Cyclic amp phosphodiesterase activity inhibitor

Abstract

To find a highly safe natural product with cyclic AMP phosphodiesterase activity inhibitory action, and to provide a cyclic AMP phosphodiesterase activity inhibitor that contains the same as an active ingredient.SOLUTION: A compound represented by the formula (I) in the figure, and black ginger extract and / or catechins are used as active ingredients of the cyclic AMP phosphodiesterase activity inhibitor.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an inhibitor of cyclic AMP phosphodiesterase activity.

Background Art

[0002] In recent years, due to lifestyle habits such as overeating and lack of exercise, body fat has increased and obesity has become more common. Such an increase in obesity is seen not only in humans but also in pets and livestock. Obesity is a cause of adult diseases such as hyperlipidemia and arteriosclerosis, and thus is not only a problem in terms of beauty but also a major problem in terms of health.

[0003] Here, cyclic AMP (cAMP) is known to be involved in lipolysis in vivo. cAMP activates lipase present in vivo, and the activated lipase decomposes fat into fatty acids and glycerol. However, when cAMP phosphodiesterase is activated, the decomposition of cAMP is induced and the activation of lipase is inhibited. Therefore, it is considered that by inhibiting the activity of cAMP phosphodiesterase, the amount of cAMP in cells can be increased and the decomposition of fat can be promoted.

[0004] In addition, platelet aggregation that causes an inflammatory reaction is related to the concentration of cAMP in platelets, and it is known that when cAMP is decomposed by cAMP phosphodiesterase and the concentration of cAMP decreases, platelets tend to aggregate. Therefore, it is considered that by suppressing the action of cAMP phosphodiesterase and preventing the decrease in cAMP concentration, platelet aggregation can be prevented, and thereby allergic diseases, inflammatory diseases, etc. can be prevented, treated or improved. Tubermoside I (see Patent Document 1) etc. are known as those having an inhibitory action on cAMP phosphodiesterase activity.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

[0006] The present invention aims to provide a cyclic AMP phosphodiesterase activity inhibitor that uses a naturally occurring product with high safety as its active ingredient, by identifying such product. [Means for solving the problem]

[0007] To solve the above problems, the cyclic AMP phosphodiesterase activity inhibitor according to the present invention is characterized by comprising a compound represented by the following formula (I) and black ginger extract and / or catechins as active ingredients.

[0008] [ka] [Effects of the Invention]

[0009] According to the present invention, a cyclic AMP phosphodiesterase activity inhibitor having an effect can be provided by using a compound represented by the above formula (I) and black ginger extract and / or catechins as active ingredients. [Modes for carrying out the invention]

[0010] Embodiments of the present invention will be described below. The cyclic AMP (cAMP) phosphodiesterase activity inhibitor according to this embodiment contains a compound represented by the following formula (I) and black ginger extract and / or catechins as active ingredients.

[0011] [ka]

[0012] The compound represented by formula (I) above is a cinnamic acid derivative also known as 3-(4-Hydroxy-3-methoxyphenyl)propionic acid. Hereinafter, in this specification, the compound represented by formula (I) above may be referred to as compound (I).

[0013] Compound (I) can be produced, for example, by isolating and purifying a plant extract containing compound (I). In this case, such a plant extract containing compound (I) can be obtained by methods commonly used for plant extraction. Examples of plants containing compound (I) include rice, barley, wheat, soybeans, adzuki beans, and corn.

[0014] Compound (I) can also be produced by fermenting, for example, 3-(4-Hydroxy-3-methoxyphenyl)propenoic Acid or its derivatives, or a composition containing them (e.g., crushed or extracted plant material), with a microorganism possessing phenolic acid reductase to convert 3-(4-Hydroxy-3-methoxyphenyl)propenoic Acid to Compound (I), and then extracting, isolating, and purifying the resulting ferment. Examples of compositions containing 3-(4-Hydroxy-3-methoxyphenyl)propenoic Acid include crushed and extracted plant materials such as coffee, wheat, corn, tomato, mate, mugwort, and burdock. Furthermore, since 3-(4-Hydroxy-3-methoxyphenyl)propenoic Acid is a component of lignin in woody and herbaceous plants, lignin or a composition containing it may be used as a fermentation raw material. On the other hand, examples of microorganisms possessing phenolic acid reductase include lactic acid bacteria such as Lactobacillus plantarum, Lactobacillus fermentum, Lactobacillus gasseri, Lactobacillus johnsonii, Lactobacillus crispatus, Lactobacillus acidophilus, Lactobacillus amylovorus, Lactobacillus delbrueckii, Lactobacillus buchneri, Lactobacillus kefiranofaciens, Lactobacillus gallinarum, and Enterococus faecalis.

