WO2021187942A1 - 혈압 강하를 위한 chp(사이클로-히스프로)의 용도 - Google Patents
혈압 강하를 위한 chp(사이클로-히스프로)의 용도 Download PDFInfo
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- WO2021187942A1 WO2021187942A1 PCT/KR2021/003424 KR2021003424W WO2021187942A1 WO 2021187942 A1 WO2021187942 A1 WO 2021187942A1 KR 2021003424 W KR2021003424 W KR 2021003424W WO 2021187942 A1 WO2021187942 A1 WO 2021187942A1
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/18—Peptides; Protein hydrolysates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- 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
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/326—Foods, ingredients or supplements having a functional effect on health having effect on cardiovascular health
Definitions
- the present invention relates to the use of CHP (cyclo-hispro) for lowering blood pressure, and more particularly, to a pharmaceutical composition for lowering blood pressure comprising CHP and a health functional food composition comprising the same composition; method of lowering blood pressure using CHP; use of CHP in the manufacture of antihypertensives; A pharmaceutical composition for preventing or treating hypertension or its complications, including CHP, and a health functional food composition for preventing or improving hypertension or its complications, including the same composition; prevention or treatment of hypertension or its complications using CHP; It relates to the use of CHP in the manufacture of a medicament for preventing or treating hypertension or its complications.
- CHP cyclo-hispro
- Cerebrovascular disease the leading cause of death after cancer in Korea, is due to the high incidence of hyperlipidemia and hypertension.
- high blood pressure is a major cause of complications such as cerebrovascular disease and cardiovascular disease, and it is increasing with the westernization of diet and aging.
- the number of patients with renal impairment is also showing a gradual increase, and such causes include an increase in diabetic nephropathy due to a change in living environment, an aging population, or an increase in diabetic patients.
- the number of patients who have kidney failure due to renal dysfunction or have no choice but to introduce dialysis is increasing every year. .
- drugs that suppress the rise of blood electrolytes and a low-protein diet are prescribed for patients with renal failure.
- erythropoietin is administered, but the progression of the condition is delayed. It is considered insufficient to deter it.
- Renal diseases such as nephritis, diabetic nephropathy, and renal failure are often accompanied by high blood pressure, and hypertension is considered as one of the exacerbation factors of renal disease. is losing
- AngII angiotensin II
- AT1R AT1 receptor
- AT2R AT2 receptor
- AT1R AT1R
- AT2R AT2R
- AT1R AT1R
- AT2R AT2R
- AT1R AT1R
- AT2R AT2R
- AT1R AT1R
- AT2R AT2R
- AT1R AT1R
- AT2R AT2R
- AT1R AT2
- AT2R a type 2 receptor
- hypertension appears in hypertensive patients because the blood AngII concentration is maintained high or AT1 is expressed more strongly than AT2, and blood vessels are more likely to remain constricted rather than relaxed. Therefore, drugs that reduce the expression level of AT1 or blockers that block the binding of AngII to the AT1 receptor can be used as a treatment for hypertension (Le TH, et al. Hypertension, 42(4), 507-514, 2003).
- Arteriosclerosis peripheral blood circulation disorder, vascular stenosis, cerebral infarction, angina pectoris, myocardial infarction, and ischemic brain disease, including hypertension, are diseases caused by vasoconstriction. It refers to the narrowing of blood vessels in the back. For smooth blood circulation, an increase in blood flow in blood vessels is required, and the increase in blood flow requires expansion of blood vessels. For vasodilation, nitric oxide (NO) by the action of endothelial nitric oxide synthase (eNOS), a nitric oxide synthase of vascular endothelial cells, is involved (Ulrich Forstermann & Thomas Munzel, Circulation, 113, 1708-1714, 2006).
- NO nitric oxide
- eNOS endothelial nitric oxide synthase
- NO production is reduced.
- vascular smooth muscle is affected by several factors, and the cGMP signaling pathway of vascular smooth muscle cells by NO produced and secreted by vascular endothelial cells is a very important pathway in vascular relaxation (Zhu J, et. al., Mol). Brain, 9, 20, 2016).
- NO is produced from L-arginine by eNOS in vascular endothelial cells.
- NO secreted from vascular endothelial cells flows into vascular smooth muscle cells, activates sGC (Soluble Guanylyl Cyclase), and regulates blood pressure by relaxing vascular smooth muscle through a signal transduction system that increases cGMP production. Therefore, the NO production promoter can also be used as a therapeutic agent for hypertension.
- CHP Cyclo-HisPro
- CHP thyrotropin-releasing hormone
- the therapeutic effect (Republic of Korea Patent No. 10-2133151) is known, but the blood pressure lowering effect of CHP is not known.
- Cyclo-HisPro reduces the expression of angiotensin II type I receptor gene or protein in vascular endothelial cells; increased expression of angiotensin II type II receptor gene or protein; increased VE-cadherin gene or protein expression; increased eNOS gene or protein expression; And/or it was confirmed that the blood pressure lowering effect through the NO production increase activity, and completed the present invention.
- CHP Cyclo-HisPro
- an object of the present invention is to provide a pharmaceutical composition for lowering blood pressure comprising cyclo-Hispro or a pharmaceutically acceptable salt thereof.
- Another object of the present invention is to provide a health functional food composition for lowering blood pressure comprising cyclo-Hispro or a pharmaceutically acceptable salt thereof.
- Another object of the present invention is to provide a method for lowering blood pressure using cyclo-Hipro or a pharmaceutically acceptable salt thereof.
- Another object of the present invention is to provide the use of cyclo-Hipro or a pharmaceutically acceptable salt thereof in the manufacture of an antihypertensive agent.
- a pharmaceutical composition for preventing or treating hypertension or complications thereof including cyclo-Hispro or a pharmaceutically acceptable salt thereof.
- Another object of the present invention is to provide a health functional food composition for preventing or improving hypertension or its complications, including cyclo-Hispro or a pharmaceutically acceptable salt thereof.
