WO2010050508A1 - 抗糖尿病作用を有するペプチドおよびその用途 - Google Patents
抗糖尿病作用を有するペプチドおよびその用途 Download PDFInfo
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- WO2010050508A1 WO2010050508A1 PCT/JP2009/068504 JP2009068504W WO2010050508A1 WO 2010050508 A1 WO2010050508 A1 WO 2010050508A1 JP 2009068504 W JP2009068504 W JP 2009068504W WO 2010050508 A1 WO2010050508 A1 WO 2010050508A1
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- WIPO (PCT)
- Prior art keywords
- diabetic
- peptide
- composition
- lsel
- blood glucose
- Prior art date
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- C—CHEMISTRY; METALLURGY
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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Definitions
- the present invention relates to a novel peptide having a blood glucose level increase suppressing action and an insulin secretion enhancing action. Furthermore, this invention relates to the various uses of the peptide which has the said pharmacological action.
- the blood sugar level in the body is regulated by the balance between the blood glucose lowering action of insulin and the blood sugar rising action of adrenaline, glucagon or glucocorticoid.
- insulin suppresses glycogenolysis and gluconeogenesis in the liver, reduces the amount of glucose produced and decreases the amount released into the blood from the liver, and glucose to skeletal muscle and white adipose tissue Increases uptake and lowers blood glucose levels.
- adrenaline, glucagon, etc. conversely, promotes glycogenolysis and gluconeogenesis in the liver, promotes the release of glucose from the liver, and raises the blood glucose level.
- Diabetes is a metabolic disease in which the hyperglycemic state persists due to the acute or chronic decrease in the action of insulin, resulting in metabolic abnormalities such as sugars, lipids and amino acids.
- Insulin-dependent diabetes mellitus type I diabetes
- non-insulin dependent diabetes mellitus type II diabetes
- insulin-dependent diabetes mellitus type II diabetes
- drug therapy with hypoglycemic agents is used in combination when that is not enough.
- diabetes is a disease that causes metabolic abnormalities due to persistent hyperglycemia, and at the same time, it is a troublesome disease with various complications in the eyes, kidneys, nervous system, cardiovascular system, and skin. . Such complications are generally considered to be reduced by controlling the blood glucose level to a value close to normal (Non-patent Document 1).
- Known pharmaceutical preparations for correcting hyperglycemia include insulin preparations, sulfonylurea preparations, biguanides, preparations for improving insulin resistance, ⁇ -glucosidase inhibitors, and the like.
- the insulin preparation is a therapeutic agent for insulin-dependent diabetes and can surely lower the blood glucose level, but there is also a risk of hypoglycemia.
- Sulfonylurea preparation is a drug that lowers blood glucose level by stimulating the secretion of endogenous insulin by stimulating pancreatic ⁇ cells.
- hypoglycemia is caused as a side effect. There is.
- Biguanides are drugs that lower blood sugar by inhibiting gluconeogenesis in the liver, increasing sugar utilization in skeletal muscle, etc., or inhibiting intestinal absorption of sugar, and are suitable for both healthy and diabetic patients. Although there is an advantage that it does not cause hypoglycemia, there is a problem that it is likely to cause relatively severe lactic acidosis. Drugs that improve insulin resistance (such as thiazolidine derivatives) are drugs that enhance insulin action and activate insulin receptor kinase to lower blood glucose levels. However, side effects include digestive symptoms and edema. It has been pointed out that red blood cell count, hematocrit and hemoglobin decrease and LDH increase (Non-patent Document 2).
- ⁇ -Glucosidase inhibitors also have the effect of delaying the digestion and absorption of carbohydrates in the gastrointestinal tract and suppressing postprandial blood sugar elevation, but side effects such as bloating, belly and diarrhea are problematic. (Non-patent document 3).
- peptides having an action of suppressing an increase in blood sugar level an action to suppress an increase in blood sugar level
- an action of enhancing the secretion of insulin insulin secretion enhancing action
- Another object of the present invention is to provide a pharmaceutical composition, a food composition, or a feed composition having an action of suppressing an increase in blood glucose level or an action of enhancing insulin secretion by using such a peptide as an active ingredient.
- an object of the present invention is to provide these compositions as a composition for suppressing an increase in blood glucose, a composition for enhancing insulin secretion, or a composition for treating or preventing diabetes or its complications.
- the inventors of the present invention have been diligently studying day and night in order to solve the above-mentioned problems.By administering a tetrapeptide (Leu-Ser-Glu-Leu) to an artificially hyperglycemic mouse, It was found that the blood glucose level was lowered and the hyperglycemic state was improved. Further, through further research, the present inventors have confirmed that the inhibitory action on the increase in blood glucose level of the peptide LSEL is caused by the action on enhancing insulin secretion.
- the present inventors have found that the peptide LSEL suppresses and improves the hyperglycemic state of diabetic patients or borderline diabetic patients in the pre-diabetes state (hyperglycemic blood glucose level). I was convinced that it is effective for the prevention or treatment of diseases caused by hyperglycemia such as diabetes and its complications.
- the present invention has been completed based on these findings.
- the present invention includes the following aspects.
- composition (II) A pharmaceutical composition, food composition or feed composition comprising the peptide described in (I) as an active ingredient.
- II-2 A composition for suppressing an increase in blood glucose level, comprising as an active ingredient the peptide described in (I).
- II-3) A composition for enhancing insulin secretion comprising the peptide described in (I) as an active ingredient.
- III-4) A composition for preventing or treating a disease caused by hyperglycemia, comprising the peptide according to (I) as an active ingredient.
- II-5) The composition described in (II-4), wherein the disease caused by hyperglycemia is diabetes or a complication thereof.
- diabetes The above complications of diabetes are diabetic acidosis, diabetic xanthoma, diabetic muscular atrophy, diabetic ketosis, diabetic coma, diabetic gastric disorder, diabetic gangrene, diabetic ulcer, diabetic complications , Diabetic diarrhea, diabetic microangiopathy, diabetic endometriosis, diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic blister, diabetic cataract, diabetic skin disorder, diabetic edema
- the composition according to (II-5) which is at least one selected from the group consisting of systemic sclerosis, diabetic retinopathy, diabetic lipoid necrosis, and diabetic blood flow disorder.
