Angiotensin II1 receptor inhibitors, antihypertensive agents, and agents for the prevention and / or improvement of hypertension.

Abstract

To provide a novel angiotensin II type 1 receptor inhibitor, and further to provide a blood pressure lowering agent, as well as to provide an agent for preventing and / or improving hypertension.SOLUTION: Provided are: an angiotensin II type 1 receptor inhibitor containing propolis from Hawaii, USA and / or propolis from Taiwan; an angiotensin II type 1 receptor inhibitor containing propolis derived from a plant of Macaranga; and a blood pressure lowering agent and an agent for preventing and / or improving hypertension, each containing the angiotensin II type 1 receptor inhibitor.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an angiotensin II type 1 receptor inhibitor, a hypotensive agent, and a preventive and / or ameliorative agent for hypertension. More specifically, it relates to an angiotensin II type 1 receptor inhibitor, a hypotensive agent, and a preventive and / or ameliorative agent for hypertension, which contain propolis.

Background Art

[0002] In Japan, the number of patients with hypertension is approximately 10 million (in 2017), the annual medical cost is approximately 1.8 trillion yen (in 2017), and the number of deaths due to hypertension is approximately 9,600 (in 2017). Therefore, there is a demand for foods, drinks, and pharmaceuticals having a hypotensive effect that are useful and safe for the prevention and treatment of hypertension.

[0003] The renin-angiotensin system is involved in the homeostasis regulation functions such as systemic blood pressure, body water volume, and body electrolyte balance. Angiotensin II is a peptide having a strong hypertensive effect, and it is known that angiotensin II exhibits its action through the angiotensin II receptor on the cell membrane.

[0004] The angiotensin II receptor (ATR) is a G protein-coupled receptor that plays a crucial role in regulating blood pressure. There are two types of ATR receptors: type 1 (sometimes referred to as "AT1"), which raises blood pressure, and type 2 (AT2), which lowers it. Blood pressure is regulated by the cooperation of these two types of receptors, and this coordination is controlled by the bioactive peptide angiotensin II. Whether blood pressure rises or falls depends on which receptor angiotensin II binds to. Therefore, angiotensin II is a target for the treatment of hypertension, and angiotensin receptor antagonists, which inhibit its binding, are widely used as medications for hypertension. Hypertension, also known as a lifestyle-related disease, is a significant risk factor for life-threatening conditions such as cerebral infarction, myocardial infarction, and arteriosclerosis (https: / / www.kyoto-u.ac.jp / sites / default / files / embed / jaresearchresearch_results2018documents180702_201.pdf).

[0005] Propolis is a gelatinous substance formed by honeybees mixing tree sap, plant buds, and extracts with beeswax and other materials. It is known to have antibacterial, antioxidant, anti-inflammatory, antitumor, and anti-allergic properties.

[0006] Because the composition of propolis is influenced by the type and proportion of the source plants from which it is made, it is known that the types, amounts, and physiological activity of active ingredients in propolis can vary considerably depending on the country or region from which it is harvested.

[0007] In recent years, research has been conducted on the components of propolis from different regions. For example, in Brazilian propolis, which uses Baccharis dracuifolia as its main source plant, cinnamic acid derivatives such as p-coumaric acid, artepillin C, dorupanin, and baccharin have been detected as the main components. On the other hand, in propolis from China, Europe, and Australia, which use poplar as their source plant, flavonoids such as chrysin and galangin have been detected as the main components.

[0008] Patent Document 1 reports an angiotensin II receptor antagonist composition containing propolis characterized by containing quercetin, p-coumaric acid, and artepillin C, and further containing chrysin, galangin, or caffeic acid phenethyl ester. Examples of propolis origins include Brazilian propolis, Chinese propolis, Australian propolis, Uruguayan propolis, and Japanese propolis, with a preferred example being a mixture of Brazilian and Chinese propolis. Quercetin derivatives, p-coumaric acid, and artepillin C are mainly found in Brazilian propolis, while chrysin, galangin, and caffeic acid phenethyl ester are found in Chinese and Uruguayan propolis. Therefore, these propolis are known to contain a large amount of polyphenols. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] Japanese Patent Publication No. 2004-161664 [Overview of the project] [Problems that the invention aims to solve]