[0015] The method for extracting, isolating, and purifying compound (I) from the above-mentioned plants or fermented products is not particularly limited and can be carried out according to conventional methods. For example, the extraction process can be carried out by drying the above-mentioned plants or fermented products as extraction raw materials, then crushing them as is or using a crusher, and then subjecting them to extraction with an extraction solvent. Drying can be carried out in the sun or using a commonly used drying oven. Alternatively, the raw materials may be pretreated by degreasing with a non-polar solvent such as hexane before being used as extraction raw materials. Pretreatment such as degreasing allows for more efficient extraction with a polar solvent.

[0016] As the extraction solvent, it is preferable to use a polar solvent, such as water or a hydrophilic organic solvent. It is preferable to use these individually or in combination of two or more at room temperature or below the boiling point of the solvent.

[0017] Water that can be used as an extraction solvent includes pure water, tap water, well water, mineral water, mineral water, hot spring water, spring water, fresh water, etc., as well as water that has undergone various treatments. Treatments applied to water include, for example, purification, heating, sterilization, filtration, ion exchange, osmotic pressure adjustment, buffering, etc. Therefore, in this embodiment, water that can be used as an extraction solvent also includes purified water, hot water, ion-exchanged water, physiological saline, phosphate buffer, phosphate-buffered physiological saline, etc.

[0018] Examples of hydrophilic organic solvents that can be used as extraction solvents include lower aliphatic alcohols having 1 to 5 carbon atoms, such as methanol, ethanol, propyl alcohol, and isopropyl alcohol; polyhydric alcohols having 2 to 5 carbon atoms, such as 1,3-butylene glycol, propylene glycol, and glycerin; and lower aliphatic ketones, such as acetone and methyl ethyl ketone.

[0019] When using a mixed solution of two or more polar solvents as an extraction solvent, the mixing ratio is arbitrary and can be adjusted as appropriate. For example, when using a mixed solution of water and a hydrophilic organic solvent as an extraction solvent, it can be mixed and used at any ratio, that is, exceeding 0:100 and less than 100:0 (volume ratio, hereinafter expressed in the same way), and can be adjusted as appropriate. For example, when using a mixed solution of water and a lower aliphatic alcohol as an extraction solvent, the mixing ratio (volume ratio) of water and the lower aliphatic alcohol can be 9:1 or more, and further 7:3 or more, or the mixing ratio of water and the lower aliphatic alcohol can be 1:9 or less, and further 2:8 or less. Also, when using a mixed solution of water and a polyhydric alcohol, the mixing ratio of water and the polyhydric alcohol can be 8:2 or more, or 1:9 or less. When using a mixed solution of water and a lower aliphatic ketone, the mixing ratio of water and the lower aliphatic ketone can be 9:1 or more, or 2:8 or less.

[0020] The extraction treatment is not particularly limited as long as the soluble components contained in the extraction raw material can be eluted into the extraction solvent, and can be carried out according to a conventional method. For example, the extraction raw material can be immersed in an extraction solvent that is 5 to 15 times the amount (mass ratio) of the extraction raw material, and the soluble components can be extracted at room temperature or under reflux heating, and then filtered to remove the extraction residue to obtain an extract. When the solvent is distilled off from the obtained extract, a paste-like concentrate is obtained, and when this concentrate is further dried, a dried product is obtained.

[0021] The method for isolating and purifying compound (I) from the extract obtained as described above, the concentrate of the extract, or the dried product of the extract is not particularly limited and can be carried out by conventional methods. For example, the extract is dissolved in a developing solvent and subjected to column chromatography using porous substances such as silica gel and alumina, porous resins such as styrene-divinylbenzene copolymer and polymethacrylate, etc., to recover the fraction containing compound (I). In this case, the developing solvent may be appropriately selected according to the stationary phase used. Further, the fraction containing compound (I) obtained by column chromatography may be purified using any organic compound purification means such as reverse-phase silica gel chromatography using ODS, recrystallization, liquid-liquid countercurrent extraction, column chromatography using an ion exchange resin, etc.

