JP7690265B2 - Chinese herbal medicine - Google Patents

Description

The present invention relates to a herbal medicine containing Seishinrenshi-in extract.

Seishinrenshi-in extract is an extract of a mixture of herbs containing nine kinds of herbs, and is used for the following symptoms in people with general fatigue, dry mouth and tongue, and heavy urination: residual urine, frequent urination, and painful urination (Non-Patent Documents 1, 2).

The most common method for producing Seishinrenshi-in extract is to decoct a mixture of herbs using water (Non-Patent Documents 1 and 2).

Glycyrrhizic acid, which is contained in licorice used in the production of Seishinrenshi-in extract, has been reported to have many pharmacological effects, including anti-inflammatory, immunomodulatory, and hepatocyte proliferation effects (Non-Patent Document 3). Glycyrrhizic acid is also known to be about 170 times sweeter than sugar (Non-Patent Document 4).

Pharmaceutical interview form, April 2013 (Revised 3rd Edition), Kampo preparation Tsumura Seishinrenshi-in Extract Granules (medical use) Pharmaceutical interview form, revised in February 2017 (3rd edition), Kampo preparation Junko Seishinrenshi-in FC extract granules for medical use Nikkei Medical Prescription Drug Dictionary, Digestive Organ Drugs, Liver Disease Drugs, Glycyrrhizin Preparations, [online], [Searched June 10, 2020], Internet <URL: https://medical.nikkeibp.co.jp/inc/all/drugdic/article/556e7e5c83815011bdcf8340.html> Kinki-Chugoku-Shikoku Agricultural Research Center Research Report No. 6, 55-69, 2007

It is believed that the more glycyrrhizinic acid derived from licorice contained in Seishinrenshi-in extract, the more effectively the pharmacological effects of this ingredient can be enjoyed. Even with the manufacturing methods normally used industrially, it is possible to obtain Seishinrenshi-in extract with a high content of glycyrrhizinic acid, depending on the content of ingredients contained in the licorice. However, the inventor's investigations have shown that when the glycyrrhizinic acid content in Seishinrenshi-in extract is 0.22% by weight or more, the sweetness of this ingredient is too strong, and Seishinrenshi-in extract preparations exhibit a peculiar, unpleasant sweetness.

The present invention aims to provide a formulation that suppresses the unpleasant sweetness characteristic of glycyrrhizinic acid in a herbal medicine containing Seishinrenshi-in extract, which contains 0.22% by weight or more of glycyrrhizinic acid.

The inventors have used their own manufacturing method to vary the ratios of various components contained in Seishinrenshiin extract, and have found that by adjusting the content of ononin to 8 parts by weight or more per 100 parts by weight of glycyrrhizinic acid, the unpleasant sweetness characteristic of glycyrrhizinic acid can be suppressed. The present invention was completed based on this finding and through further investigation.

That is, the present invention provides the following aspects.
Item 1. A herbal medicine containing Seishinrenshiin extract,
The Chinese herbal medicine, wherein the seishinrenshi-in extract contains 0.22% by weight or more of glycyrrhizic acid and contains 8 parts by weight or more of ononin per 100 parts by weight of glycyrrhizic acid.
Item 2. The herbal preparation according to Item 1, which is in the form of a powder, fine granules, granules, lozenges, or chewable preparation.
Item 3. A method for suppressing the sweetness of glycyrrhizinic acid in a herbal medicine containing Seishinrenshi-in extract containing 0.22% by weight or more of glycyrrhizinic acid, comprising:
The method comprises adjusting the content of ononin in the Seishinrenshi-in extract to 8 parts by weight or more per 100 parts by weight of glycyrrhizinic acid.

According to the present invention, it is possible to suppress the unpleasant sweetness characteristic of glycyrrhizinic acid in a herbal medicine preparation containing Seishinrenshi-in extract, which contains 0.22% by weight or more of glycyrrhizinic acid.

The herbal preparation of the present invention is characterized by containing a seishinrenshiin extract containing specific ingredients in specific ratios. The herbal preparation of the present invention will be described in detail below.

Seishinrenshiin is described in the Chinese Ming Dynasty medical book Banbyo Kaishun, and is a mixture of herbs containing lotus root, Chinese radish, bupleurum, ginseng, Chinese scutellaria, Scutellaria baicalensis, Astragalus chinensis, jikoppi, and licorice.

