 | Suntory Holdings Limited | Composition having effects of preventing or ameliorating conditions or diseases caused by brain hypofunction |
US10864223B2 (en) | 2015-02-11 | 2020-12-15 | Aker Biomarine Antarctic As | Lipid compositions |
EP3750533A4 (en) * | 2018-02-09 | 2021-11-03 | Nippon Suisan Kaisha, Ltd. | Agent for improving lymphatic circulation |
US11447441B2 (en) | 2015-11-23 | 2022-09-20 | Retrotope, Inc. | Site-specific isotopic labeling of 1,4-diene systems |
US11779910B2 (en) | 2020-02-21 | 2023-10-10 | Biojiva Llc | Processes for isotopic modification of polyunsaturated fatty acids and derivatives thereof |
GR20220100576A (en) * | 2022-07-13 | 2024-02-09 | Σταυρουλα Κωνσταντινου Μπασακιδου | Edible oils enriched with nutrients to boost brain function |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7935365B2 (en) * | 2003-10-22 | 2011-05-03 | Enzymotec, Ltd. | Glycerophospholipids for the improvement of cognitive functions |
IL158552A0 (en) * | 2003-10-22 | 2004-05-12 | Enzymotec Ltd | Lipids containing omega-3 fatty acids |
US9085527B2 (en) | 2008-07-08 | 2015-07-21 | Catabasis Pharmaceuticals, Inc. | Fatty acid acylated salicylates and their uses |
AU2011214344A1 (en) * | 2010-02-11 | 2012-08-16 | KATHOLIEKE UNIVERSITEIT LEUVEN, KULeuven R&D | Phospholipid profiling and cancer |
RU2467334C2 (en) * | 2010-08-24 | 2012-11-20 | Федеральное государственное бюджетное учреждение "Дальневосточный научный центр физиологии и патологии дыхания" Сибирского отделения РАМН | Method for assessing erythrocyte membrane microviscosity by calculating pyrene eximerisation coefficient cex in pregnant women suffered aggravated herpes viral infection in third trimester of pregnancy with regard to evaluation of percentage of oleic acid in erythrocyte membranes |
GB201016139D0 (en) * | 2010-09-24 | 2010-11-10 | Univ Leuven Kath | Cancer phosholipidome |
CN104144691A (en) * | 2012-03-02 | 2014-11-12 | N·V·努特里奇亚 | Method for improving functional synaptic connectivity |
CN103242407A (en) * | 2013-05-15 | 2013-08-14 | 张雅茹 | Polyunsaturated fatty acyl group-containing phosphatidyl sterol and/or phosphatidyl stanol, and preparation method and application of same |
CN103609752B (en) * | 2013-12-02 | 2016-05-25 | 内蒙古伊利实业集团股份有限公司 | A kind of composition and method of making the same and application that improves brain cognitive function |
WO2017009711A1 (en) * | 2015-07-13 | 2017-01-19 | Enzymotec Ltd. | Phospholipid preparations for the improvement of sleep |
KR101744203B1 (en) * | 2016-01-12 | 2017-06-20 | (주)노터스생명과학 | Pharmaceutical composition comprising phosphatidylcholine as an active ingredient for treatment or prevention of renal disease |
CN109793802A (en) * | 2017-11-16 | 2019-05-24 | 西双版纳华坤生物科技有限责任公司 | A kind of substance and preparation method and purposes for preventing and treating parkinsonism |
US20210069146A1 (en) * | 2018-01-31 | 2021-03-11 | Kinjirushi Co., Ltd. | Recognition ability improving agent |
CN108721269A (en) * | 2018-07-10 | 2018-11-02 | 广东海洋大学 | A kind of application of EPA with DHA intermixtures in terms of prevention anxiety and anhedonia |
JPWO2022050355A1 (en) * | 2020-09-04 | 2022-03-10 | ||
CN113749255B (en) * | 2021-09-15 | 2022-11-29 | 江南大学 | Application of phospholipid composition in repairing muscle injury |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2907778A1 (en) * | 1978-02-28 | 1979-08-30 | Nippon Shoji Kaisha Ltd | USE OF PHOSPHATIDYL COMPOUNDS IN MEDICINAL PRODUCTS AGAINST PERCEPTION, AWARENESS AND MOVEMENT |