- II-7 The composition according to (II-5) or (II-6), wherein the diabetes is type II diabetes.
- (III) A method for preventing or treating a disease caused by hyperglycemia (III-1)
- the composition described in any of (II-1) to (II-7) is administered to a patient having a disease caused by hyperglycemia.
- a method for preventing or treating a disease caused by hyperglycemia in the patient III-2) The method according to (III-1), wherein the disease caused by hyperglycemia is diabetes or a complication thereof.
- diabetes The above complications of diabetes are diabetic acidosis, diabetic xanthoma, diabetic muscular atrophy, diabetic ketosis, diabetic coma, diabetic gastric disorder, diabetic gangrene, diabetic ulcer, diabetic complications , Diabetic diarrhea, diabetic microangiopathy, diabetic endometriosis, diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic blister, diabetic cataract, diabetic skin disorder, diabetic edema (III-2), which is at least one selected from the group consisting of systemic sclerosis, diabetic retinopathy, diabetic lipoid necrosis, and diabetic blood flow disorder. (III-4) The method according to (III-2) or (III-3), wherein the diabetes is type II diabetes.
- IV Use of peptide
- IV-1 Use of a peptide comprising the amino acid sequence represented by Leu-Ser-Glu-Leu for the preparation of a composition for preventing or treating a disease caused by hyperglycemia.
- IV-2) The use according to (IV-1), wherein the disease caused by hyperglycemia is diabetes or a complication thereof.
- diabetes The above complications of diabetes are diabetic acidosis, diabetic xanthoma, diabetic muscular atrophy, diabetic ketosis, diabetic coma, diabetic gastric disorder, diabetic gangrene, diabetic ulcer, diabetic complications , Diabetic diarrhea, diabetic microangiopathy, diabetic endometriosis, diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic blister, diabetic cataract, diabetic skin disorder, diabetic edema
- IV-2 which is at least one selected from the group consisting of systemic sclerosis, diabetic retinopathy, diabetic lipoid necrosis, and diabetic blood flow disorder.
- (IV-4) The use according to (IV-2) or (IV-3), wherein the diabetes is type II diabetes.
- IV-5) A peptide having an amino acid sequence represented by Leu-Ser-Glu-Leu, which is used for prevention or treatment of a disease caused by hyperglycemia.
- IV-6) The peptide according to (IV-5), wherein the disease caused by hyperglycemia is diabetes or a complication thereof.
- diabetes The above complications of diabetes are diabetic acidosis, diabetic xanthoma, diabetic muscular atrophy, diabetic ketosis, diabetic coma, diabetic gastric disorder, diabetic gangrene, diabetic ulcer, diabetic complications , Diabetic diarrhea, diabetic microangiopathy, diabetic endometriosis, diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic blister, diabetic cataract, diabetic skin disorder, diabetic edema
- IV-6 which is at least one selected from the group consisting of systemic sclerosis, diabetic retinopathy, diabetic lipoid necrosis, and diabetic blood flow disorder.
- IV-8 The use according to (IV-6) or (IV-7), wherein the diabetes is type II diabetes.
- Peptide (Leu-Ser-Glu-Leu) The present invention provides a tetrapeptide comprising the amino acid sequence of Leu-Ser-Glu-Leu (hereinafter also referred to as “peptide LSEL” or “peptide of the present invention”).
- peptide LSEL the amino acid sequence of Leu-Ser-Glu-Leu
- the peptide can be administered orally and parenterally to suppress the increase in blood glucose level and enhance insulin secretion. Demonstrate the effect. That is, the peptide is a physiologically active peptide having a blood glucose level increase suppressing action and an insulin secretion enhancing action.
- the peptide of the present invention can be produced by a general chemical synthesis method according to its amino acid sequence.
- the method includes peptide synthesis methods using ordinary liquid phase methods and solid phase methods. More specifically, the peptide synthesis method is based on the stepwise erosion method in which each amino acid is sequentially linked to extend the chain based on the amino acid sequence information provided in the present invention, and a fragment consisting of several amino acids. And fragment condensation method in which each fragment is subjected to a coupling reaction.
- the peptide of the present invention can be synthesized by any of them.
- the condensation method employed in the peptide synthesis can also follow various known methods. Specific examples thereof include, for example, azide method, mixed acid anhydride method, DCC method, active ester method, redox method, DPPA (diphenylphosphoryl azide) method, DCC + additive (1-hydroxybenzotriazole, N-hydroxysuccinamide) N-hydroxy-5-norbornene-2,3-dicarboximide, etc.), Woodward method and the like. Solvents that can be used in each of these methods can be appropriately selected from general solvents that are well known to be used in this type of peptide condensation reaction.
- Examples thereof include dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexaphosphoroamide, dioxane, tetrahydrofuran (THF), ethyl acetate and the like, and mixed solvents thereof.
- DMF dimethylformamide
- DMSO dimethyl sulfoxide
- THF tetrahydrofuran
- ethyl acetate examples thereof include dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexaphosphoroamide, dioxane, tetrahydrofuran (THF), ethyl acetate and the like, and mixed solvents thereof.
- amino acids that are not involved in the reaction and carboxyl groups in the peptide are generally esterified, for example, lower alkyl esters such as methyl ester, ethyl ester, and tertiary butyl ester, such as benzyl ester, p- It can be protected as a methoxybenzyl ester, p-nitrobenzyl ester aralkyl ester or the like.
- the deprotection reaction of these protecting groups in the amino acids having the above-mentioned protecting groups, peptides and finally obtained peptides of the present invention is also carried out by conventional methods such as catalytic reduction, liquid ammonia / sodium, hydrogen fluoride, odor. It can be carried out according to a method using hydrogen fluoride, hydrogen chloride, trifluoroacetic acid, acetic acid, formic acid, methanesulfonic acid or the like.
- the peptide of the present invention thus obtained can be obtained in the field of peptide chemistry such as ion exchange resin, partition chromatography, gel chromatography, affinity chromatography, high performance liquid chromatography (HPLC), countercurrent distribution method and the like according to a conventional method.
