JP5984328B2 - Independent Kakkonto extract combination agent - Google Patents

Description

  The present invention relates to an independent kakkonto extract compounding agent. In particular, the present invention relates to an independent kakkonto extract compound containing paeoniflorin at a certain ratio or more with respect to the total amount of glycyrrhizic acid and salts thereof.

  Symptoms often experienced in daily life include stiff shoulders, falling asleep, forty shoulders and fifty shoulders. For example, in the recent advanced information society, operations using computers are increasing. In such a work environment, it is easy to put a burden on the shoulder due to work directed to VDT (Visual Display Terminal) for a long time, and therefore, complaints such as stiff shoulders are a problem. In addition, sleeping mistakes may be accompanied by severe pain, and it is required to quickly reduce or eliminate the pain. In this way, symptoms such as stiff shoulders, sleeping mistakes, forty shoulders, fifty shoulders, etc. cause physical and mental pain such as pain, discomfort, fatigue, and thus quality of life. Therefore, there is a strong demand for an effective method for improving these symptoms.

  As one of the methods for improving these symptoms, drugs corresponding to the symptoms are used. For example, non-steroidal anti-inflammatory analgesics when so-called “stiffness” is used, muscle relaxants are used when muscle tension is high or induration is palpated, and Kokukokuto is used as a traditional Chinese medicine. .

  Dokatsu Kakkonto is a Chinese herbal medicine that has antioxidant, anti-inflammatory, analgesic, and blood circulation promoting effects (eg, Patent Document 1, Non-Patent Documents 1 and 2), and is widely applied to shoulder and back symptoms including shoulder stiffness Has been. However, the conventional application target of Kokukatsu Kakkento is limited to those with mild symptoms, that is, there is a problem that the effect of Kokukokukokuto is insufficient.

  Moreover, in the field of Kampo, there is a provision about the blending ratio of the crude drug used as a raw material, but there is no clear provision about the amount of each active ingredient contained in the Kampo preparation finally obtained. Therefore, the quality of the crude drug itself used as a raw material varies depending on the production area, harvest time, and the like, and the amount of active ingredients in the Kampo preparations thus prepared is often not kept constant. In addition, the amount of active ingredient to be extracted varies greatly depending on the extraction conditions, etc., and the extraction conditions are left to the discretion of the formulator. (For example, see Non-Patent Documents 3 and 4).

  In addition, in Chinese medicines containing licorice such as Tokatsu Kakkonto, attempts are often made to increase the extraction efficiency of glycyrrhizic acid, which is a component in licorice, in order to increase its effectiveness. However, when the content of glycyrrhizic acid in a Chinese medicine preparation is increased, it causes a side effect such as the onset of pseudoaldosteronism due to excessive intake of glycyrrhizic acid (see, for example, Non-Patent Documents 5 and 6).

  From these backgrounds, a Kampo preparation with high antioxidative action, anti-inflammatory action and analgesic action and high safety has been demanded.

JP 2001-288101 A

Monthly Kampo Therapy Vol.12, No 1 (2008) 31-43 Japanese and Chinese Journal of Pharmaceutical Sciences Vol.13, No 2 (1996) 185-189 Monthly Pharmaceutical Affairs Vol.27, No.6, (1985) 1927-1933 Clinical Pharmacology Vol.21, No.1, (1990) pp. 305-310 Journal of the Japan Hospital Pharmacists Association Vol.43, No.9, (2007) 1171-1173 Kampo Preparation Research Vol.13, No.1, (2005) 14-17

  Therefore, an object of the present invention is to provide an independent kakkonto extract compounding agent having high antioxidant action, anti-inflammatory action, analgesic action and high safety.