EP0609078A1 (en) * | 1993-01-27 | 1994-08-03 | Scotia Holdings Plc | Formulations containing unsaturated fatty acids |
WO1997039759A2 (en) * | 1996-04-24 | 1997-10-30 | Brigham And Women's Hospital | Omega-3 fatty acids and omega-3 phosphatidylcholine in the treatment of bipolar disorder |
US5925669A (en) * | 1994-03-22 | 1999-07-20 | Molecular/Structural Bio Technologies, Inc. | Carrier compositions for anti-neoplastic drugs |
US6005004A (en) * | 1994-08-05 | 1999-12-21 | Molecular / Structural Biotechnologies, Inc. | Lipophilic-polycationic delivery systems |
WO2004049907A2 (en) * | 2002-11-27 | 2004-06-17 | University Of Louisville Research Foundation | Compositions and methods for treating transplants |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2524217B2 (en) * | 1988-04-18 | 1996-08-14 | マルハ株式会社 | Brain function improving composition, learning ability enhancing agent, memory enhancing agent, dementia preventive agent or dementia therapeutic agent |
JPH0279311A (en) * | 1988-09-14 | 1990-03-19 | Ngk Insulators Ltd | Electric field relaxing structure for fore end of grounding layer at high voltage terminal of electric equipment and manufacture thereof |
JPH03188088A (en) * | 1989-12-15 | 1991-08-16 | Ajinomoto Co Inc | Novel lysophosphatidylserine |
JPH0717855A (en) * | 1992-09-02 | 1995-01-20 | Maruha Corp | Cerebral function-improving composition, learning ability-enhancing agent, mnemonic agent, dementia-preventing agent, dementia-treating agent, or functional food having cerebral function-improving effect |
JP3467794B2 (en) * | 1993-03-09 | 2003-11-17 | 日本油脂株式会社 | Learning ability improver |
JPH06279311A (en) * | 1993-03-26 | 1994-10-04 | Sagami Chem Res Center | Activation agent for protein kinase c isozyme |
US6344482B1 (en) * | 1997-04-23 | 2002-02-05 | Andrew L. Stoll | Omega-3 fatty acids in the treatment of bipolar disorder |
FR2762993B1 (en) * | 1997-05-06 | 1999-08-13 | Inst Rech Biolog Sa | NEW USE OF PHOSPHOLIPIDS OF ANIMAL ORIGIN IN THERAPEUTICS AND / OR DIETETICS |
IL158552A0 (en) * | 2003-10-22 | 2004-05-12 | Enzymotec Ltd | Lipids containing omega-3 fatty acids |
-
2003
- 2003-10-22 IL IL15855203A patent/IL158552A0/en unknown
-
2004
- 2004-10-21 AU AU2004282006A patent/AU2004282006C1/en active Active
- 2004-10-21 CA CA2542504A patent/CA2542504C/en not_active Expired - Fee Related
- 2004-10-21 EP EP10180547.1A patent/EP2258377B1/en active Active
- 2004-10-21 KR KR1020067007683A patent/KR101331658B1/en active IP Right Grant
- 2004-10-21 JP JP2006536258A patent/JP2007509131A/en active Pending
- 2004-10-21 BR BRPI0415744A patent/BRPI0415744B8/en active IP Right Grant
- 2004-10-21 RU RU2006116267/15A patent/RU2362566C2/en active
- 2004-10-21 CN CN2013102535938A patent/CN103381172A/en active Pending
- 2004-10-21 WO PCT/IL2004/000957 patent/WO2005037848A2/en active Application Filing
- 2004-10-21 EP EP04791827A patent/EP1689413A2/en not_active Withdrawn
- 2004-10-21 KR KR1020127022875A patent/KR20120115419A/en not_active Application Discontinuation
- 2004-10-21 CN CNA200480038107XA patent/CN1897955A/en active Pending
-
2006
- 2006-04-11 IL IL174925A patent/IL174925A/en active IP Right Grant
-
2012
- 2012-06-06 JP JP2012141384A patent/JP5835671B2/en active Active
-
2013
- 2013-02-28 IL IL224977A patent/IL224977A/en active IP Right Grant