[0010] The present invention aims to provide a novel angiotensin II1 receptor inhibitor. Furthermore, it aims to provide an antihypertensive agent and an agent for the prevention and / or improvement of hypertension. [Means for solving the problem]

[0011] Since propolis is made from plants collected by honeybees, its composition varies depending on the region of origin, and therefore its effects are expected to differ depending on the region. To achieve the above objective, the inventors conducted diligent research and discovered that propolis from Hawaii, USA, Taiwan, and propolis derived from plants of the genus *Macaranga*, all originating from different plants, exhibit superior angiotensin II1 receptor inhibitory activity compared to Brazilian propolis. This led to the completion of the present invention.

[0012] In other words, the present invention relates to the following [1] to [7]. [1] An angiotensin II1 receptor inhibitor containing propolis from Hawaii, USA and / or Taiwan. [2] An angiotensin II1 receptor inhibitor containing propolis derived from plants of the genus Panax. A blood pressure lowering agent containing an angiotensin II1 receptor inhibitor as described in [3][1]. A blood pressure lowering agent containing an angiotensin II1 receptor inhibitor as described in [4][2]. A prophylactic and / or ameliorative agent for hypertension, comprising an angiotensin II1 receptor inhibitor as described in [5][1]. A prophylactic and / or ameliorative agent for hypertension, comprising an angiotensin II1 receptor inhibitor as described in [6][2]. [7] A food or beverage, pharmaceutical or quasi-drug, as described in any one of items [1] to [6]. [Effects of the Invention]

[0013] Propolis from Hawaii, USA, propolis from Taiwan, and propolis derived from plants of the genus Panax have excellent angiotensin II1 receptor inhibitory activity and are therefore useful as active ingredients in angiotensin II1 receptor inhibitors, antihypertensive agents, and preventive and / or ameliorative agents for hypertension.

[0014] Furthermore, since propolis has been used as a food ingredient for a long time, it is highly safe. [Modes for carrying out the invention]

[0015] The following describes in detail embodiments for carrying out the present invention, but the present invention is not limited to the following embodiments.

[0016] In this specification, "comprise" encompasses both the meanings of "essentially consist of" and "consist of."

[0017] Furthermore, in this specification, "angiotensin" means angiotensin.

[0018] In this specification, the term "angiotensin II type 1 receptor inhibitory effect" refers to the effect of antagonizing angiotensin II and inhibiting its binding to the angiotensin II type 1 receptor, and is also called angiotensin II type 1 receptor antagonistic effect. The angiotensin II type 1 receptor inhibitory effect can be evaluated according to known methods. For example, using cells expressing the angiotensin II type 1 receptor, the amount of angiotensin II bound when angiotensin II is added can be measured, and the measured values ​​with and without the sample can be compared for evaluation.

[0019] The angiotensin II1 receptor inhibitor of the present invention contains propolis from Hawaii, USA and / or Taiwan as an active ingredient.

[0020] In another embodiment, the angiotensin II1 receptor inhibitor of the present invention contains propolis derived from plants of the genus Panax as an active ingredient.

[0021] Propolis is a resinous or waxy substance that constitutes the nest wall of a honeybee hive, and is a substance made by mixing the new shoots and resins of plants collected by honeybees with the saliva of bees. Propolis can be obtained as a beekeeping product, for example, according to a conventional method. In one embodiment of the present invention, propolis from Hawaii, United States of America and Taiwan is used. In addition to Hawaii, United States of America and Taiwan, propolis from other production areas such as China, European countries, Russia, Oceania, and America may also be combined and used. Propolis can be used alone or in combination with those from two or more production areas.

[0022] The propolis used in one embodiment of the present invention is not particularly limited as long as it is collected in Hawaii, United States of America and Taiwan. Among them, as propolis from Hawaii, United States of America and Taiwan, those whose original plant is a plant of the genus Macaranga are preferable.

[0023] In another embodiment of the present invention, propolis is propolis derived from a plant of the genus Macaranga.