The inventors of the present invention have made extensive studies in order to solve the above problems, and surprisingly, by adjusting the ratio of glycyrrhizic acid and paeoniflorin contained in Sotsukatsu Kakkonto extract to a certain ratio, It was found that the oxidative action, anti-inflammatory action and analgesic action are remarkably enhanced. The present invention has been completed based on such knowledge and includes the following embodiments.
Item 1. An independent kakkonto extract compounding agent containing 0.5 parts by weight or more of paeoniflorin with respect to 1 part by weight of the total amount of glycyrrhizic acid and its salt.
Item 2. The independent kakkonto extract compounding agent of claim | item 1 containing 0.5-50 weight part of paeoniflorins with respect to 1 weight part of total amounts of glycyrrhizic acid and its salt.
Item 3. The independent kakkonto extract compounding agent of claim | item 1 or 2 containing 0.5-10 weight part of paeoniflorin with respect to 1 weight part of total amounts of glycyrrhizic acid and its salt.
Item 4. The independent kakkonto extract compounding agent in any one of claim | item 1-3 which contains 3-5 weight part of paeoniflorins with respect to 1 weight part of total amounts of glycyrrhizic acid and its salt.
Item 5. The independent kakkonto extract combination preparation according to any one of Items 1 to 4, comprising 5 to 15 mg of a total amount of glycyrrhizic acid and a salt thereof per daily dosage unit.

  The sole active kakkonto extract combination agent of the present invention contains paeoniflorin at a certain ratio or more with respect to the total amount of glycyrrhizic acid and its salt, so that it has an antioxidant action, an anti-inflammatory action and an analgesic action derived from glycyrrhizic acid. Is significantly increased.

  Conventionally, the antioxidant action and the like in glycyrrhizic acid are known, but in the independent kakkonto extract combination agent of the present invention, the antioxidant action, anti-inflammatory action, and analgesic action of glycyrrhizic acid and its salt are synergistic by paeoniflorin. Has been enhanced.

  For this reason, it is possible to reduce or eliminate diseases such as stiff shoulders, forty shoulders, fifty shoulders and the like quickly and efficiently by ingesting or taking the self-existing kakkonto extract compound of the present invention. . In addition, although the degree of inflammation is higher than that of the stiff shoulder, according to the composition of the independent kakkonto extract of the present invention, it is remarkably superior to that of such a high level of inflammation. It can be used for reducing or eliminating effects and has immediate effect.

  In addition, in the composition of the independent kakkonto extract of the present invention, the antioxidative action, anti-inflammatory action, and analgesic action of glycyrrhizic acid and its salts are synergistically enhanced, so that pseudoaldosteronism caused by excessive intake of glycyrrhizic acid can be prevented. While effectively preventing side effects such as onset, it is possible to significantly exert an antioxidant action and the like derived from glycyrrhizic acid.

The sole active kakkonto extract compounding agent of the present invention is characterized in that paeoniflorin is contained at a certain ratio or more with respect to the total amount of glycyrrhizic acid and its salt. Hereinafter, the present invention will be described in more detail.
(1) Tokatsu Kakkonto Extract Tokoku Kakkonto is a traditional Chinese medicine. In the present invention, conventionally known Kakkonto can be used.

  Tokutsu Kakkonto is specifically used as a crude drug for raw materials, and is usually used in cucumber (Pueraria lobata Ohwi), keihi (Cinnamomum cassia Blume), peonies (Paeonia lactiflora Pallas), maou (Ephedra sinica Stapf, Ephedra intermedia Schrenk et CA Meyer, Ephedra equisetina Bunge, Aralia Rhizome, Zingiber officinale Roscoe, Rehmannnia glutinosa Liboschitz var, purpurea Makino, Rehmannia glutinosa Liboschitz, Zizypus jujube Miller der. , Glycyrrhiza glabra Linne). These raw materials are used in accordance with the Japanese Pharmacopoeia, and the site of use is defined in the present invention.

  The preparation of Dokatsu Kakkonto is described in the “Revised General Kampo Prescription Guide” (supervised by the Japan Association of Official Medicines, edited by the Japanese Herbal Medicines Association, published by Yakuho Jihosha) and the “Basic Handling Policy of Kampo Preparations”. You can follow the rules. Depending on the letter, the component ratio and the like may be slightly different, but these differences are not particularly limited, and any of them are included as the above-mentioned Kokukoku-to.