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2907778A1 (en) * | 1978-02-28 | 1979-08-30 | Nippon Shoji Kaisha Ltd | USE OF PHOSPHATIDYL COMPOUNDS IN MEDICINAL PRODUCTS AGAINST PERCEPTION, AWARENESS AND MOVEMENT |
EP0609078A1 (en) * | 1993-01-27 | 1994-08-03 | Scotia Holdings Plc | Formulations containing unsaturated fatty acids |
US5925669A (en) * | 1994-03-22 | 1999-07-20 | Molecular/Structural Bio Technologies, Inc. | Carrier compositions for anti-neoplastic drugs |
US6005004A (en) * | 1994-08-05 | 1999-12-21 | Molecular / Structural Biotechnologies, Inc. | Lipophilic-polycationic delivery systems |
WO1997039759A2 (en) * | 1996-04-24 | 1997-10-30 | Brigham And Women's Hospital | Omega-3 fatty acids and omega-3 phosphatidylcholine in the treatment of bipolar disorder |
WO2004049907A2 (en) * | 2002-11-27 | 2004-06-17 | University Of Louisville Research Foundation | Compositions and methods for treating transplants |
Non-Patent Citations (7)
Title |
---|
ALEYNIK S I ET AL: "POLYENYLPHOSPHATIDYLCHOLINE PROTECTS AGAINST ALCOHOL BUT NOT IRON-INDUCED OXIDATIVE STRESS IN THE LIVER" ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH, WILLIAMS AND WILKINGS, BALTIMORE, MD, US, vol. 24, no. 2, February 2000 (2000-02), pages 196-206, XP008044292 ISSN: 0145-6008 * |
DATABASE WPI Section Ch, Week 199139 Derwent Publications Ltd., London, GB; Class B05, AN 1991-284761 XP002322994 & JP 03 188088 A (AJINOMOTO KK) 16 August 1991 (1991-08-16) * |
NAKASHIMA R ET AL: "SYNTHESIS OF DIDOCASAHEXAENOYLPHOSPHATIDYLSERINE" BIOSCIENCE BIOTECHNOLOGY BIOCHEMISTRY, JAPAN SOC. FOR BIOSCIENCE, BIOTECHNOLOGY AND AGROCHEM. TOKYO, JP, vol. 61, no. 12, 1997, pages 1991-1994, XP008044298 ISSN: 0916-8451 * |
PATENT ABSTRACTS OF JAPAN vol. 018, no. 651 (C-1285), 9 December 1994 (1994-12-09) & JP 06 256179 A (NIPPON OIL & FATS CO LTD), 13 September 1994 (1994-09-13) * |
PATENT ABSTRACTS OF JAPAN vol. 1995, no. 01, 28 February 1995 (1995-02-28) & JP 06 279311 A (SAGAMI CHEM RES CENTER; others: 01), 4 October 1994 (1994-10-04) * |
TAHARA T ET AL: "STIMULATION OF INTERFERON BETA PRODUCTION OF CULTURED CELLS BY PHOSPHOLIPIDS IN FOODSTUFFS" BIOSCIENCE BIOTECHNOLOGY BIOCHEMISTRY, JAPAN SOC. FOR BIOSCIENCE, BIOTECHNOLOGY AND AGROCHEM. TOKYO, JP, vol. 56, no. 9, 1992, pages 1465-1466, XP008044291 ISSN: 0916-8451 * |
TOCHIZAWA, KAORU ET AL: "Effects of phospholipids containing docosahexaenoic acid on differentiation and growth of HL-60 human promyelocytic leukemia cells" NIHON YUKAGAKKAISHI , 46(4), 383-390 CODEN: NIYUFC; ISSN: 1341-8327, 1997, XP008044295 * |
Cited By (82)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10744146B2 (en) | 2001-08-02 | 2020-08-18 | Suntory Holdings Limited | Composition having effects of preventing or ameliorating conditions or diseases caused by brain hypofunction |
WO2005038037A3 (en) * | 2003-10-22 | 2005-12-01 | Enzymotec Ltd | Methods for preparing phospholipids containing omega-3 and omega-6 moieties |
WO2005038037A2 (en) * | 2003-10-22 | 2005-04-28 | Enzymotec Ltd. | Methods for preparing phospholipids containing omega-3 and omega-6 moieties |
US8202907B2 (en) | 2004-09-17 | 2012-06-19 | Suntory Holdings Limited | Composition with preventive or improvement effect on symptoms or diseases associated with stress-induced behavior disorders |
US8367729B2 (en) | 2004-09-17 | 2013-02-05 | Suntory Holdings Limited | Composition with preventive or improvement effect on symptoms or diseases associated with stress-induced behavior disorders |