[0022] Black ginger is a plant of the genus Kaempferia in the Zingiberaceae family, and its scientific name is Kaempferia parviflora. Black ginger is distributed in Thailand and other parts of Southeast Asia and is easily available from this region. The constituent parts of black ginger that can be used as an extraction raw material are not particularly limited and can be appropriately selected according to the purpose. For example, the rhizome of black ginger can be used.

[0023] The black ginger extract can be easily obtained by the methods generally used for plant extraction. The black ginger extract includes any of the extract of black ginger, the diluted or concentrated solution of the extract, the dried product obtained by drying the extract, or the crude or purified products thereof.

[0024] When extracting a substance having an inhibitory effect on cAMP phosphodiesterase activity from black ginger as an extraction raw material, it is not necessary to adopt a special extraction method, and it can be extracted using any extraction device at room temperature or under reflux heating. The extraction solvent is as described above.

[0025] Specifically, the rhizome portion of black ginger, used as the raw material for extraction, is placed in a processing tank filled with extraction solvent. The tank is then left to stand for 30 minutes to 4 hours, stirring occasionally as needed, to elute the soluble components. After filtration to remove solid matter, the extraction solvent is removed from the resulting extract by distillation, and the extract is dried. The amount of extraction solvent is usually 5 to 15 times the amount of the raw material (by mass). When water is used as the extraction solvent, the extraction conditions are usually 50°C to 95°C for 1 to 4 hours. When a mixed solvent of water and ethanol is used as the extraction solvent, the conditions are usually 40°C to 90°C for 30 minutes to 4 hours. The extract obtained by solvent extraction can be used directly as the active ingredient of the cAMP phosphodiesterase activity inhibitor in this embodiment, provided that the extraction solvent is highly safe.

[0026] The resulting black ginger extract may be subjected to dilution, concentration, drying, purification, and other treatments in accordance with conventional methods to obtain a diluted or concentrated extract, a dried extract, or a crude or purified product thereof.

[0027] In this embodiment, "catechins" refers to eight catechin compounds: catechin, gallocatechin, their epi forms epicatechin and epigallocatechin, and their gallic acid esters (gallates) catechin gallate, gallocatechin gallate, epicatechin gallate, and epigallocatechin gallate.

[0028] Specific examples of plants containing catechins include tea (Thea sinensis), lily tea (Ampelopsis grossedentata), and evergreen oak (Quercus salicina).

[0029] The plant components used as extraction materials are not particularly limited; for example, leaves, branches, roots, bark, seeds, etc., can be used as extraction materials, but it is especially preferable to use leaves as the extraction material.

[0030] The method for extracting, isolating, and purifying catechins from the above-mentioned plants is not particularly limited and can be carried out according to conventional methods, for example, the same method as described for compound (I) can be used.

[0031] [cAMP phosphodiesterase activity inhibitor] The compound (I) and black ginger extract obtained as described above have excellent cAMP phosphodiesterase activity inhibitory properties and can therefore be used as active ingredients in cAMP phosphodiesterase activity inhibitors. Furthermore, the compound (I) and catechins obtained in the manner described above have excellent cAMP phosphodiesterase activity inhibitory effects and can therefore be used as active ingredients in cAMP phosphodiesterase activity inhibitors. The cAMP phosphodiesterase activity inhibitor of this embodiment can be used in a wide range of applications, including pharmaceuticals, quasi-drugs, and cosmetics.

[0032] In addition, as the active ingredient of the cAMP phosphodiesterase activity inhibitor according to this embodiment, a composition containing compound (I) may be used instead of the isolated compound (I). Here, the "composition containing compound (I)" in this embodiment includes extracts obtained using plants containing compound (I) as extraction raw materials, fermented products containing compound (I), and extracts obtained using the fermented products as extraction raw materials. Furthermore, the "extract" includes extracts obtained by extraction treatment, diluted or concentrated extracts, or dried products obtained by drying the extract.

[0033] When using a composition containing compound (I) as the active ingredient of the cAMP phosphodiesterase activity inhibitor according to this embodiment, it is preferable that the composition contains 0.1% by mass or more of compound (I), more preferably 5% by mass or more, and particularly preferably 50% by mass or more. By using compound (I) with increased purity as the active ingredient, a cAMP phosphodiesterase activity inhibitor with even better efficacy can be obtained.