- Another object of the present invention is to provide a method for preventing or treating hypertension or its complications using cyclo-Hipro or a pharmaceutically acceptable salt thereof.
- Another object of the present invention is to provide the use of cyclo-Hispro or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of hypertension or its complications.
- the present invention provides a pharmaceutical composition for lowering blood pressure comprising cyclo-Hispro or a pharmaceutically acceptable salt thereof; And it provides a health functional food composition for lowering blood pressure comprising cyclo-Hispro or a pharmaceutically acceptable salt thereof.
- the present invention also provides a method for lowering blood pressure, comprising administering to a subject in need thereof cyclo-Hipro or a pharmaceutically acceptable salt thereof; and cyclo-Hispro or a pharmaceutically acceptable salt thereof in the manufacture of an antihypertensive agent.
- the cyclo-Hipro or a pharmaceutically or pharmaceutically acceptable salt thereof can induce blood pressure through at least one activity selected from the group consisting of the following a) to e) in vascular endothelial cells. It can have a depressant effect:
- the present invention provides a pharmaceutical composition for preventing or treating hypertension or complications thereof, including cyclo-Hispro or a pharmaceutically acceptable salt thereof, and cyclo-Hispro or a pharmaceutically acceptable salt thereof, comprising: It provides a health functional food composition for preventing or improving hypertension or its complications.
- the present invention also provides a method for preventing or treating hypertension or its complications, comprising administering cyclo-Hipro or a pharmaceutically acceptable salt thereof to a subject in need thereof; And it provides the use of cyclo-hispro or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of hypertension or its complications.
- the complications include arteriosclerosis, coronary artery disease, myocardial infarction, heart failure, angina pectoris, peripheral blood circulation disorder, vascular stenosis, stroke, cerebral infarction, cerebral hemorrhage, ischemic brain disease, renal failure, glomerulitis, It may be selected from the group consisting of diabetes, diabetic nephropathy, diabetic retinopathy, proteinuria, uremia, edema, visual impairment due to stenosis of blood vessels of the eye, and glaucoma.
- composition comprising CHP of the present invention reduces the expression of angiotensin II type I receptor gene or protein in vascular endothelial cells; increased expression of angiotensin II type II receptor gene or protein; increased VE-cadherin gene or protein expression; increased eNOS gene or protein expression; And/or because it exhibits a blood pressure lowering effect through the activity of increasing NO production, it is useful for the prevention, improvement or treatment of hypertension or its complications, and it is a natural product-derived ingredient that is safe for the human body, so it replaces the existing synthetic ACE inhibitors showing some side effects It can be applied to therapeutic agents and food compositions.
- 1 is a graph showing the results of measuring systolic blood pressure at 2, 6 and 8 weeks, respectively, by administering cyclo-Hispro 3 days before making 5/6 nephrectomy rats.
- FIG. 2 is a graph showing the results of measuring systolic blood pressure at 2, 6, and 8 weeks after administration of cyclo-Hispro from 2 weeks after making 5/6 nephrectomy rats (Post-treatment).
- Figure 3 confirms the change in the expression level of AT1R (Angiotensin II type I receptor), AT2R (Angiotensin II type 2 receptor) and VE-cadherin (VE-cadherin) proteins according to the treatment of angiotensin II and CHP in HUVEC cells.
- AT1R Angiotensin II type I receptor
- AT2R Angiotensin II type 2 receptor
- VE-cadherin VE-cadherin
- FIG. 4 is a graph showing that the expression of eNOS gene in SVEC4-10 cells increases in a CHP concentration-dependent manner.
- Figure 5 confirms the increase in NO production according to CHP treatment in HMVEC-L cells using DAF-FM DA (scale bar 50 ⁇ m).
- CHP cyclo-HisPro
- the first aspect of the present invention is a health function for lowering blood pressure comprising a pharmaceutical composition for lowering blood pressure comprising cyclo-Hispro or a pharmaceutically acceptable salt thereof and cyclo-Hispro or a pharmaceutically acceptable salt thereof. It relates to a food composition.
- Cyclo-HisPro refers to a naturally occurring circular dipeptide composed of histidine-proline, a metabolite of thyrotropin-releasing hormone (TRH) or It is a physiologically active dipeptide that is also synthesized in the body through TRH metabolism and de novo, and refers to a substance widely distributed in the brain, spinal cord, and gastrointestinal tract.
- the CHP may be synthesized or commercially available. In addition, it can be used after purification from substances containing CHP, for example, prostate extract and soybean hydrolyzate.
- purified it is intended to mean that CHP is in a concentrated form compared to a form obtainable from a natural origin, such as a prostate extract.
- Purified ingredients can be concentrated from their natural sources or obtained through chemical synthesis methods.
- a first aspect of the present invention also relates to a method for lowering blood pressure comprising administering to a subject in need thereof an effective amount of cyclo-Hipro or a pharmaceutically acceptable salt thereof.
- a first aspect of the present invention relates to the use of cyclo-Hipro or a pharmaceutically acceptable salt thereof in the manufacture of an antihypertensive agent.
- the CHP or a pharmaceutically or food acceptable salt thereof exhibits a blood pressure lowering effect in vascular endothelial cells through at least one activity selected from the group consisting of the following a) to e).
- CHP or a pharmaceutically or pharmaceutically acceptable salt thereof of the present invention can be utilized to prevent, improve or treat hypertension and/or complications thereof.
- a second aspect of the present invention is a pharmaceutical composition for the prevention or treatment of hypertension or complications thereof, including cyclo-Hispro or a pharmaceutically acceptable salt thereof, and hypertension including cyclo-Hispro or a pharmaceutically acceptable salt thereof. Or it relates to a health functional food composition for preventing or improving its complications.
- hypertension of the present invention
- the World Health Organization defines hypertension as a case in which the systolic blood pressure is 160 mmHg or more and the diastolic blood pressure is 95 mmHg or more. It is divided into essential hypertension of unknown cause and secondary hypertension caused by a causative disease, and it is known that more than 90% of these are essential hypertension.