- the purification can be appropriately performed according to a widely used method.
- the peptide of the present invention can be produced by the chemical synthesis method described above, and can also be prepared by enzymatic degradation or hydrolysis of a polypeptide or protein partially containing the amino acid sequence (Leu-Ser-Glu-Leu). You can also.
- the origin of such polypeptide or protein is not particularly limited, and may be any of animals, seafood, and plants.
- FASTA amino acid sequence database
- animals, seafood, and plants having polypeptides or proteins partially containing the amino acid sequence (Leu-Ser-Glu-Leu) The search results are shown in FIG.
- peptide LSEL has a physiological activity (pharmacological action) such as an action to suppress an increase in blood glucose level and an action to enhance insulin secretion by oral administration and parenteral administration, so that it is a pharmaceutical composition, food composition or feed composition. It can be suitably used as an active ingredient.
- physiological activity such as an action to suppress an increase in blood glucose level and an action to enhance insulin secretion by oral administration and parenteral administration, so that it is a pharmaceutical composition, food composition or feed composition. It can be suitably used as an active ingredient.
- composition of the present invention comprises the peptide LSEL as an active ingredient.
- the pharmaceutical composition provided by the present invention includes a composition for suppressing an increase in blood glucose level (a blood glucose level increase inhibitor), a composition for enhancing insulin secretion (an insulin secretion enhancer), and prevention or treatment of a disease caused by hyperglycemia.
- Composition preventive or therapeutic agent for diseases caused by hyperglycemia).
- the composition for suppressing an increase in blood glucose contains an effective amount of peptide LSEL that prevents or ameliorates the hyperglycemia state of a diabetic patient or a so-called borderline diabetic patient in a pre-diabetes state (suppresses an increase in blood glucose level).
- the composition for enhancing insulin secretion contains an effective amount of peptide LSEL that enhances insulin secretion in diabetic patients or borderline diabetic patients.
- a composition for preventing or treating a disease caused by hyperglycemia contains the effective amount of peptide LSEL for preventing or treating the above-mentioned disease by exhibiting the above-mentioned action for suppressing the increase in blood sugar level or the action for enhancing insulin secretion. is there.
- the pharmaceutical composition of the present invention may comprise only the peptide LSEL as long as it contains the above peptide LSEL in an effective amount that exerts a blood glucose level increase inhibitory action or an insulin secretion enhancing action.
- it is prepared together with a pharmaceutically acceptable carrier or additive.
- excipients that are usually used according to the administration form of the pharmaceutical composition (formulation)
- Solubilizers that are usually used according to the administration form of the pharmaceutical composition (formulation)
- buffers emulsifiers
- suspending agents and the like.
- additives stabilizers, preservatives, buffers, tonicity agents, chelating agents, pH adjusters, surfactants, coloring agents, flavoring agents, flavoring agents that are usually used according to the dosage form of the preparation And sweeteners.
- the dosage unit form (pharmaceutical preparation form) of such a pharmaceutical composition can be appropriately selected depending on the administration route, and these are largely oral preparations and parenteral preparations (for example, pulmonary administration agents, nasal administration agents). , Sublingual, injection, infusion).
- oral preparations and parenteral preparations for example, pulmonary administration agents, nasal administration agents). , Sublingual, injection, infusion.
- solid dosage forms such as tablets, pills, powders, powders, granules, and capsules
- liquid dosage forms such as solutions, suspensions, emulsions, syrups, and elixirs according to conventional methods.
- Or can be prepared. Further, it may be prepared as a dry product that can be made liquid by adding an appropriate carrier before use. Any of these can be prepared according to a conventional method.
- the ratio of peptide LSEL blended in the pharmaceutical composition of the present invention is not particularly limited, but it can be usually prepared in a dosage form containing about 0.1 to 80% by weight depending on each dosage form.
- the dosage of the pharmaceutical composition thus obtained is the purpose of the pharmaceutical composition (suppression of blood sugar level increase, insulin secretion enhancement, prevention or treatment of diseases caused by hyperglycemic conditions), administration method and administration of the composition. It is appropriately selected depending on the form, age, weight or symptom (severity of diabetes) of the patient to be administered. In general, it is preferable to administer the peptide LSEL within a range of about 10 mg to 1000 mg per adult per day.
- the administration does not necessarily have to be once a day, and can be divided into 3 to 4 times a day.
- suitable administration routes according to the form for example, in the form of injections, intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal administration, etc. It can be administered by oral administration or the like.
- the pharmaceutical composition of the present invention has an insulin secretion enhancing action due to peptide LSEL as shown in the experimental examples described later, improves the hyperglycemic state caused by a decrease or deficiency of insulin action, and suppresses an increase in blood glucose level Demonstrate the effect. For this reason, the pharmaceutical composition of the present invention is effective as a composition for preventing or treating various diseases caused by a hyperglycemic state caused by a decrease or deficiency of insulin action.
- Such diseases include diabetes and diabetic complications.
- the target diabetes is preferably insulin-independent type 2 diabetes.
- the blood glucose level is 200 mg / dL or higher
- the fasting blood glucose level is 126 mg / dL or higher
- the 75 g oral glucose tolerance test 2-hour value is 200 mg / dL or higher
- HbA 1c hemoglobin A 1c
- the HbA 1c value is regarded as important, and the main determination is made based on this.
- the HbA 1c value is an index that reflects the average blood glucose level of the patient over the past 1 to 2 months, and is the most important index of blood glucose control status with little variation in the value of one patient.
- diabetes targeted by the present invention includes not only the case where diabetes is determined according to the above criteria, but also the pathological condition in the border zone (boundary diabetes).
- borderline diabetes can be determined when the fasting blood glucose level is between 110 and 125 mg / dl, or when the glucose tolerance test 2 hour value is between 140 and 199 mg / dl.
- a diabetic complication is a systemic or local disease that is caused by diabetes (preferably non-insulin-dependent type 2 diabetes) directly or indirectly, and specifically includes diabetic acidosis and diabetic yellow.