WO2007004685A2 (en) * | 2005-06-30 | 2007-01-11 | Suntory Limited | Compositions for ameliorating a reduced higher brain function resulting from organic brain lesions |
WO2007004685A3 (en) * | 2005-06-30 | 2007-06-14 | Suntory Ltd | Compositions for ameliorating a reduced higher brain function resulting from organic brain lesions |
US9168241B2 (en) | 2005-06-30 | 2015-10-27 | Suntory Holdings Limited | Compositions ameliorating a reduced diurnal activity and/or depressive symptoms |
WO2007100566A3 (en) * | 2006-02-28 | 2008-10-09 | Bristol Myers Squibb Co | Use of dha and ara in the preparation of a composition for regulating gene expression |
WO2007100566A2 (en) * | 2006-02-28 | 2007-09-07 | Bristol-Myers Squibb Company | Use of dha and ara in the preparation of a composition for regulating gene expression |
JP2008260743A (en) * | 2006-08-03 | 2008-10-30 | Nagase Chemtex Corp | Nqo1 expression promoter |
US8383677B2 (en) | 2006-12-28 | 2013-02-26 | Suntory Holdings Limited | Nerve-regenerating agent |
US11865143B2 (en) | 2007-03-28 | 2024-01-09 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US9730966B2 (en) | 2007-03-28 | 2017-08-15 | Aker Biomarine Antartic As | Method of reducing appetite in a human subject comprising administering krill oil composition |
US9644170B2 (en) | 2007-03-28 | 2017-05-09 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US9816046B2 (en) | 2007-03-28 | 2017-11-14 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US9889163B2 (en) | 2007-03-28 | 2018-02-13 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US10010567B2 (en) | 2007-03-28 | 2018-07-03 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US8697138B2 (en) | 2007-03-28 | 2014-04-15 | Aker Biomarine As | Methods of using krill oil to treat risk factors for cardiovascular, metabolic, and inflammatory disorders |
US9644169B2 (en) | 2007-03-28 | 2017-05-09 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US10543237B2 (en) | 2007-03-28 | 2020-01-28 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
RU2488283C2 (en) * | 2007-11-01 | 2013-07-27 | Энзимотек Лтд. | Lipid mixture for infant alimentation |
KR20100094490A (en) * | 2007-11-01 | 2010-08-26 | 엔지모테크 리미티드 | Lipid mixture for infant nutrition |
RU2611808C2 (en) * | 2007-11-01 | 2017-03-01 | Энзимотек Лтд. | Lipid mixture for infant nutrition |
KR101597372B1 (en) * | 2007-11-01 | 2016-02-24 | 엔지모테크 리미티드 | Lipid mixture for infant nutrition |
US8372812B2 (en) | 2009-02-26 | 2013-02-12 | Aker Biomarine Asa | Phospholipid and protein tablets |
US9351982B2 (en) | 2009-07-23 | 2016-05-31 | U.S. Nutraceuticals, LLC | Krill oil and reacted astaxanthin composition and associated method |
EP3335713A1 (en) * | 2009-10-29 | 2018-06-20 | Acasti Pharma, Inc. | Concentrated therapeutic phospholipid compositions |
EP2493478A4 (en) * | 2009-10-29 | 2013-02-27 | Acasti Pharma Inc | Concentrated therapeutic phospholipid compositions |
US10617702B2 (en) | 2009-10-29 | 2020-04-14 | Acasti Pharma Inc. | Concentrated therapeutic phospholipid compositions |
EP2493478A1 (en) * | 2009-10-29 | 2012-09-05 | Acasti Pharma, Inc. | Concentrated therapeutic phospholipid compositions |
WO2011050474A1 (en) | 2009-10-29 | 2011-05-05 | Acasti Pharma, Inc. | Concentrated therapeutic phospholipid compositions |