- the term “complication of hypertension” may be a symptom or disease that causes hypertension, or a symptom or disease that occurs due to hypertension.
- complications of hypertension include arteriosclerosis, coronary artery disease, myocardial infarction, heart failure, angina pectoris, peripheral blood circulation disorder, vascular stenosis, stroke, cerebral infarction, cerebral hemorrhage, ischemic brain disease, renal failure, glomerulitis, diabetes, diabetic nephropathy, It may be a symptom or disease selected from the group consisting of diabetic retinopathy, proteinuria, uremia, edema, visual impairment due to stenosis of blood vessels of the eye, and glaucoma.
- prevention refers to any action, disease or condition that inhibits or delays the onset of the disease or condition. means any action that improves or beneficially alters the disease, and any action that delays, stops or reverses the progression of a disease or condition.
- the kidney is involved in water and sodium metabolism and is closely related to the renin-angiotensin system, so kidney disease itself, that is, glomerulitis or renal failure, can cause hypertension and play an important role in the development of primary hypertension. Therefore, in one embodiment of the present invention, the CHP blood pressure lowering effect was confirmed in the nephrectomy animal model, and as shown in FIGS. 1 and 2 , the systolic blood pressure significantly decreased according to the CHP administration before or after the renal resection. was able to confirm
- the CHP of the present invention is particularly useful for the prevention, improvement or treatment of complications related to kidney disease such as renal failure, glomerulitis, diabetic nephropathy, proteinuria or uremia.
- AngII angiotensin II
- AT1R AT1 receptor
- AT2R AT2 receptor
- AT2R AT2R
- the expression levels of AT1R, AT2R and VE-cadherin proteins according to AngII and CHP treatment in HUVEC cells were confirmed, and as shown in FIG. 3, CHP treatment was performed with AngII decreased AT1R protein expression level increased by AngII, increased AT2R protein expression level decreased by AngII, and increased VE-cadherin protein expression decreased by AngII. Accordingly, it was confirmed that CHP exerts a blood pressure lowering effect by increasing the expression level of AT1R protein that induces vasoconstriction and decreasing the expression level of AT2R protein that relaxes blood vessels.
- Vasoconstriction refers to a phenomenon in which blood vessels such as arteries or veins including the aorta are narrowed as the walls of blood vessels contract. For smooth blood circulation, an increase in blood flow in blood vessels is required, and the increase in blood flow requires expansion of blood vessels.
- nitric oxide (NO) For vasodilation, nitric oxide (NO) by the action of endothelial nitric oxide synthase (eNOS), a nitric oxide synthase of vascular endothelial cells, is involved (Ulrich Forstermann & Thomas Munzel, Circulation, 113, 1708-1714, 2006). Indeed, in the case of hypertension, NO production is reduced.
- vascular smooth muscle is affected by several factors, and the cGMP signaling pathway of vascular smooth muscle cells by NO produced and secreted by vascular endothelial cells is a very important pathway in vascular relaxation (Zhu J, et. al., Mol). Brain, 9, 20, 2016).
- NO is produced from L-arginine by eNOS in vascular endothelial cells.
- NO secreted from vascular endothelial cells flows into vascular smooth muscle cells, activates sGC (Soluble Guanylyl Cyclase), and regulates blood pressure by relaxing vascular smooth muscle through a signal transduction system that increases cGMP production. Therefore, in order to treat blood pressure control disorders caused by vascular diseases, it is necessary to develop drugs that can promote NO production.
- the eNOS gene expression level according to CHP treatment in SVEC4-10 cells and NO generation according to CHP treatment in HMVEC-L cells were confirmed.
- the eNOS gene expression level was increased by the CHP treatment as confirmed in FIG. 4
- NO production was increased by the CHP treatment as confirmed in FIG. 5 . Accordingly, it was confirmed that CHP exerts a blood pressure lowering effect by relaxing blood vessels by increasing NO production.
- a second aspect of the present invention also relates to a method for preventing or treating hypertension or its complications, comprising administering to a subject in need thereof an effective amount of cyclo-Hipro or a pharmaceutically acceptable salt thereof. .
- a second aspect of the present invention relates to the use of cyclo-Hipro or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of hypertension or its complications.
- the term "pharmaceutically acceptable” refers to those that are physiologically acceptable and do not normally cause allergic reactions or similar reactions when administered to humans, and the salt includes a pharmaceutically acceptable free acid (free acid). acid) is preferred.
- the pharmaceutically acceptable salt may be an acid addition salt formed using an organic acid or an inorganic acid, and the organic acid is, for example, formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid, Malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, dichloroacetic acid, aminooxyacetic acid, benzenesulfonic acid, p- toluenesulfonic acid or methanesulfonic acid.
- the organic acid is, for example, formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid
- Inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid or boric acid.
- the acid addition salt may preferably be in the form of hydrochloride or acetate, and more preferably in the form of hydrochloride.
- additional salts available include gaba salt, gabapentin salt, pregabalin salt, nicotinate salt, adipate salt, hemimalonate, cysteine salt, acetylcysteine salt, methionine salt, arginine salt, lysine salt, ornithine salt or aspartate salt etc.
- the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration.
- Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
- Carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycols, and the like.
- it may further include a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid.
- Suitable preservatives are benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
- the pharmaceutical composition of the present invention may be administered to mammals including humans by any method.
- it may be administered orally or parenterally, and parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal. , intranasal, enteral, topical, sublingual or rectal administration.
- the pharmaceutical composition of the present invention may be formulated as a formulation for oral administration or parenteral administration according to the administration route as described above.
- one or more buffers e.g., saline or PBS
- carbohydrates e.g., glucose, mannose, sucrose, or dextran, etc.
- antioxidants e.g., bacteriostats, chelating agents (e.g., EDTA) or glutathione)
- fillers e.g., bulking agents, binders, adjuvants (eg aluminum hydroxide), suspending agents, thickening agents, wetting agents, disintegrating or surfactants, diluents or excipients.