- diabetes preferably non-insulin-dependent type 2 diabetes
- Diabetic muscular atrophy, diabetic ketosis, diabetic coma, diabetic gastric disorder, diabetic gangrene, diabetic ulcer, diabetic complications, diabetic diarrhea, diabetic microangiopathy, diabetic endometriosis Diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic blister, diabetic cataract, diabetic skin disorder, diabetic edema sclerosis, diabetic retinopathy, diabetic lipoid necrosis, diabetic
- a blood flow disorder or the like can be exemplified.
- the pharmaceutical composition of the present invention is effectively used for preventing or treating the above-mentioned diseases of the patient by being administered to a patient suffering from the above-mentioned various diseases caused by a hyperglycemic state.
- the pharmaceutical composition of the present invention includes not only human pharmaceutical compositions but also animal pharmaceutical compositions.
- the food composition of the present invention comprises the peptide LSEL described above as an active ingredient.
- the food composition provided by the present invention includes foods for specific health (including conditional foods for specific health) that have been given the ability to suppress an increase in blood glucose levels, foods for specific health that have been given the ability to enhance insulin secretion (conditional specific health) Special health foods (including conditional special health foods) that are used to prevent or ameliorate diseases caused by hyperglycemia by having a blood glucose level increase inhibitory action or an insulin secretion enhancing function action Is included.
- the above-mentioned food for specified health use imparted with a blood glucose level increase suppressing function contains an effective amount of peptide LSEL that prevents or ameliorates the hyperglycemic state (suppresses the increase in blood glucose level) of diabetic patients or borderline diabetic patients.
- the food product can be described in terms of its action and effect (blood glucose level increase inhibiting action) on food packaging packages or advertisements.
- the food for specified health use with an insulin secretion-enhancing function is characterized by containing an effective amount of peptide LSEL that enhances insulin secretion in diabetic patients or borderline diabetic patients. It is a food that can be used to add a description about its action effect (insulin secretion enhancement) to an advertisement.
- the food for specified health used for preventing or ameliorating a disease caused by hyperglycemia exerts a preventive or ameliorating effect on the above-mentioned disease based on the above-mentioned blood glucose level increase inhibiting action or insulin secretion enhancing action. It is a food containing an effective amount of peptide LSEL and capable of adding a description regarding its action effect (anti-diabetic action) to a food packaging package or advertisement.
- the food composition of the present invention may be composed only of peptide LSEL as long as it contains the above-described peptide LSEL in an effective amount that exhibits an action to suppress an increase in blood glucose level or an action to enhance insulin secretion.
- it is prepared with a carrier or additive that can be used as a food.
- the peptide LSEL does not have to be purified peptide LSEL as long as it has a blood glucose elevation-inhibiting action or an insulin secretion-increasing action.
- the fraction may be used as an active ingredient of the food composition of the present invention.
- the peptide LSEL is mixed with food-acceptable carriers and additives as necessary, together with tablets, pills, capsules, granules, powders, powders, or solutions (drinks) Supplements (functional foods) prepared in the form of foods, food additives, and general foods and drinks containing the peptide LSEL are included.
- Such foods and drinks include milk drinks, lactic acid bacteria drinks, fruit juice soft drinks, soft drinks, carbonated drinks, fruit juice drinks, vegetable drinks, vegetable / fruit drinks, alcoholic drinks, powdered drinks, coffee drinks, tea drinks, green tea drinks, barley tea Beverages such as beverages; custard pudding, milk pudding, souffle pudding, puddings such as pudding with fruit juice, desserts such as jelly, bavaroa and yogurt; ice cream, ice milk, lacto ice, milk ice cream, ice cream with fruit juice and Frozen confectionery such as soft ice cream, ice candy, sherbet, ice confectionery; gums such as chewing gum and bubble gum (plate gum, sugar-coated granule gum); strawberry chocolate, blueberry chocolate, melon chocolate, etc.
- coated chocolate such as marble chocolate of Chocolates such as chocolate with taste; hard candy (including bonbons, butterballs, marbles, etc.), soft candy (including caramels, nougat, gummy candy, marshmallows, etc.), caramels such as drops, toffees; hard biscuits Baked confectionery such as cookie, rice cracker, rice cracker (confectionery); soups such as consomme soup and potage soup; jams such as strawberry jam, blueberry jam, marmalade, apple jam, apricot jam, prasab; red wine etc.
- Fruit wine for processing syrup pickled cherries, apricots, apples, strawberries, peaches, etc .; processed meat such as ham, sausage, grilled pork; fish ham, fish sausage, fish meat surimi, salmon, bamboo rings, hampen, fried satsuma , Date rolls, Whale bacon etc. Ri products; can Etc side dishes and bran, and the like various processed foods such as Denbu; udon, hiyamugi, somen, buckwheat, buckwheat Chinese, spaghetti, macaroni, rice vermicelli, noodles such as vermicelli and wonton. Beverages and confectionery are preferred.
- the amount of active ingredient (peptide LSEL) to be contained in the food composition or the amount to be taken is not particularly limited, and may vary depending on the type of food composition, the desired degree of improvement, and other conditions. Accordingly, it is appropriately selected from a wide range.
- the intake varies depending on the type of food composition, but can be appropriately selected from the range of about 10 to 1000 mg / 60 kg in terms of the amount of peptide LSEL per intake for a human weighing 60 kg. .
- the food composition of the present invention has an action of enhancing insulin secretion due to the peptide LSEL, improves the hyperglycemic state caused by a decrease or deficiency of the insulin action, and exhibits an action of suppressing an increase in blood sugar level. For this reason, the food composition of the present invention can be effectively used as a food composition for preventing or ameliorating various diseases caused by a hyperglycemic state caused by a decrease or deficiency of insulin action. That is, the food composition of the present invention is effectively used for preventing or ameliorating the disease of the patient by being ingested by a patient suffering from various diseases caused by a hyperglycemic state.
- Feed composition The feed composition of the present invention is characterized by containing peptide LSEL as an active ingredient.
- the feed composition provided by the present invention is caused by hyperglycemia by having a feed imparted with a blood glucose level elevation inhibiting function, a feed imparted with an insulin secretion enhancing function, a blood glucose level elevation inhibiting action or an insulin secretion enhancing function action It includes feed used for the prevention or amelioration of disease.