  Although not limited, for example, Kokukatsu Kakkonto is converted into the dry weight of the crude drug used as a raw material, and is 2.5, Keihi 1.5, Peonies 1.5, Maow 1, Dokkatsu 1, Shokyo 0.5, It can be set to Zio 2.0, Tiso 0.5, and Licorice 0.5.

  In the present invention, Kokukoku-to extract is an extract obtained from a mixture of the raw herbal medicines of Kokukoku-koku-to. For example, Tokatsu Kakkonto extract is about 10 to 20 times the amount of water added to the herbal medicine mixture, stirred and extracted at about 80 to 100 ° C. for about 1 to 3 hours, centrifuged or filtered, and extracted. Can be obtained by obtaining The resulting Kokukokuto extract may be liquid, may be concentrated or diluted, may be dried by a known method such as spray-drying treatment or freeze-drying treatment, and if necessary after drying It is good also as a powder form by grind | pulverizing, The form should just be determined suitably according to a use aspect, and is not restrict | limited.

  Tokutsu Kakkonto extract is not limited in more detail. For example, about 10 times the amount of water is added to the herbal medicine mixture, and the mixture is stirred and extracted at about 95 to 100 ° C. for about 1 hour. After filtration (centrifugation or natural filtration) corresponding to 100 to 200 mesh, the filtrate is concentrated under reduced pressure at 60 to 70 ° C. or less and then spray-dried.

  Each herbal medicine, which is the raw material for Kokukatsu Kakkonto, varies in quality depending on the production area and harvest time of the herbal medicine. Moreover, the amount of active ingredients contained in the extract also changes depending on the blending ratio of each herbal medicine used as a raw material for Kokukatsu Kakkonto. For this reason, the acquisition of the Kokukatsu Kakkonto extract is carried out with appropriate fine adjustment according to the quality of the herbal medicine used and the blending ratio of each herbal medicine. The fine adjustment can be naturally performed by those skilled in the art. In addition, for example, glycyrrhizic acid is contained in licorice and paeoniflorin is contained in peony and the like. Specifically, the shearing method of licorice and peony is adjusted (finely or roughly chopped), licorice and peony. Examples include selecting the production area and harvest time, adjusting the extraction solvent, adjusting the extraction temperature, adjusting the extraction time, increasing or decreasing the number of extractions, selecting a concentration method, and a drying method. By these methods, the yield and content of glycyrrhizic acid, its salt, and paeoniflorin are adjusted, and the content of these components in the resulting sotsukatsu kakkonto extract is confirmed to prepare the compounding agent of the present invention. be able to.

  Thus, by obtaining Kokukokuto extract, Kokuketsuto extract containing paeoniflorin in the following ratio with respect to the total amount of glycyrrhizic acid and its salt can be obtained.

  That is, it is important that the obtained Kokukokuto extract obtained contains paeoniflorin at a certain ratio or more with respect to the total amount of glycyrrhizic acid and its salt. Specifically, the self-existing Kakkonto extract contains 0.5 parts by weight or more of paeoniflorin with respect to 1 part by weight of the total amount of glycyrrhizic acid and its salt. In addition, the sole active kakkonto extract preferably contains 0.5 to 50 parts by weight of paoniflorin, more preferably 0.5 to 10 parts by weight with respect to 1 part by weight of the total amount of glycyrrhizic acid and its salt. Contained, particularly preferably 3 to 5 parts by weight. Within this range, the antioxidant, anti-inflammatory and analgesic effects of Kokukokukokuto extract can be synergistically increased, and the content of glycyrrhizic acid and salts thereof that cause side effects can be reduced.

  Here, examples of the salt of glycyrrhizic acid include salts with alkali metals such as sodium and potassium; ammonium salts and the like. Specific examples include salts with alkali metals such as disodium glycyrrhizinate, trisodium glycyrrhizinate, dipotassium glycyrrhizinate and tripotassium glycyrrhizinate; and ammonium salts such as monoammonium glycyrrhizinate. Among these, Preferably it is a salt with an alkali metal, More preferably, dipotassium glycyrrhizinate is illustrated. These glycyrrhizic acid salts may be used alone or in any combination of two or more.