In the present invention, there is no particular restriction on the mixing ratio of the herbs that make up Seishinrenshi-in, but typically includes 2-5 parts by weight of Lotus Root, preferably 3-4 parts by weight; 1.5-4 parts by weight of Bakumondou, preferably 2-3 parts by weight; 2-4 parts by weight of Poria Root, preferably 2.5-3.5 parts by weight; 1.5-5 parts by weight of Ginseng, preferably 2-4 parts by weight; 1.5-3 parts by weight of Shazenshi, preferably 2-2.5 parts by weight; 1.5-3 parts by weight of Scutellaria Root, preferably 2-2.5 parts by weight; 1-4 parts by weight of Astragalus Root, preferably 2-3 parts by weight; 1-3 parts by weight of Jikoppi, preferably 2-2.5 parts by weight; and 0.7-2 parts by weight of Licorice, preferably 0.7-1 part by weight.

Suitable examples of herbal medicine preparations used in the manufacture of the Seishinrenshiin extract used in the present invention include 3.5 parts by weight of Lotus Root, 2.1 parts by weight of Bakumondou, 2.8 parts by weight of Poria Coccinea, 3.5 parts by weight of Ginseng, 2.1 parts by weight of Shazenshi, 2.1 parts by weight of Scutellaria Root, 2.8 parts by weight of Astragalus Root, 2.1 parts by weight of Jikoppi, and 0.7 parts by weight of Licorice.

The Seishinrenshi-in extract used in the present invention contains 0.22% by weight or more of glycyrrhizinic acid. Thus, herbal preparations containing Seishinrenshi-in extracts with a high content of glycyrrhizinic acid have a characteristic unpleasant sweetness, but the herbal preparation of the present invention has a high content of glycyrrhizinic acid, yet the characteristic unpleasant sweetness is suppressed.

The herbal preparation of the present invention has an excellent effect of suppressing the specific unpleasant sweetness, and therefore can effectively suppress the unpleasant sweetness even when the content of glycyrrhizinic acid is much higher. From this viewpoint, suitable examples of the glycyrrhizinic acid contained in the Seishinrenshi-in extract used in the present invention include 0.3% by weight or more, more preferably 0.4% by weight or more, even more preferably 0.45% by weight or more, and even more preferably 0.48% by weight or more. There is no particular limit to the upper limit of the glycyrrhizinic acid contained in the Seishinrenshi-in extract used in the present invention, but examples include 1% by weight or less, preferably 0.9% by weight or less.

The Seishinrenshi-in extract used in the present invention contains 8 parts by weight or more of ononin per 100 parts by weight of glycyrrhizinic acid. This suppresses the unpleasant sweetness that is specific to high contents of glycyrrhizinic acid. From the viewpoint of further enhancing the effect of suppressing the unpleasant sweetness, preferred examples of the ononin content per 100 parts by weight of glycyrrhizinic acid include 8.3 parts by weight or more or 9 parts by weight or more, more preferably 11 parts by weight or more, even more preferably 13 parts by weight or more, even more preferably 15 parts by weight or more, and particularly preferably 16 parts by weight or more. There is no particular limit to the upper limit of the ononin content per 100 parts by weight of glycyrrhizinic acid, but examples include 23 parts by weight or less, preferably 19 parts by weight or less.

The content of ononin in the Seishinrenshiin extract used in the present invention is not particularly limited as long as the amount relative to 100 parts by weight of glycyrrhizinic acid is the amount described above, but examples include 0.02% by weight or more, preferably 0.028% by weight or more, more preferably 0.05% by weight or more, even more preferably 0.07% by weight or more, and particularly preferably 0.08% by weight or more. The upper limit of the ononin content contained in the Seishinrenshiin extract used in the present invention is not particularly limited, but examples include 0.4% by weight or less, preferably 0.2% by weight or less.

At least a portion of the glycyrrhizic acid contained in the Seishinrenshiin extract used in the present invention is derived from the licorice that constitutes Seishinrenshiin, but preferably all of it is derived from the licorice that constitutes Seishinrenshiin.

At least a portion of the ononin contained in the seishinrenshiin extract used in the present invention is derived from the Astragalus radix that constitutes seishinrenshiin, but preferably all of it is derived from the Astragalus radix that constitutes seishinrenshiin.

One example of a method for adjusting the content of glycyrrhizinic acid and the ratio of ononin to glycyrrhizinic acid in Seishinrenshi-in extract to fall within the above range is to add the missing glycyrrhizinic acid and/or ononin after adjusting Seishinrenshi-in extract. In this method, the components used to add glycyrrhizinic acid and/or ononin may be purified compounds thereof, or may be an extract of liquorice root extract, Astragalus membranaceus extract, or a mixed herbal extract of licorice root and Astragalus membranaceus.