- the feed can be suitably used as a feed for pet animals such as dogs and cats.
- the feed provided with the function of suppressing the increase in blood glucose level contains an effective amount of peptide LSEL that prevents or ameliorates the hyperglycemic state of an animal that becomes diabetic or its previous state (suppresses an increase in blood glucose level). To do.
- the feed provided with the insulin secretion enhancing function is characterized by containing an effective amount of peptide LSEL that enhances insulin secretion in an animal that is diabetic or in its previous state.
- a feed used for preventing or ameliorating a disease caused by hyperglycemia contains an effective amount of peptide LSEL that exerts the above-described action of suppressing the increase in blood glucose level or the action of enhancing insulin secretion.
- the peptide LSEL is prepared in the form of tablets, pills, capsules, granules, powders, powders, solutions, etc., with carriers and additives that can be blended with the feed as necessary.
- a general feed containing the peptide LSEL is included.
- the peptide LSEL does not have to be purified peptide LSEL as long as it has a blood glucose elevation-inhibiting action or an insulin secretion-increasing action. You may use the fraction as an active ingredient of the feed composition of this invention.
- the amount of active ingredient (peptide LSEL) to be contained in the feed composition or the amount to be taken is not particularly limited, and the type of feed composition, the type of animal ingesting the feed, the intended improvement effect and its It is appropriately selected from a wide range according to the degree and other various conditions.
- the amount of intake varies depending on the type of feed composition, it can be appropriately selected from the range of about 1 to 100 mg / 10 kg in terms of the amount of peptide LSEL per intake for an animal weighing 10 kg. .
- mice blood glucose levels of mice fasted overnight (about 18 hours) were measured, and the mice were divided into 6 groups based on the blood glucose levels obtained (3 groups: LSEL oral administration group, 1 group: LSEL subcutaneous administration group). 1 group: oral administration control group, 1 group: subcutaneous administration control group). Table 1 shows the peptide LSEL dose, administration route and number of cases in the LSEL oral administration group and the LSEL subcutaneous administration group.
- glucose (2 g / kg body weight) and peptide LSEL (10 mg / kg body weight, 25 mg / kg body weight, or 50 mg / kg body weight) were mixed and administered orally at the same time. Blood glucose levels were measured after 90 minutes and 120 minutes.
- peptide LSEL 25 mg / kg body weight
- blood glucose level was 30 minutes, 60 minutes, 90 minutes and 120 minutes after administration.
- physiological saline was subcutaneously administered.
- blood glucose levels were measured at 30, 60, 90 and 120 minutes after administration.
- Glucose was dissolved in physiological saline and used so that the administration volume was 10 mL / kg (the same applies to the following experiments).
- the blood glucose level was measured with a small blood glucose meter Keassy (Roche) using one drop of blood collected from the tail vein.
- Figure 2 shows the changes in blood glucose levels over time in the LSEL oral administration group (peptide LSEL dosage: 50 mg / kg body weight) and the control group, and in the LSEL subcutaneous administration group (peptide LSEL dosage: 25 mg / kg body weight) and in the control group
- the change with time is shown in FIG.
- the area under the 2-hour curve (AUC 0-2h ) was determined for each group, and the blood glucose AUC 0-2h inhibition rate (%) was determined from the following formula. The results are shown in Table 1.
- peptide LSEL exerts an action of suppressing an increase in blood glucose both in oral administration and subcutaneous administration.
- mice blood glucose levels of mice fasted overnight (about 18 hours) were measured, and the mice were divided into 4 groups based on the obtained blood glucose levels (3 groups: LSEL oral administration group, 1 group: control) group).
- Table 2 shows the peptide LSEL dose and the number of cases in the LSEL oral administration group.
- glucose (2 g / kg body weight) and peptide LSEL 25 mg / kg body weight, 50 mg / kg body weight or 100 mg / kg body weight
- Blood glucose levels were measured after 60, 90 and 120 minutes.
- glucose (2 g / kg body weight) and distilled water were mixed and administered orally at the same time.
- the blood glucose level was 30 minutes, 60 minutes, 90 minutes and 120 minutes after administration. It was measured. Sucrose was used after being dissolved in physiological saline so that the administration volume was 10 mL / kg. The blood glucose level was measured with Kay assist (Roche) using one drop of blood collected from the tail vein.
- FIG. 4 shows changes in blood glucose levels over time in the LSEL oral administration group (dose: 100 mg / kg body weight) and the control group.
- dose 100 mg / kg body weight
- control group 100 mg / kg body weight
- AUC 0-2h the area under the 2-hour curve
- % the blood glucose AUC 0-2h inhibition rate
- mice fasted overnight were measured, and the mice were divided into two groups based on the blood glucose levels obtained (1 group: LSEL oral administration group, 1 group: control) group).
- Table 3 shows the peptide LSEL dose and the number of cases in the LSEL oral administration group.
- sucrose (2 g / kg body weight) and peptide LSEL 25 mg / kg body weight were mixed and administered orally at the same time, and blood glucose levels were measured at 30, 60, 90 and 120 minutes after administration. It was measured.
- sucrose (2 g / kg body weight) and distilled water were mixed and administered orally at the same time.
- blood sugar levels were measured at 30, 60, 90 and 120 minutes after administration. It was measured.
- the blood glucose level was measured with Kay assist (Roche) using one drop of blood collected from the tail vein.
- FIG. 5 shows changes in blood glucose levels over time in the LSEL oral administration group and the control group.
- the area under the 2-hour curve (AUC 0-2h ) was determined, and the blood glucose AUC 0-2h inhibition rate (%) was determined according to the above formula 1. The results are shown in Table 3.
- mice fasted overnight were measured and divided into two groups based on the obtained blood glucose levels (LSEL oral administration group, control group).
- Table 4 shows the amount of peptide LSEL administered and the number of cases in the LSEL oral administration group.
- glucose (2 g / kg body weight) and peptide LSEL 50 mg / kg body weight
- 15 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes after administration Later plasma insulin concentrations were measured.
- glucose (2 g / kg body weight) and distilled water were mixed and administered orally at the same time.
- 15 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes after administration The plasma insulin concentration was measured.