The content of glycyrrhizic acid and its salt, and paeoniflorin in Tokatsu Kakkonto extract is measured by the following method.
<Quantitative method of glycyrrhizic acid and its salt>

After sufficiently extracting 0.6 g of Tokatsu Kakkonto extract with methanol, it is quantified according to the quantification method described in the 15th revised Japanese Pharmacopoeia Manual (herbal medicine, etc.), pages D-142 to D-151 “kanzo”. The column uses COSMOSIL “5C18-MS-II” (inner diameter 4.6 × 150 mm). At a column temperature of 20 ° C., the absorbance at 232 nm is measured with an ultraviolet absorptiometer using a mixture of distilled water, acetonitrile and phosphoric acid at 850: 150: 1 as the mobile phase.
<Quantification method of paeoniflorin>

  After sufficiently extracting 0.6 g of Dokatsu Kakkonto extract with methanol, it is quantified according to the quantification method described in the 15th revision Japanese Pharmacopoeia Manual (herbal medicine, etc.) D-324-D-329 “Rakuyaku”. The column uses COSMOSIL “5C18-MS-II” (inner diameter 4.6 × 150 mm). At a column temperature of 20 ° C., the absorbance at 254 nm is measured with an ultraviolet absorptiometer using a mixed solution of acetic acid and acetonitrile diluted 15-fold with distilled water as a mobile phase at a column temperature of 20 ° C.

By this measurement, the amount of glycyrrhizic acid and its salt and the amount of paeoniflorin in the obtained Kokukokuto extract can be quantified.
(2) Dokatsu Kakkonto extract combination agent The Dokoku Kakkonto extract combination agent of the present invention contains Dokatsu Kakkonto extract, which contains paeoniflorin at a certain ratio or more with respect to the total amount of glycyrrhizic acid and its salt. It is characterized by being.

  Specifically, the sole active kakkonto extract compounding agent of the present invention is characterized by containing 0.5 parts by weight or more of paeoniflorin with respect to 1 part by weight of the total amount of glycyrrhizic acid and its salt. Moreover, the sole active kakkonto extract compounding agent of the present invention preferably contains 0.5-50 parts by weight of paeoniflorin, more preferably 0.5-10 parts per 1 part by weight of the total amount of glycyrrhizic acid and its salt. It is characterized by containing 3 parts by weight, more preferably 3-5 parts by weight.

  Examples of the glycyrrhizic acid salt include those described above. In addition, the quantification of glycyrrhizic acid and its salt and the quantification of paeoniflorin in Dokatsu Kakkonto extract compounding agent are carried out in the same manner according to the aforementioned quantification method.

  Glycyrrhizic acid and its salt, and paeoniflorin contained in the composition of the sole active kakkonto extract of the present invention, may be composed only of those contained in the sole active kakkonto extract. In addition, when the content of paeoniflorin does not satisfy the above-mentioned ratio, the glycyrrhizic acid and its salt and paeoniflorin may be appropriately adjusted so as to obtain a predetermined blending ratio. For example, glycyrrhizic acid (manufactured by Wako Pure Chemical Industries, Ltd.), dipotassium glycyrrhizinate (manufactured by Maruzen Pharmaceutical Co., Ltd.), paeoniflorin (manufactured by Wako Pure Chemical Industries, Ltd.), etc. are commercially available as those that can be externally added. It is.

  Preferably, glycyrrhizic acid and paeoniflorin in the combination agent of the Kokukokuto extract of the present invention are composed only of those contained in the Kakkonto extract, more preferably, described in the above “(1) Kakkonto extract”. It is composed only of those contained in the Kokukokuto extract.

  The blending amount of the sotsukatsu kekkonto extract in the soot kakkonto extract composition of the present invention is not limited as long as the total amount of glycyrrhizic acid and its salt and the amount of paeoniflorin satisfy the above ratio.

