TW202227107A - Pde5 inhibitor - Google Patents

Abstract

An object of the present invention is to provide a substance having a novel PDE5 inhibitory effect. A PDE5 inhibitor according to the present invention contains pupa powder or extracts thereof.

Description

PDE5 inhibitors

The present invention discloses a technology related to phosphodiesterase (PDE: Phosphodiesterase) 5 inhibitor.

Substances having a PDE5 inhibitory effect are known to be effective in preventing or improving urinary tract disorders and pulmonary arterial pulmonary hypertension (Non-Patent Document 1). Naturally derived substances having a PDE5 inhibitory effect are also known (Patent Documents 1 and 2).

[Prior Art Literature]

[Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. 2019-34920

[Patent Document 2] Japanese Patent Laid-Open No. 2018-154610

[Non-patent literature]

[Non-Patent Document 1] Japanese Pharmacological Journal, 154, 265-269, 2019

An object of the present invention is to provide a novel substance with PDE5 inhibitory effect.

In order to solve the above problem, after repeated and careful research, it was found that silkworm pupa powder has PDE5 inhibitory effect. Based on the above-mentioned findings, we have further repeated studies and provided inventions represented by the following.

item 1

A PDE5 inhibitor, which contains silkworm chrysalis powder or its extract.

item 2

The PDE5 inhibitor as described in Item 1 is in the form of a food and drink composition.

item 3

The PDE5 inhibitor as described in item 1 or 2 is used for the prevention or improvement of urination disorders and/or pulmonary arterial pulmonary hypertension.

item 4

A use of silkworm chrysalis powder or its extract is used to manufacture PDE5 inhibitor.

item 5

A use of silkworm chrysalis powder or its extract is used to manufacture a composition for preventing or improving urination disorder and/or pulmonary arterial pulmonary hypertension.

item 6

In one method, silkworm chrysalis powder or an extract thereof is administered to a subject who must inhibit PDE5.

item 7

The method according to item 6, wherein the subject needs to prevent or improve urination disorders and/or pulmonary arterial pulmonary hypertension.

item 8

A silkworm chrysalis powder or its extract is used for the inhibition of PDE5.

item 9

A silkworm chrysalis powder or its extract is used for the prevention or improvement of urination disorder and/or pulmonary arterial pulmonary hypertension.

The present invention provides substances with PDE5 inhibitory effect. In one embodiment, a means for preventing or ameliorating dysuria and/or pulmonary arterial pulmonary hypertension using PDE5 inhibition is provided.

Figure 1 shows the results of measuring the PDE5 inhibitory activity against the water extract of silkworm pupae powder. "Sample" means a silkworm pupae powder water extract. "Substrate" means cGMP.

FIG. 2 shows the results of measuring the PDE5 inhibitory activity on the DMSO extract of silkworm pupa powder. "Sample" means silkworm pupae powder DMSO extract. "Substrate" means cGMP.

The PDE5 inhibitor preferably contains silkworm chrysalis powder or an extract thereof. Silkworm chrysalis powder is made by drying silkworm chrysalis into powder. As the silkworm chrysalis powder, a commercially available one can be used, or it can be produced from silkworm chrysalis and used. The particle size and the like of the powder are not limited, and can be appropriately set according to the purpose of use and the like.

In one embodiment, the PDE5 inhibitor preferably contains an extract of silkworm chrysalis powder. The method and conditions used to obtain the extract are arbitrary. For example, the silkworm chrysalis powder can be directly extracted with an appropriate solvent, or the silkworm chrysalis powder can be further pulverized and then extracted with an appropriate solvent. The type of solvent is not particularly limited, for example, water; lower alcohols such as methanol, ethanol, and isopropanol; polyols such as propylene glycol and 1,3-butanediol; ketones such as acetone; diethyl ether, dioxane, Acetonitrile; Esters such as ethyl acetate; Dimethyl sulfite, xylene, benzene, chloroform, etc. In one embodiment, the preferred solvent is water. The temperature system of the solvent is not particularly limited, and can be, for example, 10°C or higher and 20°C or higher.