- Plasma insulin concentration was measured with an insulin measurement kit (Levis® insulin-mouse T, manufactured by Shiba Goat Co., Ltd.) using plasma obtained by collecting blood from the orbit using heparin and centrifuging.
- FIG. 6 shows changes over time in plasma insulin concentrations in the LSEL oral administration group and the control group.
- the area under the 2-hour curve (AUC 0-2h ) was determined, and the increase rate (%) of insulin AUC 0-2h was determined according to the following formula.
- oral administration of peptide LSEL 50 mg / kg increased the area under the 2-hour curve of plasma insulin concentration (AUC 0-2h ) by 252.0% compared to the control group (p. ⁇ 0.05).
- peptide LSEL has a high possibility of suppressing an increase in blood sugar through the secretion of insulin.
- Example 1 Green Tea Beverage 8 kg of green tea was placed in 300 L of hot water at 80 ° C. and extracted at the same temperature for 4 minutes. The obtained extract was cooled and then centrifuged, and a clear supernatant was collected to obtain a green tea extract. To this extract, 0.4 kg of vitamin C was added, and 50 g of the peptide LSEL prepared in Preparation Example 1 was added, and the final volume was adjusted to 1000 L with hot water. This was heated to 85 ° C. or higher, filled into a metal can, and sterilized by retort (125 ° C., 5 minutes) to give a green tea beverage.
- retort 125 ° C., 5 minutes
- Example 2 Tablets All the following ingredients were kneaded and granulated by a conventional method, dried and compressed to obtain tablets containing 5% by weight (10 mg) of peptide LSEL in 1 tablet (200 mg). .
- the tablet can be provided as a pharmaceutical preparation or supplement having the pharmacological action of peptide LSEL (blood glucose level increase inhibiting action, insulin secretion enhancing action, antidiabetic action).
- Example 3 Feed The premix containing vitamins, minerals, etc. is mixed with the peptide LSEL prepared in Preparation Example 1 at a rate of 0.1%, and this is added to a commercial dog feed at a rate of 10% to secrete insulin.
- a dog food having an enhancing action or an inhibitory action on an increase in blood glucose level was prepared.
- compositions having a blood glucose level increase suppressing action or an insulin secretion enhancing action by containing peptide LSEL as an active ingredient.
- These compositions have the effect of lowering the blood glucose level in a hyperglycemic state for subjects (including humans and animals) in diabetes or its previous state based on the blood glucose level increase inhibitory effect or insulin secretion enhancing effect. Therefore, the composition of the present invention can be effectively used for the prevention or treatment of diseases caused by hyperglycemia, specifically, diabetes and diabetic complications.
- mice, seafood, and plants having a polypeptide or protein partially containing an amino acid sequence are shown.
- mouth at the time of LSEL oral administration is shown.
- mouth at the time of LSEL subcutaneous administration is shown.
- mouth at the time of LSEL oral administration is shown.
- FIG. In Experimental example 4 the change of the insulin concentration in the plasma of the glucose load ICR mouse
- SEQ ID NO: 1 is the amino acid sequence of a novel tetrapeptide.
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Abstract
Description
Leu-Ser-Glu-Leuで示されるアミノ酸配列からなるペプチド。
(II-1)(I)に記載するペプチドを有効成分とする医薬組成物、食品組成物または飼料組成物。
(II-2)(I)に記載するペプチドを有効成分とする血糖値上昇抑制用組成物。
(II-3)(I)に記載するペプチドを有効成分とするインスリン分泌亢進用組成物。
(II-4)(I)に記載するペプチドを有効成分とする、高血糖に起因する疾患の予防または治療用組成物。
(II-5)高血糖に起因する疾患が、糖尿病またはその合併症である(II-4)に記載する組成物。