[0034] In addition, as the active ingredient of the cAMP phosphodiesterase activity inhibitor according to this embodiment, a composition containing catechins may be used instead of isolated catechins. Here, the "composition containing catechins" in this embodiment includes extracts obtained from plants containing catechins as extraction materials, fermented products containing catechins, and extracts obtained from said fermented products as extraction materials. Furthermore, the "extract" includes extracts obtained by extraction treatment, diluted or concentrated extracts of said extract, or dried products obtained by drying said extract.

[0035] When a composition containing catechins is used as the active ingredient of the cAMP phosphodiesterase activity inhibitor according to this embodiment, it is preferable that the composition contains 0.1% by mass or more of catechins, more preferably 5% by mass or more, and particularly preferably 50% by mass or more. By using a highly purified form of catechins as the active ingredient, a cAMP phosphodiesterase activity inhibitor with even greater efficacy can be obtained. In this specification, the mass of catechins refers to the total mass of the eight catechin compounds listed above, and synonyms (including mass percentage and mass ratio) are treated similarly.

[0036] In the cAMP phosphodiesterase activity inhibitor according to this embodiment, the content ratio (mass ratio) of compound (I) and black ginger extract can be appropriately adjusted according to their activity, but a preferred content ratio is 1:0.01 to 1:1000, and a particularly preferred content ratio is 1:0.1 to 1:100. When a composition containing compound (I) as an active ingredient is used, the above content ratio is the value converted to the mass of compound (I).

[0037] Furthermore, in the cAMP phosphodiesterase activity inhibitor according to this embodiment, the mixing ratio (mass ratio) of compound (I) and catechins can be appropriately adjusted according to their activity, but a preferred content ratio is 1:0.01 to 1:1000, and a particularly preferred content ratio is 1:0.1 to 1:100. When a composition containing compound (I) as an active ingredient is used, the above content ratio is the value converted to the mass of compound (I). Similarly, when a composition containing catechins as an active ingredient is used, the above content ratio is the value converted to the mass of catechins.

[0038] The cAMP phosphodiesterase activity inhibitor of this embodiment may consist only of compound (I) or a composition containing compound (I) and black ginger extract, or it may be a formulation of these. The cAMP phosphodiesterase activity inhibitor of this embodiment may consist only of compound (I) or a composition containing compound (I), and catechins or a composition containing catechins, or these may be formulated into a pharmaceutical product.

[0039] The cAMP phosphodiesterase activity inhibitor of this embodiment can be formulated into any dosage form, such as powder, granules, tablets, or liquid, by conventional methods using pharmaceutically acceptable carriers such as dextrin and cyclodextrin, or other optional excipients. In this case, excipients such as excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, and deodorizing agents can be used. The cAMP phosphodiesterase activity inhibitor can be used in combination with other compositions (e.g., skin cosmetics, hair cosmetics, etc.), as well as in ointments, topical solutions, patches, etc.

[0040] When the cAMP phosphodiesterase activity inhibitor of this embodiment is formulated, the content of compound (I) or the composition containing compound (I), and the content of black ginger extract are not particularly limited and can be appropriately set depending on the purpose. When the cAMP phosphodiesterase activity inhibitor of this embodiment is formulated, the content of compound (I) or a composition containing compound (I), and the content of catechins or a composition containing catechins are not particularly limited and can be appropriately set depending on the purpose.

[0041] Furthermore, the cAMP phosphodiesterase activity inhibitor of this embodiment may be further formulated with other natural extracts or the like that have cAMP phosphodiesterase activity inhibitory properties, and used as an active ingredient, if necessary.

[0042] Methods of administering the cAMP phosphodiesterase activity inhibitor of this embodiment to patients include oral administration and transdermal administration, but a method suitable for prevention or treatment should be appropriately selected depending on the type of disease. Furthermore, the dosage of the cAMP phosphodiesterase activity inhibitor of this embodiment should be appropriately increased or decreased depending on the type and severity of the disease, individual differences in the patient, method of administration, duration of administration, etc.