As another example of a method for adjusting the content of glycyrrhizinic acid and the content ratio of ononin in Seishinrenshi-in extract to the above range from the viewpoint of further enhancing the effect of suppressing unpleasant sweetness, a method is preferred in which finely chopped pieces crushed to a size that passes through a sieve with a nominal mesh size of 1 mm are used as at least a part of the Astragalus Root or the finely chopped pieces of licorice and Astragalus Root used in the herbal mixture constituting Seishinrenshi-in. In this method, when the finely chopped pieces are used as part of the Astragalus Root or the finely chopped pieces of licorice and Astragalus Root used in the herbal mixture constituting Seishinrenshi-in (i.e., when a part of the finely chopped pieces is the finely chopped pieces and the rest is normal-sized finely chopped pieces crushed to a size that does not pass through a sieve with a nominal mesh size of 4 mm), the ratio of the finely chopped pieces of licorice to 1 part by weight of the total finely chopped pieces of licorice and the ratio of the finely chopped pieces of Astragalus Root to 1 part by weight of the total finely chopped pieces of Astragalus Root are both 0.3 parts by weight or more. From the viewpoint of further enhancing the effect of suppressing unpleasant sweetness, the ratio is preferably 0.5 parts by weight or more, more preferably 0.7 parts by weight or more, and even more preferably 0.9 parts by weight or more. From the viewpoint of further enhancing the effect of suppressing unpleasant sweetness, it is most preferable that all of the finely chopped Astragalus Root or the finely chopped Licorice and Astragalus Root used in the herbal mixture constituting Seishinrenshi-in are the above-mentioned finely chopped products.

The extract of Seishinrenshiin can be obtained by subjecting the above-mentioned mixed herbal medicines to an extraction process, and concentrating or further drying the resulting extract as necessary.

The extraction solvent used in the extraction process of Seishinrenshiin extract is not particularly limited, and may be water or aqueous ethanol, preferably water. The liquid extract of Seishinrenshiin can be obtained by concentrating the obtained extract. Furthermore, the dried extract powder of Seishinrenshiin can be obtained by drying the liquid extract. The method of drying is not particularly limited, and may be, for example, spray drying or a method in which a suitable adsorbent (e.g., silicic anhydride, starch, etc.) is added to a soft extract with a high extract concentration to obtain an adsorbed powder.

The extract form of Seishinrenshiin can be either a liquid extract such as a liquid extract or a soft extract, or a solid dried extract powder.

The content of Seishinrenshiin extract in the herbal preparation of the present invention is not particularly limited as long as the effects of the present invention are achieved, but may be 10 to 100% by weight, preferably 20 to 90% by weight, more preferably 40 to 80% by weight, and even more preferably 60 to 70% by weight, calculated as the amount of dried extract powder of Seishinrenshiin extract. In the present invention, the amount of dried extract powder of Seishinrenshiin refers to the amount of the dried extract powder itself when a dried extract powder of Seishinrenshiin is used, and refers to the amount converted to the amount remaining after removing the solvent when a liquid extract of Seishinrenshiin is used. In addition, when the dried extract powder of Seishinrenshiin contains additives such as adsorbents added during production, the amount refers to the amount excluding the additives.

Other components The herbal preparation of the present invention may be composed of the seishinrenshiin extract alone, or may contain additives and bases according to the preparation form. Such additives and bases are not particularly limited as long as they are pharmacologic acceptable, and examples thereof include excipients, binders, disintegrants, lubricants, isotonicity agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers, suspending agents, adhesives, coating agents, glossing agents, water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, metal soaps, lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV inhibitors, preservatives, flavorings, fragrances, powders, thickeners, dyes, chelating agents, etc. These additives may be used alone or in combination of two or more. The content of these additives and bases is appropriately set according to the type of additives and bases used, the preparation form of the herbal preparation, etc.

In addition, the herbal preparation of the present invention may contain other nutritional components and pharmacological components as necessary in addition to the Seishinrenshi-in extract. Such nutritional components and pharmacological components are not particularly limited as long as they are pharmacologic acceptable, but examples thereof include antacids, stomachic agents, digestive agents, intestinal regulators, antispasmodics, mucosal repair agents, anti-inflammatory agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, sedatives, hypnotics, antihistamines, caffeine, cardiac diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, herbal extracts, vitamins, and menthols. These nutritional components and pharmacological components may be used alone or in combination of two or more. The content of these components is appropriately set depending on the type of components used.