(II-6)上記糖尿病の合併症が、糖尿病アシドーシス、糖尿病性黄色腫、糖尿病性筋萎縮症、糖尿病性ケトーシス、糖尿病性昏睡、糖尿病性胃障害、糖尿性壊疽、糖尿病性潰瘍、糖尿病性合併症、糖尿病性下痢症、糖尿病性細小血管症、糖尿病性子宮体硬化症、糖尿病性心筋症、糖尿病性ニューロパシー、糖尿病性腎症、糖尿病性水疱、糖尿病性白内障、糖尿病性皮膚障害、糖尿病性浮腫性硬化症、糖尿病性網膜症、糖尿病性リポイド類壊死症、および糖尿病性血流障害からなる群から選択されるいずれか少なくとも1種である(II-5)に記載する組成物。
(II-7)糖尿病が、II型糖尿病である(II-5)または(II-6)に記載する組成物。
(III-1)(II-1)~(II-7)のいずれかに記載する組成物を、高血糖に起因する疾患患者に投与する工程を有する、当該患者について高血糖に起因する疾患を予防または治療する方法。
(III-2)高血糖に起因する疾患が、糖尿病またはその合併症である(III-1)に記載する方法。
(III-3)上記糖尿病の合併症が、糖尿病アシドーシス、糖尿病性黄色腫、糖尿病性筋萎縮症、糖尿病性ケトーシス、糖尿病性昏睡、糖尿病性胃障害、糖尿性壊疽、糖尿病性潰瘍、糖尿病性合併症、糖尿病性下痢症、糖尿病性細小血管症、糖尿病性子宮体硬化症、糖尿病性心筋症、糖尿病性ニューロパシー、糖尿病性腎症、糖尿病性水疱、糖尿病性白内障、糖尿病性皮膚障害、糖尿病性浮腫性硬化症、糖尿病性網膜症、糖尿病性リポイド類壊死症、および糖尿病性血流障害からなる群から選択されるいずれか少なくとも1種である(III-2)に記載する方法。
(III-4)上記糖尿病が、II型糖尿病である(III-2)または(III-3)に記載する方法。
(IV-1)Leu-Ser-Glu-Leuで示されるアミノ酸配列からなるペプチドの、高血糖に起因する疾患の予防または治療用組成物の調製のための使用。
(IV-2)高血糖に起因する疾患が、糖尿病またはその合併症である(IV-1)に記載する使用。
(IV-3)上記糖尿病の合併症が、糖尿病アシドーシス、糖尿病性黄色腫、糖尿病性筋萎縮症、糖尿病性ケトーシス、糖尿病性昏睡、糖尿病性胃障害、糖尿性壊疽、糖尿病性潰瘍、糖尿病性合併症、糖尿病性下痢症、糖尿病性細小血管症、糖尿病性子宮体硬化症、糖尿病性心筋症、糖尿病性ニューロパシー、糖尿病性腎症、糖尿病性水疱、糖尿病性白内障、糖尿病性皮膚障害、糖尿病性浮腫性硬化症、糖尿病性網膜症、糖尿病性リポイド類壊死症、および糖尿病性血流障害からなる群から選択されるいずれか少なくとも1種である(IV-2)に記載する使用。
(IV-4)上記糖尿病が、II型糖尿病である(IV-2)または(IV-3)に記載する使用。
(IV-5)高血糖に起因する疾患の予防または治療のために使用される、Leu-Ser-Glu-Leuで示されるアミノ酸配列からなるペプチド。
(IV-6)高血糖に起因する疾患が、糖尿病またはその合併症である(IV-5)に記載するペプチド。
(IV-7)上記糖尿病の合併症が、糖尿病アシドーシス、糖尿病性黄色腫、糖尿病性筋萎縮症、糖尿病性ケトーシス、糖尿病性昏睡、糖尿病性胃障害、糖尿性壊疽、糖尿病性潰瘍、糖尿病性合併症、糖尿病性下痢症、糖尿病性細小血管症、糖尿病性子宮体硬化症、糖尿病性心筋症、糖尿病性ニューロパシー、糖尿病性腎症、糖尿病性水疱、糖尿病性白内障、糖尿病性皮膚障害、糖尿病性浮腫性硬化症、糖尿病性網膜症、糖尿病性リポイド類壊死症、および糖尿病性血流障害からなる群から選択されるいずれか少なくとも1種である(IV-6)に記載する使用。
(IV-8)上記糖尿病が、II型糖尿病である(IV-6)または(IV-7)に記載する使用。
本発明は、Leu-Ser-Glu-Leuのアミノ酸配列からなるテトラペプチド(以下、「ペプチドLSEL」、または「本発明のペプチド」ともいう)を提供する。当該ペプチドは、人為的に高血糖状態にした正常マウスおよび糖尿病モデルマウスに対して行った実験例(後述)で示すように、経口投与および非経口投与によって、血糖値上昇抑制作用およびインスリン分泌亢進作用を発揮する。すなわち、当該ペプチドは、血糖値上昇抑制作用およびインスリン分泌亢進作用を有する生理活性ペプチドである。
本発明の医薬組成物は、上記ペプチドLSELを有効成分として含有することを特徴とする。
本発明の食品組成物は、前述するペプチドLSELを有効成分として含有することを特徴とする。
本発明の飼料組成物は、ペプチドLSELを有効成分として含有することを特徴とする。
アミノ酸配列Leu-Ser-Glu-Leu(配列番号1)からなるペプチド(ペプチドLSEL)を、定法の液相法に従って合成した(Shanghai C-Strong社(上海,中国)に製造委託)。得られたペプチドについて、液相自動エドマン分解法(装置:アプライドバイオシステムズ製Procise HT, Protein Sequencing System)によりアミノ酸配列を分析したところ、上記アミノ酸配列からなるテトラペプチドであることが確認された。
調製例1で調製したペプチドLSELをグルコース負荷正常マウスに経口投与または皮下投与して、当該ペプチドの上記マウスの血糖値に及ぼす影響を調べた。試験には、7週齢の雄性ICRマウス(日本エスエルシー)を用いた。
調製例1で調製したペプチドLSELをグルコース負荷2型糖尿病モデルKK-Ayマウスに経口投与して、当該ペプチドの上記マウスの血糖値に及ぼす影響を調べた。試験には、9週齢の雄性2型糖尿病モデルKK-Ayマウス(日本クレア)を用いた。
調製例1で調製したペプチドLSELを、スクロース負荷正常マウスに経口投与して、当該ペプチドの上記マウスの血糖値に及ぼす影響を調べた。試験には7週齢の雄性ICRマウス(日本エスエルシー)を用いた。
調製例1で調製したペプチドLSELを、グルコース負荷正常マウスに経口投与して、当該ペプチドの上記マウスの血漿インスリン濃度に及ぼす影響を調べた。試験には7週齢の雄性ICRマウス(日本エスエルシー)を用いた。
調製例1で調製したペプチドLSELをマウスに経口投与した場合、2g/kg体重でも全く毒性を発現しなかった。このことから、ペプチドLSEL のLD50は2g/kg体重をはるかに上まわることが判明した。
緑茶8kgを80℃の熱水300Lに入れ、同温度で4分間抽出した。得られた抽出液を冷却後、遠心分離し、清澄な上清を採取してこれを緑茶抽出物とした。この抽出物にビタミンCを0.4kg配合し、さらに調製例1で調製したペプチドLSELを50g添加して、熱水で最終容量が1000Lになるよう調製した。これを85℃以上に加熱し、金属缶に充填して、レトルト殺菌(125℃、5分)して緑茶飲料とした。
下記の全成分を、常法により練合および造粒し、乾燥後打錠して1錠(200mg)中、ペプチドLSELを5重量%(10mg)の割合で含む錠剤を得た。当該錠剤は、ペプチドLSELの薬理作用(血糖値上昇抑制作用、インスリン分泌亢進作用、抗糖尿病作用)を有する医薬製剤またはサプリメントとして提供することができる。
ペプチドLSEL(調製例1) 50mg
ソルビトール 190mg
ショ糖脂肪酸エステル 10mg
合計 250mg。
ビタミン、ミネラル等が配合されたプレミックスに調製例1で調製したペプチドLSELを0.1%の割合で配合し、これを市販のドッグ用飼料に10%の割合で添加し、インスリン分泌亢進作用または血糖値上昇抑制作用を有するドッグフードを調製した。
Claims (12)
- Leu-Ser-Glu-Leuで示されるアミノ酸配列からなるペプチド。
- 請求項1に記載するペプチドを有効成分とする医薬組成物、食品組成物または飼料組成物。
- 請求項1に記載するペプチドを有効成分とする血糖値上昇抑制用組成物。
- 請求項1に記載するペプチドを有効成分とするインスリン分泌亢進用組成物。
- 請求項1に記載するペプチドを有効成分とする、高血糖に起因する疾患の予防または治療用組成物。
- 高血糖に起因する疾患が、糖尿病またはその合併症である請求項5に記載する組成物。
- 上記糖尿病の合併症が、糖尿病アシドーシス、糖尿病性黄色腫、糖尿病性筋萎縮症、糖尿病性ケトーシス、糖尿病性昏睡、糖尿病性胃障害、糖尿性壊疽、糖尿病性潰瘍、糖尿病性合併症、糖尿病性下痢症、糖尿病性細小血管症、糖尿病性子宮体硬化症、糖尿病性心筋症、糖尿病性ニューロパシー、糖尿病性腎症、糖尿病性水疱、糖尿病性白内障、糖尿病性皮膚障害、糖尿病性浮腫性硬化症、糖尿病性網膜症、糖尿病性リポイド類壊死症、および糖尿病性血流障害から選択される少なくとも1種である、請求項6に記載する組成物。