[0043] The cAMP phosphodiesterase inhibitor of this embodiment promotes cAMP production through the cAMP phosphodiesterase activity inhibitory effect of the active ingredients compound (I) and black ginger extract, as well as compound (I) and catechins, thereby suppressing platelet aggregation and preventing, treating, or improving allergic diseases and various inflammatory diseases. Furthermore, the cAMP phosphodiesterase inhibitor of this embodiment can promote the breakdown of adipocytes through the cAMP phosphodiesterase activity inhibitory effect of compound (I) and black ginger extract, as well as compound (I) and catechins, thereby preventing and improving obesity and various lifestyle-related diseases associated with it, such as arteriosclerosis, diabetes, and metabolic syndrome. However, the cAMP phosphodiesterase inhibitor of this embodiment can be used in all applications where exhibiting cAMP phosphodiesterase activity inhibitory effect is significant, in addition to these applications.

[0044] Furthermore, since the cAMP phosphodiesterase activity inhibitor of this embodiment exhibits excellent activity in inhibiting cAMP phosphodiesterase activity, it can be suitably used as a reagent for research on these mechanisms of action.

[0045] [Oral composition for inhibiting cAMP phosphodiesterase activity] Compound (I) and black ginger extract exhibit excellent activity in inhibiting cAMP phosphodiesterase activity, making them suitable for incorporation into oral compositions. In this case, compound (I) or a composition containing compound (I) and black ginger extract may be incorporated as is, or a cAMP phosphodiesterase inhibitor formulated from these may be incorporated. This makes it possible to create an oral composition suitable for cAMP phosphodiesterase activity inhibition applications. The above-mentioned effects, particularly the effect of promoting the breakdown of adipocytes, are more easily exerted when incorporated into an oral composition, making it a suitable choice.

[0046] Compound (I) and catechins are suitable for incorporation into oral compositions because they exhibit excellent activity in inhibiting cAMP phosphodiesterase activity. In this case, compound (I) or a composition containing compound (I) and catechins or a composition containing catechins may be incorporated as is, or a cAMP phosphodiesterase inhibitor formulated from these may be incorporated. This makes it possible to create an oral composition suitable for cAMP phosphodiesterase activity inhibition applications. The above-mentioned effects, particularly the effect of promoting the breakdown of adipocytes, are favored because their effects are easily exerted when imparted to an oral composition.

[0047] Here, "oral composition" refers to a substance that poses little risk to human health and is ingested orally or via the gastrointestinal tract in normal social life, and is not limited to administrative classifications such as food, pharmaceuticals, or quasi-drugs. Therefore, "oral composition" in this embodiment broadly includes general foods, animal feed, health foods, functional foods (foods for specified health uses, foods with nutritional function claims, functional food beverages), quasi-drugs, pharmaceuticals, etc., that are ingested orally. The oral composition according to this embodiment is preferably an oral composition that can display the desirable effects of compound (I) on the oral composition or its packaging, and is particularly preferably a functional food (foods for specified health uses, foods with functional function claims, foods with nutritional function claims), a quasi-drug, or a pharmaceutical.

[0048] When compound (I) or a composition containing compound (I) and black ginger extract, or a cAMP phosphodiesterase activity inhibitor formulated from these, is incorporated into an oral composition, the amount of active ingredients can be appropriately adjusted considering the intended use, symptoms, gender, etc. Considering the general intake of the oral composition to be added, it is preferable that the daily intake of compound (I) for adults be approximately 1 to 1000 mg, and that the daily intake of black ginger extract for adults be approximately 1 to 1000 mg. When the oral composition to be added is in the form of granules, tablets, or capsules, the amount of compound (I) or a composition containing compound (I) and a cAMP phosphodiesterase activity inhibitor formulated from black ginger extract added is usually 0.1 to 100% by mass, preferably 5 to 100% by mass, relative to the oral composition to be added.

[0049] When compound (I) or a composition containing compound (I) and catechins or a composition containing catechins, or a cAMP phosphodiesterase inhibitor formulated from these, are incorporated into an oral composition, the amount of active ingredients can be appropriately adjusted considering the intended use, symptoms, gender, etc. Considering the general intake of the oral composition to be added, it is preferable that the daily intake of compound (I) for adults be approximately 1 to 1000 mg, and that the daily intake of catechins for adults be approximately 1 to 1000 mg. When the oral composition to be added is in the form of granules, tablets, or capsules, the amount of compound (I) or a composition containing compound (I) and a cAMP phosphodiesterase inhibitor formulated from catechins or a composition containing catechins added is usually 0.1 to 100% by mass, preferably 5 to 100% by mass, relative to the oral composition to be added.