- adjuvants eg aluminum hydroxide
- Solid preparations for oral administration include tablets, pills, powders, granules, liquids, gels, syrups, slurries, suspensions or capsules, etc., and these solid preparations include at least one excipient in the pharmaceutical composition of the present invention, for example , Starch (including corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose , methyl cellulose, sodium carboxymethyl cellulose and hydroxypropylmethyl-cellulose or gelatin may be mixed and prepared.
- tablets or dragees can be obtained by blending the active ingredient with a solid excipient, grinding it, adding suitable adjuvants, and processing it into a granule mixture.
- Liquid formulations for oral use include suspensions, solutions, emulsions, or syrups, and various excipients, such as wetting agents, sweetening agents, fragrances, or preservatives, in addition to water or liquid paraffin, which are commonly used simple diluents, may be included. .
- cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant, and an anti-aggregating agent, lubricant, wetting agent, flavoring agent, emulsifying agent and preservative may be additionally included.
- the pharmaceutical composition of the present invention may be formulated according to methods known in the art in the form of injections, transdermal administrations and nasal inhalants together with suitable parenteral carriers.
- suitable parenteral carriers include, but are not limited to, water, ethanol, polyols (eg, glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof, and/or a solvent or dispersion medium containing vegetable oil.
- suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) with triethanolamine or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose. etc. can be used.
- PBS phosphate buffered saline
- isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose. etc.
- it may further include various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- the injection may further contain isotonic agents such as sugars or sodium chloride.
- transdermal administration forms such as ointment, cream, lotion, gel, external solution, pasta, liniment, and air are included.
- 'transdermal administration' means that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin by topically administering the pharmaceutical composition to the skin.
- the compounds for use according to the invention may be administered in pressurized packs or using a suitable propellant, for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be conveniently delivered in the form of an aerosol spray from a nebulizer.
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- gelatin capsules and cartridges used in inhalers or insufflators may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch. Formulations for parenteral administration are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a recipe commonly known to all pharmaceutical chemistry.
- the pharmaceutical composition of the present invention contains cyclo-Hispro in an effective amount, it is possible to provide a desirable effect of lowering blood pressure, prevention, improvement or treatment of hypertension or complications thereof.
- the term "effective amount" refers to an amount that exhibits a response higher than that of a negative control group, and preferably refers to an amount sufficient to prevent, ameliorate or treat hypertension or its complications.
- the pharmaceutical composition of the present invention may contain 0.01 to 99.9% of cyclo-Hispro, and the remaining amount may be occupied by a pharmaceutically acceptable carrier.
- the effective amount of cyclo-Hipro included in the pharmaceutical composition of the present invention will vary depending on the form in which the composition is commercialized.
- the total effective amount of the pharmaceutical composition of the present invention may be administered to a patient as a single dose, and may be administered by a fractionated treatment protocol in which multiple doses are administered for a long period of time.
- the pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the severity of the disease. For example, it may be administered in one to several divided doses so as to be administered in an amount of preferably 0.001 to 100 mg, more preferably 0.01 to 70 mg per 1 kg of body weight per day based on cyclo-Hipro.
- the dose of cyclo-Hispro is effective administration to the patient considering various factors such as the age, weight, health status, sex, severity of the disease, diet and excretion rate of the patient, as well as the route of administration and the number of treatments of the pharmaceutical composition. Since the amount is determined, those of ordinary skill in the art can administer the cyclo-Hispro in an appropriate effective dosage according to the specific use for lowering blood pressure, or preventing, treating or improving hypertension or its complications, considering this point. will be able to determine
- the pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as the effect of the present invention is exhibited.
- composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, or a biological response modifier.
- composition of the present invention may also be provided in the form of an external application containing cyclo-Hispro.
- the composition of the present invention may be a quasi-drug composition for lowering blood pressure, or preventing or improving hypertension or its complications, and a quasi-drug comprising the composition.
- the external preparation may be applied directly to the skin.
- a fatty substance an organic solvent, a solubilizer, a thickening agent and a gelling agent, an emollient, an antioxidant, a suspending agent, a stabilizer, a foaming agent, a fragrance, a surfactant, Water, ionic emulsifiers, non-ionic emulsifiers, fillers, sequestering agents, chelating agents, preservatives, vitamins, blockers, wetting agents, essential oils, dyes, pigments, hydrophilic active agents, lipophilic active agents or lipid vesicles, etc. It may contain adjuvants commonly used in the field of dermatology, such as any other ingredients commonly used. In addition, the ingredients may be introduced in an amount generally used in the field of dermatology.
- the present invention is not limited thereto, but may be in the form of a liquid, ointment, patch, gel, cream or spray.
- the quasi-drug of the present invention may include an ointment, a mask, a poultice, a patch, and a transdermal absorbent.
- cyclo-Hispro When the pharmaceutical composition of the present invention is used as a quasi-drug composition, cyclo-Hispro may be added as it is or may be appropriately used in combination with other quasi-drug ingredients according to a conventional method.
- the mixing amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment).
- the contents of the pharmaceutical composition and health functional food composition of the present invention may be applied mutatis mutandis to the quasi-drug composition and quasi-drug of the present invention.
- health functional food includes both the meanings of "functional food” and “health food”.
- the term "functional food” is the same term as food for special health use (FoSHU), and has medical and medical effects processed to efficiently exhibit bioregulatory functions in addition to nutritional supply. It means high food.
- health food refers to food having an active health maintenance or promotion effect compared to general food
- health supplement food refers to food for the purpose of health supplementation.
- functional food, health food, and dietary supplement are preferred.
- the food may be prepared in various forms such as tablets, capsules, powders, granules, liquids, pills, and the like.
- composition As a specific example of such a functional food, by using the composition, it is possible to manufacture a processed food with good storage properties while at the same time being transformed by taking advantage of the characteristics of agricultural products, livestock products or aquatic products.
- the health functional food composition of the present invention may also be prepared in the form of nutritional supplements, food additives, and feed, and is intended for consumption by animals, including humans or livestock.