Preparation form The preparation form of the herbal preparation of the present invention is not particularly limited, as long as it can be administered orally. Examples of the preparation form include solid preparations such as powders, fine granules, granules, tablets (preferably plain tablets), troches, chewable tablets, capsules (soft capsules, hard capsules), and pills; semi-solid preparations such as jellies; and liquid preparations such as solutions, suspensions, and syrups. Preferred are powders, fine granules, granules, troches, and chewable tablets.

Manufacturing method: The manufacturing method for the herbal preparation of the present invention is to use the Seishinrenshi-in extract obtained by the above-mentioned method, which contains specific ingredients in specific ratios, and to formulate it using other ingredients as necessary, according to conventional formulation methods used in the pharmaceutical field.

2. Method for suppressing sweetness As described above, by adjusting the content of ononin in Seishinrenshi-in extract, which has a high content of glycyrrhizinic acid, to a specific amount relative to glycyrrhizinic acid, the effect of suppressing the unpleasant sweetness specific to high content of glycyrrhizinic acid is exhibited.Therefore, the present invention further provides a method for suppressing the sweetness of glycyrrhizinic acid in a herbal medicine containing Seishinrenshi-in extract containing 0.22% by weight or more of glycyrrhizinic acid, by adjusting the content of ononin in Seishinrenshi-in extract to 8 parts by weight or more relative to 100 parts by weight of glycyrrhizinic acid.

In the method of suppressing sweetness of the present invention, the contents and ratios of the ingredients contained in the Seishinrenshiin extract used, the method for adjusting said contents and ratios, the types and contents of the ingredients blended in the herbal preparation, and the formulation form are as described above in "1. Herbal Preparations."

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

(1) Preparation of Seishinrenshiin Extract As raw herbal medicines, 3.5 parts by weight of Lotus Root, 2.1 parts by weight of Bakumondou, 2.8 parts by weight of Poria Root, 3.5 parts by weight of Ginseng, 2.1 parts by weight of Shazenshi, 2.1 parts by weight of Scutellaria Root, 2.8 parts by weight of Astragalus Root, 2.1 parts by weight of Jicopsis Root, and 0.7 parts by weight of Licorice were used. Of these, for Licorice Root and Astragalus Root, normal shredded material (shredded material of a size that does not pass through a sieve with a nominal mesh size of 4 mm), fine shredded material (shredded material of a size that passes through a sieve with a nominal mesh size of 1 mm), or a mixture of 0.5 parts by weight of normal shredded material and 0.5 parts by weight of fine shredded material were used. The shredded material of Licorice Root and Astragalus Root was the same size. For other herbal medicines, normal shredded material (shredded material of a size that does not pass through a sieve with a nominal mesh size of 4 mm) was used.

These finely chopped herbs were mixed and extracted with 10 times the weight of water at approximately 100°C for 1 hour, then centrifuged to obtain an extract. The extract was concentrated under reduced pressure and dried using a spray dryer to obtain Seishinrenshi-in extract powder. The Seishinrenshi-in extract powder obtained weighed 2238 mg per 21.7 g of raw herb mixture. Drying using a spray dryer was performed by dropping the extract into an atomizer rotating at 10,000 rpm and supplying hot air at 150°C.

(2) Measurement of glycyrrhizinic acid and ononin The contents of glycyrrhizinic acid and ononin contained in the obtained Seishinrenshi-in extract were measured by the following method. In the following, the notation "(x→y)" regarding the dilution ratio of a diluted reagent means that x parts by volume of the reagent was diluted with y parts by volume of water.

<Measurement of glycyrrhizic acid>
About 0.2 g of the dried extract was precisely weighed, 20 mL of ethyl acetate and 10 mL of water were added, and the mixture was shaken for 10 minutes. This was centrifuged, the upper layer was removed, and then 20 mL of ethyl acetate was added and the same procedure was repeated to remove the upper layer. 10 mL of methanol was added to the resulting aqueous layer, and the mixture was shaken for 30 minutes, then centrifuged, and the supernatant was separated. 20 mL of diluted methanol (1 → 2) was added to the residue, and the mixture was shaken for 5 minutes, then centrifuged, and the supernatant was separated, combined with the previous supernatant, and diluted methanol (1 → 2) was added to make exactly 50 mL, which was used as the sample solution. Separately, about 10 mg of glycyrrhizic acid standard was precisely weighed, and dissolved in diluted methanol (1 → 2) to make exactly 100 mL, which was used as the standard solution.