[0050] The oral composition of this embodiment may be compound (I) and black ginger extract, or compound (I) and catechins, in any oral composition that does not interfere with the activity of these compounds, or it may be a nutritional supplement mainly composed of compound (I) and black ginger extract, or compound (I) and catechins.

[0051] When preparing the oral composition of this embodiment, any auxiliary agents such as sugars like dextrin and starch; proteins like gelatin, soy protein, and corn protein; amino acids like alanine, glutamine, and isoleucine; polysaccharides like cellulose and gum arabic; and oils and fats like soybean oil and medium-chain triglycerides can be added to create an oral composition of any shape.

[0052] Oral compositions that may contain compound (I) and black ginger extract, or compound (I) and catechins, are not particularly limited, but specific examples include: beverages such as soft drinks, carbonated drinks, nutritional drinks, fruit drinks, and lactic acid drinks (including concentrated stocks and powders for adjusting these beverages); frozen desserts such as ice cream, ice sherbet, and shaved ice; noodles such as soba, udon, vermicelli, gyoza wrappers, shumai wrappers, Chinese noodles, and instant noodles; candy, chewing gum, chocolate, tablets, snacks, biscuits, jelly, and jam. Examples of oral compositions include: confectionery such as creams and baked goods; processed seafood and livestock products such as fish cakes, ham, and sausages; dairy products such as processed milk and fermented milk; oils and processed foods such as salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, and dressings; seasonings such as sauces and dips; soups, stews, salads, prepared foods, and pickles; and various other forms of health and nutritional supplements; as well as tablets, capsules, and drinks. When compound (I) is incorporated into these oral compositions, commonly used auxiliary ingredients and additives can be used in combination.

[0053] [Topical skin agent for inhibiting cAMP phosphodiesterase activity] Compound (I) and black ginger extract exhibit excellent activity in inhibiting cAMP phosphodiesterase activity, making them suitable for incorporation into topical skin preparations. In this case, compound (I) or a composition containing compound (I) and black ginger extract may be incorporated as is, or a cAMP phosphodiesterase activity inhibitor formulated from these may be incorporated. This makes it possible to create a topical skin preparation suitable for cAMP phosphodiesterase activity inhibition applications. The above-mentioned effects, particularly the platelet aggregation inhibitory effect, are more easily exerted when incorporated into topical skin preparations, making them suitable for this purpose.

[0054] Compound (I) and catechins exhibit excellent activity in inhibiting cAMP phosphodiesterase activity, making them suitable for incorporation into topical skin preparations. In this case, compound (I) or a composition containing compound (I) and catechins may be incorporated as is, or a cAMP phosphodiesterase activity inhibitor formulated from these may be incorporated. This makes it possible to create a topical skin preparation suitable for cAMP phosphodiesterase activity inhibition. The above-mentioned activity, particularly the platelet aggregation inhibitory activity, is favored because its effects are easily exerted when incorporated into a topical skin preparation.

[0055] Here, there are no restrictions on the classification of topical skin preparations, and they broadly include pharmaceuticals, quasi-drugs, cosmetics, etc. that are used transdermally. Specifically, examples include ointments, creams, lotions, serums, creams, masks, foundations, lip balms, bath additives, hair tonics, hair lotions, soaps, body washes, etc.

[0056] The amount of compound (I) in the topical skin preparation can be appropriately adjusted depending on the type of topical skin preparation, but the preferred concentration is 0.0001 to 10% by mass, and the particularly preferred concentration is 0.001 to 1% by mass. Similarly, the amount of black ginger extract in the topical skin preparation can be appropriately adjusted depending on the type of topical skin preparation, but the preferred concentration is 0.0001 to 10% by mass, and the particularly preferred concentration is 0.001 to 1% by mass.

[0057] The amount of compound (I) in the topical skin preparation can be appropriately adjusted depending on the type of topical skin preparation, but the preferred concentration is 0.0001 to 10% by mass, and the particularly preferred concentration is 0.001 to 1% by mass. Furthermore, the amount of catechins in the topical skin preparation can be appropriately adjusted depending on the type of topical skin preparation, but the preferred concentration is 0.0001 to 10% by mass, and the particularly preferred concentration is 0.001 to 1% by mass.