In one embodiment, the extraction of silkworm chrysalis powder is preferably performed while applying ultrasonic waves. Preferably, it is obtained by the following method. In addition, the mixing ratio of silkworm chrysalis powder and solvent at the time of extraction is arbitrary, for example, 5 to 20 parts by weight or 7 to 15 parts by weight of solvent can be used with respect to 1 part by weight of dry powder.

The moisture content of the silkworm pupae powder or its extract is not particularly limited, but can be, for example, 20% by weight or less, 10% by weight or less, 8% by weight or less, or 5% by weight or less.

The PDE5 inhibitor may consist of only silkworm chrysalis powder or its extract, or may further contain any other components. Examples of other components include excipients, binders, disintegrating agents, lubricants, wetting agents, fluidizing agents, preservatives, surfactants, stabilizers, diluents, dissolving agents, isotonicity agents, and bactericides. , preservatives, flavors, odorants, colorants, fragrances, etc. Other ingredients can also be selected from other ingredients with PDE5 inhibitory activity or other physiologically active ingredients. The form of the PDE5 inhibitor is arbitrary, and for example, it can be in the form of powder, granules, lozenges, capsules, or liquids.

The amount of silkworm chrysalis powder or its extract contained in the PDE5 inhibitor is arbitrary, but can be set in the range of 0.1% or more and 100% or less in terms of dry weight, for example. The lower limit of the content can be, for example, 1% or more, 2% or more, 5% or more, 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, or 70% or more. % or more, and the upper limit can be set to 99% or less, 95% or less, 90% or less, 80% or less, 70% or less, or 60% or less. These lower and upper limits can be arbitrarily combined.

In one embodiment, the PDE5 inhibitor is preferably in the form of food and drink. Foodstuffs include not only general foods but also health functional foods (specifically, foods for specified health use, nutritional functional foods, and functionally indicated foods), foods for patients, supplements, and the like.

In one embodiment, the form of the PDE5 inhibitor can be: liquid forms such as liquids, emulsions, suspensions, syrups, etc.; powders, granules, fine granules, lozenges, pills, capsules (including hard capsules); , soft capsule), troche, chewable tablet, gel, paste, paste, mousse, tablet and other semi-solid or solid forms.

General food products are not particularly limited, and examples include beverages (for example, fruit juice drinks, vegetable juices, soft drinks, alcoholic drinks, carbonated drinks, sports drinks, nourishing and strong drinks, nutritional drinks, etc.), fruits (for example, desserts) Fruits, rice crackers, chocolate, fudge, candy, jelly, pudding, wagashi, western cakes, etc.), seasonings (for example, soy sauce, miso, mirin seasoning, mixed spice, sauce, soup, sauce, ketchup etc.), salad dressings, noodles (for example, udon noodles, soba noodles, pasta, etc.), processed meat and fish foods (for example, sausages, Vienna sausages, ham, hamburger meat, etc.), dairy products (preferably Buttermilk, milk, cheese, whipped cream, cream, etc.) etc.

In one embodiment, the above-mentioned PDE5 inhibitor can be used for the prevention or improvement of dysuria and/or pulmonary arterial pulmonary hypertension by inhibiting the activity of PDE5. Regardless of the cause or type of urinary tract disorder, urinary tract disorders with lower urinary tract symptoms can be cited.

In one embodiment, the PDE5 inhibitor can be formulated into a pharmaceutical form. The medicine containing PDE5 inhibitor can be prepared by combining pharmaceutically acceptable excipients in silkworm chrysalis powder or its extract as required.