  For example, in the case where the total amount of glycyrrhizic acid and its salt and paeoniflorin in the combination agent of the sole active kakkonto extract of the present invention are composed only of those contained in the above-mentioned self-existing kakkonto extract described in “(1) the sole active kakkonto extract”. The blending ratio of the self-existing kakkonto extract is not limited as long as the effect of the present invention is exerted. For example, the total dry weight of the extract in the compounding agent is about 10 to 90% by weight, preferably 30%. About 80 to 80 weight%, More preferably, about 50 to 70 weight% is mentioned.

  In addition, for example, in the Kokukatsu-Kento extract compounding agent, the total dry weight of glycyrrhizic acid and its salt is about 0.01 to 10% by weight, preferably about 0.1 to 1% by weight, more preferably 0.1 to 0.1% by weight. About 0.5% by weight can be mentioned.

  In addition, glycyrrhizic acid and its salt in the combination composition of Kokukokuto extract of the present invention are not limited in the same manner as described above. For example, the dose for one adult (body weight 60 kg) is usually converted into dry weight per daily dosage unit. And, for example, 5 to 15 mg, preferably 5 to 10 mg, more preferably 7 to 10 mg. According to the present invention, since the content of glycyrrhizic acid and its salt can be suppressed to this extent, it not only has excellent antioxidant action, anti-inflammatory action and analgesic action, but also originates from glycyrrhizic acid and its salt Can be used as a combination agent of Kakkonto extract with less side effects.

  The administration method of the sole active kakkonto extract combination agent of the present invention is not limited as described above, but it is usually used in the form of oral administration divided into 2 to 3 times a day. The dose time is not particularly limited, but is preferably before or between meals.

  As a matter of course, the blending ratio, dosage, etc. of the solitary kakkonto extract, glycyrrhizic acid, etc. in the solitary kakkonto extract combination agent of the present invention are the dosage form of the compounding agent described later, the administration time to the subject, individual differences, etc. Further, it can be set as appropriate according to the above.

  When the glycyrrhizic acid or the like in the composition of the sole active kakkonto extract of the present invention is derived from something other than the sole active kakkonto extract described in the above-mentioned “(1) the sole active kakkonto extract”, the combination agent is as described above. It may be prepared based on this. This preparation can be naturally performed by those skilled in the art based on the above description.

  The form of the kokukokuto extract combination agent of the present invention is not particularly limited, and is not limited as long as it can be administered orally. The form that can be administered orally includes any conventional form and is not particularly limited. Examples of such forms include solid preparations such as tablets, pills, powders, fine granules, granules, tablets, capsules (including soft capsules); liquid preparations (suspensions) such as liquids (including syrups) Including the agent). Preferably, the sole active kakkonto extract combination agent of the present invention is a solid preparation from the viewpoint of ease of ingestion or taking. Independent Kakkonto extract compounding agents in various forms are produced according to ordinary methods.

  In the case where the solitary kakkonto extract compounding agent of the present invention is a tablet, a well-known carrier in the art can be widely used as a pharmaceutically acceptable carrier together with the above-described solitary kakkonto extract. Examples of such carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, silicic acid, hydrous silicon dioxide; water, ethanol, propanol, simple syrup, glucose solution, Binders such as starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, crystalline cellulose, hydroxypropylcellulose, hypromellose, carmellose calcium, sodium alginate; dry starch, kanteng powder, laminaran powder, carbonic acid Sodium hydrogen, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, crospovidone, povidone, low substituted hydroxypropyl cellulose Disintegrating agents such as stearin, cocoa butter, hydrogenated oil, etc .; absorption accelerators such as quaternary ammonium salts and sodium lauryl sulfate; humectants such as glycerin; starch, lactose, kaolin, bentonite, colloidal Adsorbents such as silicic acid; lubricants such as purified talc, magnesium stearate, stearate, boric acid powder, and polyethylene glycol can be used.

  Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.

  Moreover, also when using the independent active kakkonto extract compounding agent of this invention as a pill, a conventionally well-known thing can be widely used in the said field | area as a pharmaceutically acceptable carrier. Examples of such carriers include glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, tragacanth powder, gelatin, ethanol and other binders, laminaran, agar, etc. Agents can be used.