US9475830B2 (en) | 2009-10-29 | 2016-10-25 | Acasti Pharma Inc. | Concentrated therapeutic phospholipid compositions |
US10130644B2 (en) | 2009-10-29 | 2018-11-20 | Acasti Pharma Inc. | Concentrated therapeutic phospholipid compositions |
USRE49238E1 (en) | 2009-10-30 | 2022-10-11 | Retrotope, Inc. | Alleviating oxidative stress disorders with PUFA derivatives |
US11510888B2 (en) | 2009-10-30 | 2022-11-29 | Retrotope, Inc. | Alleviating oxidative stress disorders with PUFA derivatives |
US10052299B2 (en) | 2009-10-30 | 2018-08-21 | Retrotope, Inc. | Alleviating oxidative stress disorders with PUFA derivatives |
US9763897B2 (en) | 2010-04-30 | 2017-09-19 | U.S. Nutraceuticals, LLC | Therapeutic astaxanthin and phospholipid composition and associated method |
WO2011137160A3 (en) * | 2010-04-30 | 2012-01-19 | U.S. Nutraceuticals, Llc D/B/A Valensa International | Composition and method to improve blood lipid profiles and optionally reduce low density lipoprotein (ldl) per-oxidation in humans |
US8728531B2 (en) | 2010-04-30 | 2014-05-20 | U.S. Nutraceuticals, LLC | Composition and method to improve blood lipid profiles and optionally reduce low density lipoprotein (LDL) per-oxidation in humans |
US9192671B2 (en) | 2010-04-30 | 2015-11-24 | U.S. Nutraceuticals, LLC | Composition and method to improve blood lipid profiles and optionally reduce low density lipoprotein (LDL) per-oxidation in humans |
US10058612B2 (en) | 2011-04-26 | 2018-08-28 | Retrotope, Inc. | Impaired energy processing disorders and mitochondrial deficiency |
US10154983B2 (en) | 2011-04-26 | 2018-12-18 | Retrotope, Inc. | Neurodegenerative disorders and muscle diseases implicating PUFAs |
WO2012148926A2 (en) | 2011-04-26 | 2012-11-01 | Retrotope, Inc. | Neurodegenerative disorders and muscle diseases implicating pufas |
WO2012148926A3 (en) * | 2011-04-26 | 2013-01-17 | Retrotope, Inc. | Neurodegenerative disorders and muscle diseases implicating pufas |
US11285125B2 (en) | 2011-04-26 | 2022-03-29 | Retrotope, Inc. | Oxidative retinal diseases |
US11241409B2 (en) | 2011-04-26 | 2022-02-08 | Retrotope, Inc. | Neurodegenerative disorders and muscle diseases implicating PUFAs |
US10154978B2 (en) | 2011-04-26 | 2018-12-18 | Retrotope, Inc. | Disorders implicating PUFA oxidation |
US10058522B2 (en) | 2011-04-26 | 2018-08-28 | Retrotope, Inc. | Oxidative retinal diseases |
AU2012249917B2 (en) * | 2011-04-26 | 2017-06-15 | Biojiva Llc | Neurodegenerative disorders and muscle diseases implicating PUFAs |
US11135230B2 (en) | 2011-09-02 | 2021-10-05 | Arctic Nutrition As | Lipid compositions with high DHA content |
US8846604B2 (en) | 2011-09-02 | 2014-09-30 | Artic Nutrition AS | Lipid compositions with high DHA content |
US10076530B2 (en) | 2011-09-02 | 2018-09-18 | Arctic Nutrition As | Lipid compositions with high DHA content |
US9458409B2 (en) | 2011-09-02 | 2016-10-04 | Arctic Nutrition As | Lipid compositions with high DHA content |
US9789122B2 (en) | 2012-02-29 | 2017-10-17 | B. Braun Melsungen AS | Hormone containing emulsion |
WO2013136183A2 (en) | 2012-03-12 | 2013-09-19 | Innolipid, As | Oxidixable fatty acid composition delivery form |
WO2014045127A2 (en) | 2012-09-19 | 2014-03-27 | Aker Biomarine As | Omega-3 phospholipid supplements for females |
WO2014140873A2 (en) | 2013-03-14 | 2014-09-18 | Aker Biomarine As | Omega- 3 phospholipid supplements for improved brain maturity |