The ingestion (administration) amount of the PDE5 inhibitor is not particularly limited as long as the intended effect is exhibited, and can be appropriately set according to the physique, age, symptoms, application form, and purpose of use of the subject (subject animal). For example, the daily intake (administration) amount can be set in the range of 0.001 to 8000 mg, 0.01 to 5000 mg, etc. in terms of the dry weight of silkworm pupae powder or its extract based on an adult weighing 60 kg. The frequency of ingestion (administration) is arbitrary, and for example, it may be ingested (administered) once per day or may be ingested (administered) several times.

As described above, silkworm pupa powder or its extract can be used for the production of PDE5 inhibitor because it has a PDE5 inhibitory effect. Furthermore, in order to manufacture the composition for prevention or improvement of urination disorder and/or pulmonary arterial pulmonary hypertension, silkworm chrysalis powder or its extract can also be used.

As described above, the silkworm pupa powder or its extract has a PDE5 inhibitory effect, so the silkworm pupa powder or its extract can be administered to a subject who needs to inhibit PDE5 to provide the PDE5 inhibitory effect. Furthermore, by inhibiting PDE5, urination disorders and/or pulmonary arterial pulmonary hypertension can be prevented or improved, so by administering silkworm chrysalis powder or Its extract can carry out this prevention or improvement.

[Example]

Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited by these examples.

1. Preparation of silkworm chrysalis powder

The dried silkworm chrysalis (purchased from Usuibo Seisakusho Co., Ltd.) was pulverized with a mixer to obtain silkworm chrysalis powder. In reaction vessel, feed silkworm chrysalis powder (42g) and ultrapure water 420mL or DMSO 420mL, Extraction was performed for 15 minutes while applying ultrasonic waves with an ultrasonic cleaner. After that, the mixed solution was centrifuged at 5000 rpm for 10 minutes, and the supernatant was collected and spray-dried to obtain water extract and DMSO extract of silkworm pupae powder.

2. Determination of PDE5 inhibitory activity

The PDE5 inhibitory activity was carried out using PDE-Glo (trademark) Phosphodiesterase Assay (manufactured by Promega). The final concentrations of the water extract and DMSO extract of silkworm pupae powder were diluted with ultrapure water so that the final concentrations of 33 μg/ml, 11 μg/g, 3.7 μg/ml and 1.2 μg/ml were used, and the diluted ones were used as samples. As the enzyme, human phosphodiesterase 5A1 (manufactured by Sigma-Aldrich) was used. 1 μl of 3100 U/μl PDE was mixed with 205.7 μl of the reaction buffer to prepare a PDE solution. After mixing 15 μl of the PDE solution with 10 μl of each sample, it was spin down for 2 minutes and shaken at room temperature for 5 minutes. To 25 μl of this mixture, 25 μl of 20 μM cGMP was added and mixed, and 8 μl was dispensed into each PCR tube. This was placed on a shaker and reacted at room temperature and 400 rpm. 4 μl of detection buffer was added to each tube, briefly centrifuged, and then shaken at room temperature for 20 minutes. 10 μl of this and the Kinase-Glo reagent were dispensed into each well of a 384-well plate (manufactured by Thermo Fisher) in 10 μl, and the reaction was performed by shaking at room temperature. The test example using the sample without adding silkworm chrysalis powder extract was used as 0% control group, and the test example without adding PDE was used as 100% control group. Inhibition rate. The assay was repeated 4 times. The results are shown in Figure 1 (water extract) and Figure 2 (DMSO extract).

From the results of FIGS. 1 and 2, it was confirmed that PDE5 inhibitory activity exists in the water extract and DMSO extract of silkworm pupa powder, and the activity increases depending on the concentration. From these results, it is considered that the silkworm chrysalis powder can effectively treat or prevent diseases such as pulmonary hypertension and urination disorders.

Claims (3)

A PDE5 inhibitor, which contains silkworm chrysalis powder or its extract. The PDE5 inhibitor according to claim 1 is in the form of a food and drink composition. The PDE5 inhibitor according to claim 1 or 2 is used for preventing or ameliorating urination disorders and/or pulmonary arterial pulmonary hypertension.

Images