  In addition to the above, as additives, for example, pharmaceutically acceptable surfactants, absorption promoters, adsorbents, fillers, preservatives, stabilizers, emulsifiers, solubilizers, salts that regulate osmotic pressure Can be appropriately selected and used depending on the form to be prepared.

  Moreover, the above-mentioned Kokukokuto extract and the above-mentioned pharmaceutically acceptable carrier are further filled into a conventionally known capsule made of gelatin, pullulan, starch, gum arabic, hypromellose, etc., to form a capsule. Can do.

  Furthermore, in addition to the above, other active ingredients such as amino acids, vitamins, inorganic salts and the like can be contained in the composition of the independent kakkonto extract of the present invention. Examples of other active ingredients include valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, lysine, glycine, alanine, asparagine, glutamine, serine, cysteine, cystine, tyrosine, proline, hydroxyproline, aspartic acid, glutamic acid , Amino acids such as hydroxylysine, arginine, ornithine, histidine; vitamins such as vitamin A1, vitamin A2, carotene, lycopene (provitamin A), vitamin B6, vitamin B1, vitamin B2, ascorbic acid, nicotinamide, biotin; Examples thereof include alkali metal salts such as sodium chloride and potassium chloride, and inorganic salts such as citrate, acetate and phosphate.

  In the independent kakkonto extract combination agent of the present invention, the antioxidant action, anti-inflammatory action and analgesic action of glycyrrhizic acid and its salts are synergistically enhanced. For this reason, administration (ingestion) of the self-existing Kakkonto extract combination agent of the present invention can remarkably and efficiently reduce or eliminate diseases such as stiff shoulders, falling asleep, forty shoulders and fifty shoulders. it can. In particular, while lying down has a high degree of inflammation compared to normal shoulder stiffness etc., the self-existing kakkonto extract combination agent of the present invention is sufficiently effective for reducing or eliminating such advanced inflammation, Furthermore, it has immediate effect.

  Therefore, the independent kakkonto extract combination agent of the present invention can be suitably applied to patients suffering from diseases such as stiff shoulders, falling asleep, forty shoulders and fifty shoulders, and is more effective than conventionally known preparations.

  In addition, the combination drug of Kakkonto extract of the present invention synergistically enhances the antioxidant action, anti-inflammatory action, and analgesic action of glycyrrhizic acid and its salts, so that side effects due to excessive intake of glycyrrhizic acid are effective. Can be prevented, that is, the safety is high.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated, this invention is not limited to this.
Example: Independent Kakkonto extract combination agent The Independent Kakkonto extract combination agent used in this example was produced as follows.

1. Independence kakkonto extract In this example, in terms of the raw material dry weight, Kakonkon 2.5 (parts by weight, the same applies hereinafter), Keihi 1.5, Peonies 1.5, Maow 1.0, Dokkatsu 1.0, Show Kyo 0.5, Zhi 2.0, Tiso 0.5, and Liquorice 0.5 were extracted with 10 times the amount of water at about 100 ° C. for 1 hour, and centrifuged to obtain an extract. The obtained extract was filtered (150 mesh), concentrated under reduced pressure at 65 ° C., and then dried using spray drying to obtain “Kokukatsu Kakkonto extract”.

2. Content of glycyrrhizic acid and paeoniflorin in Tokatsu Kakkonto extract The amounts of glycyrrhizic acid, its salt and paeoniflorin contained in the souped Kakkonto extract obtained were measured according to the following method.
<Quantitative method of glycyrrhizic acid and its salt>

  After sufficiently extracting 0.6 g of the resulting Kokuketsuto extract with methanol, it was quantified according to the quantification method described in the 15th revised Japanese Pharmacopoeia Manual (herbal medicines, etc.) D-142-D-151 “kanzo”.

  As the column, COSMOSIL “5C18-MS-II” (inner diameter 4.6 × 150 mm) (manufactured by Nacalai Tesque Co., Ltd.) was used.