- Food compositions of this type can be prepared in various forms according to conventional methods known in the art.
- Common foods include, but are not limited to, beverages (including alcoholic beverages), fruits and their processed foods (eg, canned fruit, canned fruit, jam, marmalade, etc.), fish, meat and their processed foods (eg, ham, sausages) corn beef, etc.), breads and noodles (eg udon noodles, soba noodles, ramen, spagate, macaroni, etc.), fruit juice, various drinks, cookies, syrup, dairy products (eg butter, cheese, etc.), edible vegetable oils and fats, margarine , vegetable protein, retort food, frozen food, various seasonings (eg, soybean paste, soy sauce, sauce, etc.) can be prepared by adding cyclo-Hispro.
- the nutritional supplement is not limited thereto, but it can be prepared by adding cyclo-Hispro to capsules, tablets, pills, and the like.
- the health functional food is not limited thereto, but for example, the cyclo-Hispro is prepared in the form of tea, juice, and drink and consumed by liquefying, granulating, encapsulating and powdering so that it can be consumed (health drink). can do.
- the cyclo-Hispro in order to use the cyclo-Hispro in the form of a food additive, it may be prepared and used in the form of a powder or a concentrate.
- it can be prepared in the form of a composition by mixing the cyclo-Hispro with a known active ingredient known to be effective in the prevention or improvement of hypertension or its complications.
- the health drink composition may contain various flavoring agents or natural carbohydrates as an additional component like a conventional drink.
- the above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; It may be a sugar alcohol such as xylitol, sorbitol, or erythritol.
- Sweeteners include natural sweeteners such as taumatin, stevia extract; A synthetic sweetener such as saccharin or aspartame may be used.
- the proportion of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 mL of the composition of the present invention.
- Cyclo-Hispro may be contained as an active ingredient in a food composition for preventing or improving blood pressure lowering or hypertension or its complications, and the amount is an effective amount to obtain the preventive or ameliorating effect, for example, the total weight of the total composition. It is preferably 0.01 to 100% by weight, but is not particularly limited thereto.
- the food composition of the present invention may be prepared by mixing with cyclo-Hispro with other active ingredients known to be effective in lowering blood pressure, or preventing or ameliorating hypertension or its complications.
- the health functional food of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid, pectic acid salts, alginic acid, alginic acid salts, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives , glycerin, alcohol, or a carbonation agent.
- the health food of the present invention may contain fruit for the production of natural fruit juice, fruit juice beverage, or vegetable beverage. These components may be used independently or in combination. The proportion of these additives is not very important, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
- the term "subject” includes any animal (eg, human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig or rodent), but
- the present invention is not limited thereto. These terms do not denote a specific age or gender. Accordingly, adult/adult and neonatal subjects, whether female/female or male/male, as well as fetuses are intended to be included.
- a patient refers to a subject afflicted with a disease or disorder. The term patient includes human and veterinary subjects.
- the description of the composition including the effect of CHP, its administration route, the number of administration, the dosage, and the like is the same as described above, and thus the description thereof will be omitted.
- Cyclo-Hispro (CHP) used in the following Examples was purchased from Bachem and used.
- kidney disease that is, glomerulitis or renal failure, can cause hypertension and play an important role in the development of primary hypertension.
- Chronic renal failure through nephrectomy in rats leads to continued progression of hypertension, uremia, proteinuria, and glomerulosclerosis.
- the first group was set as a normal control group (SHAM) without renal resection and administered with phosphate buffered saline
- the second group was cyclo-his after 5/6 renal resection (5/6 Nx.).
- Phosphate-buffered saline was administered as a disease control group not treated with Pro
- the third group was orally administered with cyclo-Hispro at 35 mg/kg every other day for 8 weeks from 3 days before nephrectomy.
- the experimental animals were calibrated in the holder of a blood pressure meter (BP-2000 blood pressure analysis system, rat platform 2-channel, Visitech Systems, Apex, NC, USA) and then a heating chamber at 37 ° C. ) for 30 minutes, and the systolic blood pressure was measured at least 5 times in the tail artery, and the average value was obtained.
- the significance of the experimental results was verified by performing t-test for each group of the disease control group (Nx), the normal control group, and the cyclo-hispro administration group, and there was a statistically significant difference (**p ⁇ 0.005, *** p ⁇ 0.0005, ****p ⁇ 0.00005).
- the systolic blood pressure of the disease control group (Nx) significantly increased in a time-dependent manner compared to the normal control group (SHAM).
- the systolic blood pressure of the normal control group (SHAM) was 127.8 mmHg and the systolic blood pressure of the disease control group (Nx) was 196.2 mmHg, but the systolic blood pressure of the group administered with cyclo-Hispro was 156.7 mmHg. Therefore, it was confirmed that administration of cyclo-Hispro had a preventive effect on lowering blood pressure.
- a 5/6 nephrectomy model was manufactured in the same manner as in Example 1-1, and 8 mice each were divided into 3 groups. The 1st and 2nd groups were treated the same, but the 3rd group started 2 weeks after the nephrectomy. Cyclo-Hispro was administered orally at 35 mg/kg every other day for 6 weeks.
- Example 1-2 As a result of measuring the blood pressure of the rats of each group in the same manner as in Example 1-2, it was found that the systolic blood pressure of the disease control group (Nx) significantly increased in a time-dependent manner compared to the normal control group (SHAM) as shown in FIG. 2 . could observe. On the other hand, it was confirmed that the systolic blood pressure in the group administered with cyclo-Hispro was significantly reduced than that of the disease control group (Nx).
- the systolic blood pressure of the normal control group was 127.8 mmHg and the systolic blood pressure of the disease control group (Nx) was 196.2 mmHg, but the systolic blood pressure of the group administered with cyclo-Hispro was 171.6 mmHg. Therefore, it was confirmed that the administration of cyclo-Hispro had a therapeutic effect on blood pressure control.