[0058] While the cAMP phosphodiesterase activity inhibitor, the oral composition for inhibiting cAMP phosphodiesterase activity, and the topical skin preparation for inhibiting cAMP phosphodiesterase activity of this embodiment are suitably applied to humans, they can also be applied to animals other than humans (e.g., mice, rats, hamsters, dogs, cats, cattle, pigs, monkeys, etc.) as long as their respective effects are achieved. [Examples]

[0059] The present invention will be specifically described below with reference to test examples, but the present invention is not limited in any way to the following examples. Compound (I) (manufactured by Tokyo Chemical Industry Co., Ltd., 3-(4-Hydroxy-3-methoxyphenyl)propionic Acid, Sample 1) was used as the test sample, and tea catechin (manufactured by Pharmafoods Co., Ltd., product name "PF-TP80", containing 70% catechins, Sample 3) was used as the catechin in the test sample.

[0060] [Manufacturing Example 1] Production of Black Ginger Extract As the extraction material, 100 g of crushed black ginger rhizome was added to 1000 mL of 60% ethanol and kept at 80°C for 2 hours with gentle stirring, after which it was filtered. The filtrate was concentrated under reduced pressure at 40°C and further dried in a vacuum dryer to obtain 23.9 g of extract (powder) (Sample 2).

[0061] [Test Example 1] Test of cyclic AMP phosphodiesterase activity inhibition by compound (I) and black ginger extract The inhibitory effect of compound (I) (Sample 1) and black ginger extract (Sample 2) on cyclic AMP phosphodiesterase activity was tested as follows.

[0062] To 0.2 mL of 50 mmol / L Tris-HCl buffer (pH 7.5) containing 5 mmol / L magnesium chloride, 0.1 mL of 2.5 mg / mL bovine serum albumin solution, 0.1 mL of 0.1 mg / mL cyclic AMP phosphodiesterase solution, and 0.05 mL of the test sample solution (Sample 1 and / or Sample 2; see Table 1 below for final sample concentrations) were added, and the mixture was allowed to stand at 37°C for 5 minutes. Then, 0.05 mL of 0.5 mg / mL cyclic AMP solution was added, and the mixture was reacted at 37°C for 60 minutes. The reaction was then stopped by boiling in a boiling water bath for 3 minutes, and the mixture was centrifuged (2260 × g, 10 minutes, 4°C). The cyclic AMP, the reaction substrate in the supernatant, was analyzed under the high-performance liquid chromatography conditions described below. As a control, the same procedure was performed with only the solvent without the sample added. <High-performance liquid chromatography conditions> Pump: DP-8020 (manufactured by Tosoh Corporation) Ultraviolet-Visible Detector: UV-8020 (manufactured by Tosoh Corporation) Integrator: Chromatocorder21 (manufactured by Tosoh Corporation) Column oven: CO-8020 (manufactured by Tosoh Corporation) Online Degasser: SD-8022 (manufactured by Tosoh Corporation) Stationary phase: Wakosil C 18 -ODS 5μm (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) Column length: 250 mm Mobile phase: 1mmol / L TBAP in 25mmol / L KH2PO4:CH3CN=90:10 Mobile phase flow rate: 1.0mL / min Detection: 260nm

[0063] Next, the peak area of ​​the cyclic AMP standard (A), the peak area of ​​the supernatant of the reaction solution between the cyclic AMP standard and cyclic AMP phosphodiesterase without the sample (B1), and the peak area of ​​the supernatant of the reaction solution between the cyclic AMP standard and cyclic AMP phosphodiesterase with the test sample added (B2) were determined. From the obtained results, the degradation rate of the cyclic AMP standard without the sample (C) and the degradation rate of the cyclic AMP standard with the test sample added (D) were calculated using the following formula.

[0064] Decomposition rate of standard without sample (C,%) = (1 - B1 / A) × 100 Decomposition rate of the standard after adding the test sample (D,%) = (1 - B2 / A) × 100

[0065] Subsequently, based on the respective degradation rates (C, D) calculated using the above formula, the cyclic AMP phosphodiesterase activity inhibition rate (%) was calculated using the following formula.

[0066] cAMP phosphodiesterase activity inhibition rate (%) = (1 - D / C) × 100 The results are shown in Table 1.

[0067] [Table 1]

[0068] As shown in Table 1, it was confirmed that compound (I) (Sample 1) and black ginger extract (Sample 2), when combined, significantly improved cyclic AMP phosphodiesterase activity inhibition.