[0024] The propolis used in another embodiment of the present invention is not particularly limited as long as it is derived from the above-mentioned plants. For example, it may be derived from any production area such as Taiwan, European countries, Russia, Oceania, and America. Among them, propolis from Hawaii, United States of America and Taiwan is preferable.

[0025] The propolis in this invention may be, for example, raw propolis, or a propolis processed product obtained by subjecting raw propolis to some kind of treatment. The propolis processed product may be, for example, a propolis raw material that has been subjected to treatment such as crushing, extraction, concentration or powdering of the extract, or granulation of the powder, or it may be the extraction residue remaining after extraction. That is, the propolis processed product may be, for example, crushed propolis, extract, concentrated extract, extract powder, extract granules, extraction residue, etc. The extraction may be, for example, water extraction, hydrophilic organic solvent extraction, supercritical fluid extraction, etc. Examples of hydrophilic organic solvents include ethanol, glycerin, 1,3-butylene glycol, etc. The propolis extract may be obtained by extracting from raw propolis, or it may be obtained by further extraction from the residue after extraction. In addition, one type of extraction solvent may be used, or two or more types may be arbitrarily combined and used as a mixed solvent. There may be one treatment method, or two or more may be combined. As a propolis treatment product, a propolis hydrophilic organic solvent extract is preferred because it efficiently and effectively extracts the active ingredients of propolis in a balanced manner in a short time. A propolis ethanol extract is preferred as the propolis treatment product.

[0026] Propolis extracts include recovered extracts (including those further purified as needed), concentrated extracts, and solids obtained by freeze-drying, spray-drying, or other methods from which the solvent has been removed from the extract. Here, concentration, freeze-drying, and spray-drying of the extract can be carried out according to conventional methods. Propolis extracts in the present invention also include powders obtained by pulverizing such extracts, and granular forms obtained by granulating such powders.

[0027] The amount of propolis in the angiotensin II1 receptor inhibitor of the present invention is not particularly limited as long as the effects of the present invention are obtained, and can be appropriately adjusted depending on the final form, etc., relative to the total amount of solids in the angiotensin II1 receptor inhibitor, for example, 0.00001% by mass or more, 0.0001% by mass or more, 0.001% by mass or more, 0.01% by mass or more, 0.1% by mass or more, 0.5% by mass or more, 1% by mass or more, 3% by mass or more, 5% by mass or more, 7% by mass or more, 10% by mass or more, 15% by mass or more % or more, 20 mass% or more, 30 mass% or more, 40 mass% or more, 50 mass% or more, 60 mass% or more, 70 mass% or more, 80 mass% or more, or 90 mass% or more, and 100 mass% or less, 90 mass% or less, 80 mass% or less, 70 mass% or less, It may be 60% by mass or less, 55% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 7% by mass or less, 5% by mass or less, 3% by mass or less, 1% by mass or less, or 0.5% by mass or less.

[0028] The angiotensin II1 receptor inhibitor of the present invention can also be administered to humans to inhibit the binding of angiotensin II to the angiotensin II1 receptor. The angiotensin II1 receptor inhibitor of the present invention may be administered orally or parenterally. Oral administration includes enteral administration, and parenteral administration includes topical administration, and in particular transdermal administration.

[0029] Furthermore, when the angiotensin II1 receptor inhibitor of the present invention is administered orally, the dosage may vary depending on the active ingredient, composition, form, and method and amount of application. For example, if the active ingredient is propolis, a daily dose of 1 μg to 1,000 mg (based on dry solid content) can be used for an adult weighing 60 kg, preferably 3 μg to 500 mg, more preferably 5 μg to 250 mg, and even more preferably 7 μg to 100 mg. The dosage can be appropriately increased or decreased depending on factors such as the health condition of the person taking the medication, the method of administration, the type of active ingredient, and combinations with other agents.

[0030] The angiotensin II1 receptor inhibitor of the present invention may be administered once a day, or divided into multiple doses, such as twice a day or three times a day, as long as the effective daily dose is within the range described above. The angiotensin II1 receptor inhibitor of the present invention provides immediate effects after administration, but continuous administration for 1 to 4 weeks, 1 month or more, 6 months or more, or 1 year or more is preferable because it allows for a longer-lasting effect.