- Human umbilical vein endothelial cells (HUVEC, CRL-1730) were obtained from the American Type Culture Collection (ATCC) and supplemented with EBM-2 basal medium and EGM-2 MV microvascular endothelial growth medium SingleQuots. was purchased from Lonza.
- HUVEC cells were cultured in EBM-2 medium supplemented with EGM-2 MV SingleQuots at 37° C., 5% CO 2 conditions. The medium was replaced every 2-3 days, and subculture was performed at 70-80% confluency.
- HUVEC cells were divided into three groups and treated as shown in Table 1.
- HUVEC cells treated with angiotensin II and CHP were placed in 500 ul of RIPA buffer containing protease and phosphatase inhibitors, and then pulverized using IKA's T10 homogenizer. After standing on ice for 15 minutes, centrifugation was performed at 15,000 rpm at 4°C. The supernatant was collected and the protein concentration was measured by BCA quantitation, and the same amount of samples was separated using the Bolt TM protein gel electrophoresis system, and then transferred to a nitrocellulose membrane.
- the membrane was blocked with 5% skim milk at room temperature for 1 hour, and then the primary antibodies, AT1R (Angiotensin II type I receptor), AT2R (Angiotensin II type 2 receptor), VE-cadherin and ⁇ -actin antibody overnight at 4°C. After washing 3 times for 10 minutes with TBST, the reaction was performed with the secondary antibody at room temperature for 1 hour. After washing 3 times for 10 minutes with TBST, the expression level was measured by reacting with ECL. The size of the appearing band was quantified using the ImageJ program and corrected by dividing the size value of each band by the size value of the ⁇ -actin band. Statistical significance was analyzed using Student's t-test statistical method with angiotensin II-treated control group (Ang II) (*p ⁇ 0.05, **p ⁇ 0.05, ***p ⁇ 0.0005).
- AT1R AT1 receptor
- AT2 AT2R
- VE-cadherin which plays an important role in angiogenesis
- AngII angiotensin II
- CHP increases the expression of angiotensin II receptor 1 (AT1R), which induces vasoconstriction, and decreases the expression of angiotensin II receptor 2 (AT2R), which relaxes blood vessels, thereby exhibiting a blood pressure lowering effect. was confirmed, and this sufficiently proves that CHP can be applied to the treatment of hypertension.
- AT1R angiotensin II receptor 1
- AT2R angiotensin II receptor 2
- SVEC4-10 (CRL-2181), a mouse endothelial cell line, was obtained from ATCC (American Type Culture Collection), and RPMI-1640 medium and FBS were purchased from Hyclone.
- SVEC4-10 cells were cultured at 37° C., 5% CO 2 condition using RPMI-1640 medium containing 10% FBS and 1% penicillin/streptomycin, and subculture was performed every 2 days.
- SVEC4-10 cells were placed in a 6-well plate at 5x10 5 cells and cultured for 24 hours. CHP was treated with 0, 10, 100 and 250 ⁇ M in serum-free medium, respectively, and then cultured at 37° C. and 5% CO 2 conditions for 2 hours. Thereafter, the medium was removed, washed once with cold PBS, and then immediately dissolved using NucleoZOL.
- RNA was extracted according to the manufacturer's total RNA isolation protocol using NucleoZOL (MACHEREY-NAGEL), and 1 ⁇ g of RNA was subjected to reverse transcription polymerase chain reaction using iScript cDNA synthesis kit (Bio-Rad). cDNA was synthesized by Transcription Polymerase Chain Reaction). The synthesized cDNA was analyzed by real-time PCR using iQ SYBR Green Supermix (Bio-Rad) using the primer set of the eNOS gene. At this time, the primer set used was used by requesting synthesis from Bioneer with the nucleotide sequence shown in Table 2.
- HMVEC-L Human Lung Microvascular cells
- ATC American Type Culture Collection
- Silver was purchased from Lonza.
- HUVEC-L cells were cultured in EBM-2 medium supplemented with EGM-2 MV SingleQuots at 37° C., 5% CO 2 condition. The medium was replaced every 2-3 days, and subculture was performed at 70-80% confluency.
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Abstract
Description
그룹 | 처리 |
정상 대조군 (Control) | 비히클 (vehicle) |
양성 대조군 | Ang II |
CHP 처리군 | Ang II 및 CHP |
유전자 | 정방향 프라이머(5'→3') | 서열번호 | 역방향 프라이머(5'→3') | 서열번호 |
eNOS | CCCGGAAAGAGGGATTGTGT | 1 | TGCAACCAATGCTGTAGGCA | 2 |
β-액틴 | GGGAAGGTGACAGCATTG | 3 | ATGAAGTATTAAGGCGGAAGATT | 4 |
Claims (16)
- 사이클로-히스프로 또는 이의 약학적으로 허용가능한 염을 포함하는 혈압 강하용 약학 조성물.
- 제1항에 있어서, 상기 사이클로-히스프로 또는 이의 약학적으로 허용가능한 염은 혈관내피세포에서 다음의 a) 내지 e)로 이루어진 그룹으로부터 선택되는 하나 이상의 활성을 통해 혈압 강하 효과를 나타내는 것인, 혈압 강하용 약학 조성물:a) 제1형 안지오텐신 II 수용체 (Angiotensin II type I receptor) 유전자 또는 단백질 발현의 감소;b) 제2형 안지오텐신 II 수용체 (Angiotensin II type II receptor) 유전자 또는 단백질 발현의 증가;c) VE-카드헤린 (VE-cadherin) 유전자 또는 단백질 발현의 증가;d) eNOS 유전자 또는 단백질 발현의 증가; 및e) NO 생성 증가.
- 사이클로-히스프로 또는 이의 식품학적으로 허용가능항 염을 포함하는 혈압 강하용 건강기능식품 조성물.