[0069] [Test Example 2] Test of cyclic AMP phosphodiesterase activity inhibition by compound (I) and catechins Compound (I) (Sample 1) and tea catechin (Sample 3) were tested for cyclic AMP phosphodiesterase activity inhibition in the same manner as in Test Example 1. The final concentrations of the samples (Sample 3 concentration is the value converted to the total catechin content) are as shown in Table 2 below, and the cyclic AMP phosphodiesterase activity inhibition rate (%) was calculated. The results are shown in Table 2.

[0070] [Table 2]

[0071] As shown in Table 2, it was confirmed that compound (I) (Sample 1) and tea catechin (Sample 3), when combined, significantly improved the inhibitory effect on cyclic AMP phosphodiesterase activity.

[0072] [Formulation example 1] An emulsion was prepared by conventional methods according to the following composition. Compound (I) 0.01g Black ginger extract 0.01g Jojoba oil 4.00g 1,3-Butylene glycol 3.00g Arbutin 3.00g Polyoxyethylene cetyl ether (20 E.O.) 2.50g Olive oil 2.00g Squalane 2.00g Cetanol 2.00g Glyceryl monostearate 2.00g Polyoxyethylene sorbitan oleate (20E.O.) 2.00g Methyl parahydroxybenzoate 0.15g Stearyl glycyrrhetinate 0.10g Scutellaria baicalensis extract 0.10g Dipotassium glycyrrhizinate 0.10g Ginkgo biloba extract 0.10g Conchiolin 0.10g Phellodendron bark extract 0.10g Chamomile extract 0.10g Fragrance 0.05g Purified water, remaining amount (assuming a total volume of 100g)

[0073] [Formulation example 2] A cream with the following composition was manufactured by conventional methods. Compound (I) 0.01g Black ginger extract 0.01g Sophora flavescens extract 0.1g Scutellaria baicalensis extract 0.1g Liquid paraffin 5.0g 4.0g of bleached beeswax Squalane 10.0g Cetanol 3.0g Lanolin 2.0g Stearic acid 1.0g Polyoxyethylene sorbitan oleate (20E.O.) 1.5g Glyceryl monostearate 3.0g Oil-soluble licorice extract 0.1g 1,3-Butylene glycol 6.0g Methyl parahydroxybenzoate 1.5g Fragrance 0.1g Purified water, remaining amount (assuming a total volume of 100g)

[0074] [Formulation example 3] A beauty serum with the following composition was manufactured by conventional methods. Compound (I) 0.01g Tea catechins 0.01g Chamomile extract 0.1g Carrot extract 0.1g Xanthan gum 0.3g Hydroxyethylcellulose 0.1g Carboxyvinyl polymer 0.1g 1,3-Butylene glycol 4.0g Dipotassium glycyrrhizinate 0.1g Glycerin 2.0g Potassium hydroxide 0.25g Fragrance 0.01g Preservative (methyl parahydroxybenzoate) 0.15g Ethanol 2.0g Purified water, remaining amount (assuming a total volume of 100g)

[0075] [Formulation example 4] An oral liquid formulation having the following composition was manufactured by a conventional method. <Composition per ampoule (100 mL)> Compound (I) 0.3% by mass Black ginger extract 0.1% by mass Sorbitol 12.0% by mass Sodium benzoate 0.1% by mass Fragrance 1.0% by mass Calcium sulfate 0.5% by mass Purified water remainder (100% by mass)

[0076] [Formulation example 5] Tablets having the following composition were manufactured by conventional methods. Compound (I) 2.0 mg Tea catechins 3.0mg Dolomite (containing 20% ​​calcium and 10% magnesium) 83.4 mg Casein phosphopeptide 16.7 mg Vitamin C 33.4mg Maltitol 136.8mg Collagen 12.7mg Sucrose fatty acid ester 12.0 mg

Claims

1. A cyclic AMP phosphodiesterase activity inhibitor comprising as active ingredients a compound represented by the following formula (I) and a black ginger extract and / or catechins: 【Chemistry 1】

2. An anti-obesity agent comprising as active ingredients a compound represented by the following formula (I) and black ginger extract and / or catechins: 【Chemistry 1】

3. A fat decomposition promoter characterized by having as active ingredients a compound represented by the following formula (I) and black ginger extract and / or catechins: 【Chemistry 1】

Images