[0031] The angiotensin II1 receptor inhibitor of the present invention can be used as food and beverages (especially food and beverages intended for health promotion, health maintenance, etc. (e.g., health foods, functional foods, nutritional compositions, nutritional supplements, supplements, health foods, foods for specified health uses, nutrient function foods, or foods with functional claims)), quasi-drugs, pharmaceuticals, etc. Furthermore, the angiotensin II1 receptor inhibitor of the present invention also encompasses the meaning of additives that confer angiotensin II1 receptor inhibitory activity.

[0032] The above-mentioned food and beverages may use the above-mentioned propolis as is, or, as necessary, may be combined with minerals, vitamins, flavonoids, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, disintegrants, lubricants, colorants, flavorings, stabilizers, gelling agents, preservatives, sustained-release regulators, surfactants, solvents, humectants, etc.

[0033] Food and beverages include all foods and beverages that can be consumed by animals (including humans). The types of food and beverages are not particularly limited and include, for example, dairy products; fermented foods (yogurt, etc.); beverages (soft drinks such as coffee, juice, and tea, milk drinks, lactic acid bacteria drinks, lactic acid bacteria drinks, yogurt drinks, carbonated drinks, sake, Western liquors, fruit wines, etc.); spreads (custard cream, etc.); pastes (fruit paste, etc.); Western sweets (chocolate, donuts, pies, cream puffs, gum, gummies, jelly, candy, cookies, cakes, puddings, etc.); Japanese sweets (daifuku, mochi, manju, castella, anmitsu, yokan, etc.); frozen desserts (ice cream, ice pops, sherbet, etc.); food products (curry, gyudon, zosui, miso soup, soup, meat sauce, pasta, pickles, jam, etc.); and seasonings (dressings, furikake, umami seasonings, soup bases, etc.).

[0034] The manufacturing method for food and beverages is not particularly limited and may be carried out according to publicly known methods as appropriate.

[0035] There are no particular restrictions on the dosage unit form when used as a supplement; it can be selected as appropriate. Examples include chewable tablets, lozenges, capsules, granules, liquids, powders, syrups, pastes, drinks, gummies, etc.

[0036] The above-mentioned pharmaceuticals may use only the propolis, or they may be used in combination with other medicinal ingredients listed in the Japanese Pharmacopoeia, such as vitamins and herbal medicines.

[0037] When preparing the angiotensin II1 receptor inhibitor of the present invention as a pharmaceutical product, the above-mentioned propolis can be prepared together with pharmaceutical-acceptable components in the form of tablets (including uncoated tablets, sugar-coated tablets, effervescent tablets, film-coated tablets, chewable tablets, lozenges, etc.), capsules, pills, powders, granules, liquids, suspensions, emulsions, syrups, pastes, and injections (including cases where it is prepared as a liquid by mixing it with distilled water or an infusion solution such as an amino acid solution or an electrolyte solution at the time of use) to create a pharmaceutical preparation.

[0038] The administration of pharmaceuticals may be local or systemic. There are no particular restrictions on the method of administration, and they may be administered orally or parenterally. Parenteral administration routes include subcutaneous, intradermal, intramuscular, intraperitoneal, intravenous or intra-arterial administration, and transdermal administration.

[0039] In addition to propolis, the pharmaceutical product of the present invention may contain, as needed, pharmaceutically acceptable ingredients such as excipients, binders, disintegrants, lubricants, colorants, suspending agents, thickeners, antioxidants, absorption enhancers, pH adjusters, preservatives, stabilizers, surfactants, sweeteners, flavoring agents, and fragrances.

[0040] Furthermore, the pharmaceuticals of this invention also include quasi-drugs.

[0041] The angiotensin II1 receptor inhibitor of the present invention described above is applicable to mammals, including humans (preferably humans).