US9295683B2 (en) | 2013-03-14 | 2016-03-29 | Aker Biomarine Antarctic As | Omega-3 phospholipid supplements for improved brain maturity |
US10704011B2 (en) | 2013-06-14 | 2020-07-07 | Aker Biomarine Antarctic As | Lipid extraction processes |
US11578289B2 (en) | 2013-06-14 | 2023-02-14 | Aker Biomarine Antarctic As | Lipid extraction processes |
US10688070B2 (en) | 2013-12-05 | 2020-06-23 | Enzymotec Ltd. | Serine glycerophospholipid preparation and method for treatment of seizures |
US9867856B2 (en) | 2014-01-10 | 2018-01-16 | Aker Biomarine Antarctic As | Phospholipid compositions and their preparation |
US10898525B2 (en) | 2014-04-30 | 2021-01-26 | Aker Biomarine Antarctic As | Krill oil preparations and their uses |
WO2015181640A1 (en) * | 2014-04-30 | 2015-12-03 | Enzymotec Ltd. | Krill oil preparations and their uses |
WO2016079595A2 (en) | 2014-11-20 | 2016-05-26 | Enzymotec Ltd. | Phospholipid preparations for the improvement of communication skills |
WO2016079595A3 (en) * | 2014-11-20 | 2016-07-14 | Enzymotec Ltd. | Phospholipid preparations for the improvement of communication skills |
CN107249581B (en) * | 2014-11-20 | 2021-10-15 | 恩兹莫特克有限公司 | Phospholipid formulations for improved communication skills |
CN107249581A (en) * | 2014-11-20 | 2017-10-13 | 恩兹莫特克有限公司 | Phospholipid preparations for improving communication skill |
US10456412B2 (en) | 2015-02-11 | 2019-10-29 | Aker Biomarine Antarctic As | Lipid extraction processes |
US10864223B2 (en) | 2015-02-11 | 2020-12-15 | Aker Biomarine Antarctic As | Lipid compositions |
US11819509B2 (en) | 2015-02-11 | 2023-11-21 | Aker Biomarine Antarctic As | Lipid compositions |
US11447441B2 (en) | 2015-11-23 | 2022-09-20 | Retrotope, Inc. | Site-specific isotopic labeling of 1,4-diene systems |
US11453637B2 (en) | 2015-11-23 | 2022-09-27 | Retrotope, Inc. | Site-specific isotopic labeling of 1,4-diene systems |
WO2017153841A1 (en) | 2016-03-10 | 2017-09-14 | Enzymotec Ltd. | Phospholipid preparations for the improvement of brain plasticity |
ES2663392R1 (en) * | 2016-05-17 | 2018-05-10 | Universidad De La Laguna | Nutritional supplement for the protection of neurons against the risk of Alzheimer's and Parkinson's in women combining isoflavones and docosahexaenoic acid. |
CN109689041A (en) * | 2016-09-29 | 2019-04-26 | 雀巢产品技术援助有限公司 | Omega-3 fatty acid and choline as the neuroprotective agent for being not suffering from dementia patients |
US11813233B2 (en) | 2016-09-29 | 2023-11-14 | Societe Des Produits Nestle S.A. | Omega 3 fatty acids and choline as neuroprotectant in patients with no dementia |
EP3750533A4 (en) * | 2018-02-09 | 2021-11-03 | Nippon Suisan Kaisha, Ltd. | Agent for improving lymphatic circulation |
US11679091B2 (en) | 2018-02-09 | 2023-06-20 | Nippon Suisan Kaisha, Ltd. | Lymphatic circulation improving agents |
US11779910B2 (en) | 2020-02-21 | 2023-10-10 | Biojiva Llc | Processes for isotopic modification of polyunsaturated fatty acids and derivatives thereof |
GR20220100576A (en) * | 2022-07-13 | 2024-02-09 | Σταυρουλα Κωνσταντινου Μπασακιδου | Edible oils enriched with nutrients to boost brain function |
Also Published As
Publication number | Publication date |
---|---|
WO2005037848A3 (en) | 2005-05-26 |
IL224977A (en) | 2014-09-30 |
JP5835671B2 (en) | 2015-12-24 |
BRPI0415744A (en) | 2006-12-19 |
KR101331658B1 (en) | 2013-11-20 |
AU2004282006A1 (en) | 2005-04-28 |
RU2362566C2 (en) | 2009-07-27 |
KR20120115419A (en) | 2012-10-17 |