- 제3항에 있어서, 상기 사이클로-히스프로 또는 이의 식품학적으로 허용가능한 염은 혈관내피세포에서 다음의 a) 내지 e)로 이루어진 그룹으로부터 선택되는 하나 이상의 활성을 통해 혈압 강하 효과를 나타내는 것인, 혈압 강하용 건강기능식품 조성물:a) 제1형 안지오텐신 II 수용체 (Angiotensin II type I receptor) 유전자 또는 단백질 발현의 감소;b) 제2형 안지오텐신 II 수용체 (Angiotensin II type II receptor) 유전자 또는 단백질 발현의 증가;c) VE-카드헤린 (VE-cadherin) 유전자 또는 단백질 발현의 증가;d) eNOS 유전자 또는 단백질 발현의 증가; 및e) NO 생성 증가.
- 사이클로-히스프로 또는 이의 약학적으로 허용가능한 염을 유효량으로 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, 혈압 강하 방법.
- 제5항에 있어서, 상기 사이클로-히스프로 또는 이의 약학적으로 허용가능한 염은 혈관내피세포에서 다음의 a) 내지 e)로 이루어진 그룹으로부터 선택되는 하나 이상의 활성을 통해 혈압 강하 효과를 나타내는 것인, 혈압 강하 방법:a) 제1형 안지오텐신 II 수용체 (Angiotensin II type I receptor) 유전자 또는 단백질 발현의 감소;b) 제2형 안지오텐신 II 수용체 (Angiotensin II type II receptor) 유전자 또는 단백질 발현의 증가;c) VE-카드헤린 (VE-cadherin) 유전자 또는 단백질 발현의 증가;d) eNOS 유전자 또는 단백질 발현의 증가; 및e) NO 생성 증가.
- 혈압강하제의 제조 시 사이클로-히스프로 또는 이의 약학적으로 허용가능한 염의 용도.
- 제7항에 있어서, 상기 사이클로-히스프로 또는 이의 약학적으로 허용가능한 염은 혈관내피세포에서 다음의 a) 내지 e)로 이루어진 그룹으로부터 선택되는 하나 이상의 활성을 통해 혈압 강하 효과를 나타내는 것인, 용도:a) 제1형 안지오텐신 II 수용체 (Angiotensin II type I receptor) 유전자 또는 단백질 발현의 감소;b) 제2형 안지오텐신 II 수용체 (Angiotensin II type II receptor) 유전자 또는 단백질 발현의 증가;c) VE-카드헤린 (VE-cadherin) 유전자 또는 단백질 발현의 증가;d) eNOS 유전자 또는 단백질 발현의 증가; 및e) NO 생성 증가.
- 사이클로-히스프로 또는 이의 약학적으로 허용가능한 염을 포함하는 고혈압 또는 이의 합병증의 예방 또는 치료용 약학 조성물.
- 제9항에 있어서, 상기 합병증은 동맥경화, 관상동맥질환, 심근경색, 심부전증, 협심증, 말초혈액순환장애, 혈관협착, 뇌졸중, 뇌경색, 뇌출혈, 허혈성 뇌질환, 신부전증, 사구체염, 당뇨, 당뇨병성 신증, 당뇨병성 망막병증, 단백뇨, 요독증, 부종, 눈의 혈관 협착으로 인한 시력 장애 및 녹내장으로 이루어진 군에서 선택되는 것인, 고혈압 또는 이의 합병증 예방 또는 치료용 약학 조성물.
- 사이클로-히스프로 또는 이의 식품학적으로 허용가능한 염을 포함하는 고혈압 또는 이의 합병증 예방 또는 개선용 건강기능식품 조성물.
- 제11항에 있어서, 상기 합병증은 동맥경화, 관상동맥질환, 심근경색, 심부전증, 협심증, 말초혈액순환장애, 혈관협착, 뇌졸중, 뇌경색, 뇌출혈, 허혈성 뇌질환, 신부전증, 사구체염, 당뇨, 당뇨병성 신증, 당뇨병성 망막병증, 단백뇨, 요독증, 부종, 눈의 혈관 협착으로 인한 시력 장애 및 녹내장으로 이루어진 군에서 선택되는 것인, 고혈압 또는 이의 합병증 예방 또는 개선용 건강기능식품 조성물.
- 사이클로-히스프로 또는 이의 약학적으로 허용가능한 염을 유효량으로 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, 고혈압 또는 이의 합병증 예방 또는 치료 방법.
- 제13항에 있어서, 상기 합병증은 동맥경화, 관상동맥질환, 심근경색, 심부전증, 협심증, 말초혈액순환장애, 혈관협착, 뇌졸중, 뇌경색, 뇌출혈, 허혈성 뇌질환, 신부전증, 사구체염, 당뇨, 당뇨병성 신증, 당뇨병성 망막병증, 단백뇨, 요독증, 부종, 눈의 혈관 협착으로 인한 시력 장애 및 녹내장으로 이루어진 군에서 선택되는 것인, 고혈압 또는 이의 합병증 예방 또는 치료 방법.
- 고혈압 또는 이의 합병증의 예방 또는 치료를 위한 약제의 제조 시 사이클로-히스프로 또는 이의 약학적으로 허용가능한 염의 용도.
- 제15항에 있어서, 상기 합병증은 동맥경화, 관상동맥질환, 심근경색, 심부전증, 협심증, 말초혈액순환장애, 혈관협착, 뇌졸중, 뇌경색, 뇌출혈, 허혈성 뇌질환, 신부전증, 사구체염, 당뇨, 당뇨병성 신증, 당뇨병성 망막병증, 단백뇨, 요독증, 부종, 눈의 혈관 협착으로 인한 시력 장애 및 녹내장으로 이루어진 군에서 선택되는 것인, 용도.