10 μL of each sample solution and standard solution were taken accurately and tested by liquid chromatography under the following conditions, and the peak area AT of the sample solution of glycyrrhizinic acid and the peak area AS of the standard solution of glycyrrhizinic acid were measured for each solution.

(Liquid Chromatography Test Conditions)
Detector: ultraviolet spectrophotometer (measurement wavelength: 254 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm was packed with 5 μm octadecylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 40° C. Mobile phase: 3.85 g of ammonium acetate was dissolved in 720 mL of water, and 5 mL of acetic acid (100) and 280 mL of acetonitrile were added.
Flow rate: 1.0 mL per minute

Using the obtained peak areas AT and AS, the amount of glycyrrhizinic acid (mg) per weighed amount was calculated based on the following formula:

<Measurement of Ononin>
Approximately 0.5 g of the dry extract was precisely weighed, 50 mL of methanol was accurately added, and the mixture was shaken for 30 minutes, followed by ultrasonic extraction for 30 minutes. This liquid was filtered, and the filtrate was used as the sample solution. Separately, ononin standard was precisely weighed, and methanol was added to dissolve it to make exactly 100 mL. This methanol solution was irradiated with ultrasonic waves to make the standard solution. 10 μL of each of the sample solution and standard solution were precisely taken, and tested by liquid chromatography under the following conditions, and the peak area AT of the sample solution and the peak area AS of the standard solution of ononin in each sample solution were measured.

(Liquid Chromatography Test Conditions)
Detector: ultraviolet spectrophotometer (measurement wavelength: 249 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm was packed with 5 μm octadecylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 40°C Mobile phase: diluted acetic acid (1 → 500) / acetonitrile (4 / 1 (volume ratio)) mixture Flow rate: 1.0 mL per minute

The amount of ononin was calculated using the obtained peak areas AT and AS based on the following formula.

(3) Evaluation of sweetness score Ten taste-trained monitors placed 1 g of the obtained Seishinrenshi-in extract directly on their tongues and evaluated the sweetness they felt on a 5-point scale (1 being weak, 5 being strong) using a VAS, and the scores of all the monitors were averaged. The obtained average scores were classified according to the following criteria to obtain a sweetness score. The results are shown in Table 1.

<Sweetness score>
++++++: 4.7 or more ++++: 3.7 or more and less than 4.7
+++: 2.7 or more and less than 3.7
++: 1.7 or more and less than 2.7
+: Less than 1.7

As shown in Table 1, when prepared using normal shredded material, Seishinrenshi-in extracts containing 0.18% and 0.23% by weight of glycyrrhizinic acid (Reference Example 1, Comparative Example 1) were obtained, but Seishinrenshi-in extract containing 0.23% by weight of glycyrrhizinic acid (Comparative Example 1) had an extremely strong sweetness. According to monitors, this extremely strong sweetness was the unpleasant sweetness unique to glycyrrhizinic acid.

On the other hand, when half the weight of the shredded licorice and astragalus root was replaced with finely shredded pieces, Seishinrenshi-in extracts (Examples 1 and 2) were obtained in which glycyrrhizinic acid was increased and the ratio of ononin to glycyrrhizinic acid was increased. Furthermore, in these Seishinrenshi-in extracts (Examples 1 and 2), despite the high content of glycyrrhizinic acid, which causes an unpleasant strong sweetness, the sweetness was significantly reduced.

Furthermore, when the licorice and astragalus root were all finely chopped, a Seishinrenshi-in extract (Example 3) was obtained in which the amount of glycyrrhizinic acid was further increased and the ratio of ononin to glycyrrhizinic acid was also further increased. And, in this Seishinrenshi-in extract (Example 3), the sweetness was further significantly reduced, despite the fact that the content of glycyrrhizinic acid, which causes an unpleasant strong sweetness, was even higher.

Claims (3)

A herbal medicine containing Seishinrenshiin extract,
The Chinese herbal medicine, wherein the content of glycyrrhizic acid in the Seishinrenshi-in extract is 0.22-1% by weight, and the content of ononin is 8.34-23 parts by weight per 100 parts by weight of glycyrrhizic acid. The herbal preparation according to claim 1, which is in the form of a powder, fine granules, granules, lozenges, or chewable preparation. A method for suppressing the sweetness of glycyrrhizinic acid in a herbal medicine containing Seishinrenshi-in extract containing 0.22 to 1% by weight of glycyrrhizinic acid, comprising:
The method comprises adjusting the content of ononin in the Seishinrenshi-in extract to 8.34 to 23 parts by weight per 100 parts by weight of glycyrrhizinic acid.