- 上記高血糖がII型糖尿病である、請求項5に記載する組成物。
- 請求項1に記載するペプチドを有効成分とする医薬組成物または食品組成物を、高血糖に起因する疾患の患者に投与する工程を有する、当該疾患の予防または治療方法。
- 高血糖に起因する疾患が、糖尿病またはその合併症である請求項9に記載する方法。
- Leu-Ser-Glu-Leuで示されるアミノ酸配列からなるペプチドの、高血糖に起因する疾患の予防または治療用組成物の調製のための使用。
- 高血糖に起因する疾患の予防または治療のために使用される、Leu-Ser-Glu-Leuで示されるアミノ酸配列からなるペプチド。
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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AU2009310912A AU2009310912B2 (en) | 2008-10-30 | 2009-10-28 | Peptide having anti-diabetic activity and use thereof |
US13/123,784 US8691949B2 (en) | 2008-10-30 | 2009-10-28 | Peptide having anti-diabetic activity and use thereof |
KR1020117008996A KR101731252B1 (ko) | 2008-10-30 | 2009-10-28 | 항-당뇨 활성을 갖는 펩티드 및 그것의 용도 |
EP09823618.5A EP2341066B1 (en) | 2008-10-30 | 2009-10-28 | Peptide having anti-diabetic activity and use thereof |
CA2739712A CA2739712C (en) | 2008-10-30 | 2009-10-28 | Peptide having anti-diabetic activity and use thereof |
CN2009801431064A CN102197044B (zh) | 2008-10-30 | 2009-10-28 | 具有抗糖尿病活性的肽及其用途 |
HK12102085.8A HK1161280A1 (en) | 2008-10-30 | 2012-02-29 | Peptide having anti-diabetic activity and use thereof |
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JP2008-280031 | 2008-10-30 | ||
JP2008280031A JP4864064B2 (ja) | 2008-10-30 | 2008-10-30 | 抗糖尿病作用を有するペプチドおよびその用途 |
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US (1) | US8691949B2 (ja) |
EP (1) | EP2341066B1 (ja) |
JP (1) | JP4864064B2 (ja) |
KR (1) | KR101731252B1 (ja) |
CN (1) | CN102197044B (ja) |
AU (1) | AU2009310912B2 (ja) |
CA (1) | CA2739712C (ja) |
HK (1) | HK1161280A1 (ja) |
TW (1) | TWI465245B (ja) |
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JP4864064B2 (ja) * | 2008-10-30 | 2012-01-25 | エムジーファーマ株式会社 | 抗糖尿病作用を有するペプチドおよびその用途 |
JP2012046432A (ja) * | 2010-08-25 | 2012-03-08 | Takeshi Ogura | カルシウム強化海洋ミネラル複合体を有効成分とする抗ストレス剤及び糖質コルチコイドの分泌抑制剤 |
MY165122A (en) | 2013-06-12 | 2018-02-28 | Maruha Nichiro Corp | Dipeptidyl peptidase-iv (dppiv) inhibitory peptide compound, composition containing the same, and production method for the same |
WO2023098817A1 (en) * | 2021-12-03 | 2023-06-08 | The Hong Kong Polytechnic University | Glucoregulatory compound, composition and uses thereof |
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FR2809733B1 (fr) | 2000-06-02 | 2004-04-30 | Inst Nat Sante Rech Med | Substrat peptidique reconnu par la toxine botulique de type bont/b et son utilisation pour doser et/ou detecter ladite toxine ou des inhibiteurs correspondants |
AUPR595601A0 (en) * | 2001-06-27 | 2001-07-19 | International Diabetes Institute | Hypoglycaemic peptides and methods of use thereof |
KR20060026011A (ko) * | 2003-05-09 | 2006-03-22 | 노보 노르디스크 에이/에스 | 비만 치료용 펩티드 |
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- 2009-10-28 EP EP09823618.5A patent/EP2341066B1/en not_active Not-in-force
- 2009-10-28 KR KR1020117008996A patent/KR101731252B1/ko active IP Right Grant
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AU2009310912B2 (en) | 2014-05-08 |
CN102197044B (zh) | 2013-11-27 |
AU2009310912A1 (en) | 2010-05-06 |
CA2739712C (en) | 2018-05-22 |
JP4864064B2 (ja) | 2012-01-25 |
TWI465245B (zh) | 2014-12-21 |
KR20110074989A (ko) | 2011-07-05 |
TW201026319A (en) | 2010-07-16 |
CN102197044A (zh) | 2011-09-21 |
US20110201551A1 (en) | 2011-08-18 |
EP2341066A1 (en) | 2011-07-06 |
HK1161280A1 (en) | 2012-08-24 |
EP2341066B1 (en) | 2015-05-20 |
KR101731252B1 (ko) | 2017-04-28 |
CA2739712A1 (en) | 2010-05-06 |
JP2010105963A (ja) | 2010-05-13 |
US8691949B2 (en) | 2014-04-08 |
EP2341066A4 (en) | 2012-03-21 |
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