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CA3172267A CA3172267A1 (en) | 2020-03-20 | 2021-03-19 | Use of cyclo-hispro (chp) for lowering blood pressure |
EP21770955.9A EP4122484A4 (en) | 2020-03-20 | 2021-03-19 | USE OF CYCLO-HIS-PRO (CHP) FOR LOWERING BLOOD PRESSURE |
JP2022556604A JP2023518955A (ja) | 2020-03-20 | 2021-03-19 | 血圧降下のためのchp(シクロ-ヒスプロ)の用途 |
CN202180022746.0A CN115942949A (zh) | 2020-03-20 | 2021-03-19 | 用于降血压的chp的应用 |
BR112022018707A BR112022018707A2 (pt) | 2020-03-20 | 2021-03-19 | Composição farmacêutica, composição alimentícia funcional saudável e uso de ciclo-hispro ou um sal farmaceuticamente aceitável do mesmo |
US17/912,942 US20230165855A1 (en) | 2020-03-20 | 2021-03-19 | Use of cyclo-hispro (chp) for lowering blood pressure |
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KR (1) | KR102621956B1 (ko) |
CN (1) | CN115942949A (ko) |
BR (1) | BR112022018707A2 (ko) |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080242621A1 (en) * | 2005-12-09 | 2008-10-02 | Serombio Co., Ltd. | Yeast hydrolysate containing cyclo-his-pro and method of making and using the same |
KR20120089970A (ko) * | 2011-01-07 | 2012-08-16 | 대구대학교 산학협력단 | 바실러스 속 kh-15의 콩 발효물을 유효성분으로 포함하는 당뇨병 예방 및 치료용 조성물 |
KR20130006170A (ko) | 2011-07-08 | 2013-01-16 | 대구대학교 산학협력단 | CHP(cyclo(His-Pro))를 고농도로 함유한 대두 가수분해물을 포함하는 혈당 조절용 조성물 |
KR20140101974A (ko) * | 2013-02-13 | 2014-08-21 | 강원대학교산학협력단 | 라폰티신을 유효성분으로 포함하는 혈관 질환의 예방 또는 치료용 조성물 |
KR20180008305A (ko) * | 2016-07-13 | 2018-01-24 | 주식회사 노브메타파마 | 사이클로 히스티딘-프롤린을 유효성분으로 포함하는 세포 보호용 조성물 |
KR102133151B1 (ko) | 2019-03-28 | 2020-07-13 | 주식회사 노브메타파마 | Chp(사이클로-히스프로)를 포함하는 복막 섬유증의 예방, 개선 또는 치료용 조성물 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7144865B2 (en) * | 2003-01-31 | 2006-12-05 | The United States Of America As Represented By The Department Of Veterans Affairs | Compositions and methods for treating obesity |
KR20190074746A (ko) * | 2017-12-20 | 2019-06-28 | 주식회사 노브메타파마 | 시클로-히스프로를 유효성분으로 포함하는 당뇨병 예방 또는 치료용 약제학적 제제 |
-
2021
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- 2021-03-19 WO PCT/KR2021/003424 patent/WO2021187942A1/ko unknown
- 2021-03-19 BR BR112022018707A patent/BR112022018707A2/pt unknown
- 2021-03-19 US US17/912,942 patent/US20230165855A1/en active Pending
- 2021-03-19 EP EP21770955.9A patent/EP4122484A4/en active Pending
- 2021-03-19 JP JP2022556604A patent/JP2023518955A/ja active Pending
- 2021-03-19 KR KR1020210036268A patent/KR102621956B1/ko active IP Right Grant
- 2021-03-19 CN CN202180022746.0A patent/CN115942949A/zh active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080242621A1 (en) * | 2005-12-09 | 2008-10-02 | Serombio Co., Ltd. | Yeast hydrolysate containing cyclo-his-pro and method of making and using the same |
KR20120089970A (ko) * | 2011-01-07 | 2012-08-16 | 대구대학교 산학협력단 | 바실러스 속 kh-15의 콩 발효물을 유효성분으로 포함하는 당뇨병 예방 및 치료용 조성물 |
KR20130006170A (ko) | 2011-07-08 | 2013-01-16 | 대구대학교 산학협력단 | CHP(cyclo(His-Pro))를 고농도로 함유한 대두 가수분해물을 포함하는 혈당 조절용 조성물 |
KR20140101974A (ko) * | 2013-02-13 | 2014-08-21 | 강원대학교산학협력단 | 라폰티신을 유효성분으로 포함하는 혈관 질환의 예방 또는 치료용 조성물 |
KR20180008305A (ko) * | 2016-07-13 | 2018-01-24 | 주식회사 노브메타파마 | 사이클로 히스티딘-프롤린을 유효성분으로 포함하는 세포 보호용 조성물 |
KR102133151B1 (ko) | 2019-03-28 | 2020-07-13 | 주식회사 노브메타파마 | Chp(사이클로-히스프로)를 포함하는 복막 섬유증의 예방, 개선 또는 치료용 조성물 |
KR102140910B1 (ko) | 2019-03-28 | 2020-08-04 | 주식회사 노브메타파마 | Chp(사이클로-히스프로)를 포함하는 섬유증의 예방, 개선 또는 치료용 조성물 |
Non-Patent Citations (7)
Title |
---|
"Remingion's Pharmaceutical Sience", 1975, MACK PUBLISHING COMPANY, pages: 18042 |
"Remington's Pharmaceutical Sciences", 1995, MACK PUBLISHING |
ELENA KASCHINATHOMAS UNGER, BLOOD PRESS, vol. 12, no. 2, 2003, pages 70 - 88 |
LE TH ET AL., HYPERTENSION, vol. 42, no. 4, 2003, pages 507 - 514 |
See also references of EP4122484A4 |
ULRICH FORSTERMANNTHOMAS MUNZEL, CIRCULATION, vol. 113, 2006, pages 1708 - 1714 |
ZHU J, MOL BRAIN, 20 September 2016 (2016-09-20) |
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BR112022018707A2 (pt) | 2022-11-01 |
KR20210117986A (ko) | 2021-09-29 |
KR102621956B1 (ko) | 2024-01-10 |
CN115942949A (zh) | 2023-04-07 |
EP4122484A4 (en) | 2024-03-27 |
JP2023518955A (ja) | 2023-05-09 |
CA3172267A1 (en) | 2021-09-23 |
US20230165855A1 (en) | 2023-06-01 |
EP4122484A1 (en) | 2023-01-25 |
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