RU2006116267A (en) | 2007-12-10 |
IL174925A (en) | 2014-01-30 |
AU2004282006C1 (en) | 2010-10-21 |
JP2012211168A (en) | 2012-11-01 |
EP2258377A3 (en) | 2011-10-05 |
JP2007509131A (en) | 2007-04-12 |
EP2258377A2 (en) | 2010-12-08 |
IL158552A0 (en) | 2004-05-12 |
EP2258377B1 (en) | 2019-08-28 |
CA2542504A1 (en) | 2005-04-28 |
IL174925A0 (en) | 2008-02-09 |
EP1689413A2 (en) | 2006-08-16 |
CA2542504C (en) | 2014-01-07 |
AU2004282006B2 (en) | 2010-04-15 |
BRPI0415744B1 (en) | 2018-07-17 |
CN103381172A (en) | 2013-11-06 |
CN1897955A (en) | 2007-01-17 |
BRPI0415744B8 (en) | 2021-05-25 |
KR20060094526A (en) | 2006-08-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2542504C (en) | Lipids containing omega-3 and omega-6 fatty acids | |
US8470345B2 (en) | Lipids containing omega-3 and omega-6 fatty acids | |
US8052992B2 (en) | Glycerophospholipids containing omega-3 and omega-6 fatty acids and their use in the treatment and improvement of cognitive functions | |
US7935365B2 (en) | Glycerophospholipids for the improvement of cognitive functions | |
JP5697293B2 (en) | Composition having an improving effect on lowering of higher brain function due to organic brain injury | |
Schneider | Phospholipids | |
KR20040026697A (en) | Compositions having effects of preventing or ameliorating conditions or diseases caused by brain hypofunction | |
JP3467794B2 (en) | Learning ability improver | |
Tamargo et al. | Pharmacokinetics and safety profile of omega-3 polyunsaturated fatty acids | |
JP2941787B2 (en) | Pharmaceutical composition and health food containing polyunsaturated fatty acid | |
JP5496163B2 (en) | Composition having an effect of preventing or ameliorating symptoms or diseases caused by a decrease in brain function | |
Orthoefer et al. | Phospholipids/lecithin: a class of nutraceutical lipids | |
Phosphatidylcholine et al. | Michael Schneider | |
Berry et al. | Precursor Therapy with Orthomolecular Nutrition | |
MXPA99007737A (en) | Use of polyunsaturated fatty acids forreducing the incidence of necrotizing enterocolitis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200480038107.X Country of ref document: CN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10994175 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 2004994175 Country of ref document: US Kind code of ref document: A |
|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2006536258 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 174925 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2542504 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020067007683 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004282006 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006116267 Country of ref document: RU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1297/KOLNP/2006 Country of ref document: IN |
|
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2004791827 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2004282006 Country of ref document: AU Date of ref document: 20041021 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2004282006 Country of ref document: AU |
|
WWP | Wipo information: published in national office |
Ref document number: 2004791827 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1020067007683 Country of ref document: KR |
|
ENP | Entry into the national phase |
Ref document number: PI0415744 Country of ref document: BR |