[0042] The propolis from Hawaii, USA, Taiwan, or derived from plants of the genus *Macaroni*, which are contained as active ingredients in the angiotensin II1 receptor inhibitor of the present invention, have angiotensin II1 receptor inhibitory activity, as shown in the examples described later, and are therefore useful as active ingredients in angiotensin II1 receptor inhibitors. The propolis from Hawaii, USA, Taiwan, or derived from plants of the genus *Macaroni* have the effect of lowering blood pressure by inhibiting the binding of angiotensin II to the angiotensin II1 receptor, and therefore can be used as an active ingredient in antihypertensive agents and preventive and / or ameliorative agents for hypertension. The antihypertensive agent of the present invention may have not only an antihypertensive effect but also an antihypertensive effect. The angiotensin II1 receptor inhibitor of the present invention can also be expected to have an anti-atherosclerotic effect. The above description concerning angiotensin II1 receptor inhibitors can be applied to antihypertensive agents and preventive and / or ameliorative agents for hypertension. In other words, the content and dosage of propolis in the blood pressure lowering agent and the agent for preventing and / or improving hypertension of the present invention are the same as described above.

[0043] The blood pressure lowering agent and the agent for preventing and / or improving hypertension of the present invention can be used as food and beverages (especially food and beverages intended for health, health maintenance, and promotion (e.g., health foods, functional foods, nutritional compositions, nutritional supplements, supplements, health foods, foods for specified health uses, nutrient function foods, or foods with functional claims)), quasi-drugs, pharmaceuticals, etc. Furthermore, the blood pressure lowering agent and the agent for preventing and / or improving hypertension of the present invention also encompasses the meaning of additives that impart blood pressure lowering effects and effects of preventing and / or improving hypertension. The same applies to food and beverages, quasi-drugs, and pharmaceuticals as described above.

[0044] Furthermore, the angiotensin II1 receptor inhibitor, antihypertensive agent, and preventive and / or ameliorative agent for hypertension of the present invention use propolis, which has been conventionally used as a food ingredient, and therefore has high safety. [Examples]

[0045] The present invention will be described more specifically below based on examples. However, the present invention is not limited to the following examples.

[0046] Example 1 (Preparation of propolis extract) The pulverized raw propolis was mixed with 80% ethanol by volume and stirred at room temperature for 24 hours to extract the extract. The extract was filtered through filter paper (No. 2, manufactured by Advantec Toyo Co., Ltd.) and then concentrated under reduced pressure using an evaporator. The concentrated liquid was freeze-dried to obtain propolis extract.

[0047] Test Example 1 (Method for measuring angiotensin IIAT1 inhibitory activity) Human recombinant AT1 expressed in CHO-K1 cells was used in Tris-HCl buffer (Tris Hydrochloride Acid Buffer) at pH 7.4. 0.3 μg of human recombinant AT1 was incubated with 0.02 nM [125I](Sar1,Ile8)-Angiotensin II and propolis extracts (derived from plants of the genus Panax) from Hawaii, USA and Taiwan at 37°C for 180 minutes. After filtering and washing the membrane tissue, the amount of specifically bound [125I](Sar1,Ile8)-angiotensin II was counted. The amount of bound [125I](Sar1,Ile8)-angiotensin II was compared between the cases with and without propolis extract, and the inhibition rate was calculated. Table 1 shows the angiotensin II AT1 inhibition rates of the propolis samples obtained from each region.

[0048] [Table 1]

[0049] Unlike the Brazilian propolis disclosed in Japanese Patent Publication No. 2004-161664, propolis from Hawaii, USA, and Taiwan originates from plants of the genus *Macaroni* and exhibits superior angiotensin IIAT1 inhibitory activity, as confirmed in Table 1.

Claims

1. An angiotensin II1 receptor inhibitor containing propolis derived from plants of the genus *Macaranga*.

2. The agent according to claim 1, wherein the propolis is propolis from Hawaii, United States and / or propolis from Taiwan.

3. A blood pressure lowering agent comprising an angiotensin II1 receptor inhibitor as described in claim 1.

4. An agent for preventing and / or improving hypertension, comprising an angiotensin II1 receptor inhibitor as described in claim 1.

5. The agent according to any one of claims 1 to 4, which is a food or beverage, a pharmaceutical product, or a quasi-drug.

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