At a column temperature of 20 ° C., a mixed liquid in which distilled water, acetonitrile (manufactured by Wako Pure Chemical Industries, Ltd.) and phosphoric acid (manufactured by Wako Pure Chemical Industries, Ltd.) are 850: 150: 1 is used as the mobile phase, ultraviolet Absorbance at 232 nm was measured with an absorptiometer (manufactured by Shimadzu Corporation).
<Quantification method of paeoniflorin>
After 0.6 g of the obtained Kokukokuto extract obtained was sufficiently extracted with methanol, it was quantified according to the quantification method described in the 15th revised Japanese Pharmacopoeia Manual (herbal medicine, etc.) D-324-D-329 “Rakuyaku”.

  As the column, COSMOSIL “5C18-MS-II” (inner diameter 4.6 × 150 mm) (manufactured by Nacalai Tesque Co., Ltd.) was used.

At a column temperature of 20 ° C., a mixed solution in which acetic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and acetonitrile (manufactured by Wako Pure Chemical Industries, Ltd.) diluted 15 times with distilled water is used as the mobile phase is 3: 2. The absorbance at 254 nm was measured with an ultraviolet absorptiometer (manufactured by Shimadzu Corporation).
<Adjustment of content of glycyrrhizic acid and its salt and paeoniflorin>

After quantifying glycyrrhizic acid and its salt and paeoniflorin in the resulting Kokuketsu-to extract by the above method, finely chop when the extraction amount is small, or chop coarsely when the extraction amount is large Was obtained.
3. Tokatsu Kakkonto extract combination agent Here, a kokukokuto extract combination agent in the form of a tablet was produced.

Specifically, the self-existing Kakkonto extract obtained as described above, hydrous silicon dioxide (Carplex, manufactured by DSL Japan Co., Ltd.), carmellose calcium (ECG-505, manufactured by Father Lin Chemical Industry Co., Ltd.), talc (By mixing talc raw powder “Marushi”, Maruishi Pharmaceutical Co., Ltd.), magnesium stearate (Japanese Pharmacopoeia Magnesium Stearate, Taihei Chemical Sangyo Co., Ltd.), crystalline cellulose (Theolas, Asahi Kasei Chemicals Co., Ltd.) A mixture was obtained. The mixture thus obtained was tableted using a hydraulic tableting machine to obtain an independent kakkonto extract formulation in tablet form.
Test Example 1: Antioxidant Capacity Measurement Test In this test example, the antioxidant effect of glycyrrhizic acid and paeoniflorin was evaluated.

  As glycyrrhizic acid and paeoniflorin, a Japanese pharmacopoeia standard product, a glycyrrhizic acid standard product and a paeoniflorin standard product were used, respectively. For the measurement of antioxidant, an antioxidant measurement TAS (Total Antioxidant Status) kit (manufactured by Randox Laboratories Ltd) was used. The measurement was performed according to the manual included in the kit.

  Specifically, 20 μl of an aqueous solution (sample) prepared so as to contain the amounts of glycyrrhizic acid and peroniflorin shown in Table 1 below was mixed with 1 ml of chromogen, incubated at 37 ° C., and the initial absorbance A1 was measured. Thereafter, 200 μL of the substrate solution contained in the kit was added, mixed well, and the absorbance A2 was measured after 3 minutes.

  Measurements in the blank and standard were performed in the same procedure as described above, except that the blank reagent or standard included in the kit was used instead of the sample.

The antioxidant capacity was calculated according to the following formula.
A2-A1 = ΔA (Blank / Standard / Sample)

mmol / l = Factor × (ΔA blank−ΔA sample)
The “antioxidant effect” was calculated according to the following formula.

  The “antioxidant effect per blended amount of paeoniflorin” was calculated according to the following formula.

  The results are shown in Table 1 below.

  As is clear from this result, surprisingly, by combining peonyflorin (Comparative Example 2) having almost no antioxidant action with glycyrrhizic acid having an antioxidant action (Comparative Example 1) The oxidation effect increased synergistically.

  Specifically, the antioxidant effect is efficiently enhanced when the blending ratio of glycyrrhizic acid and paeoniflorin is 1: 0.5 or more in terms of weight, and even when it is 1:50, it is efficiently enhanced. Okay (Examples 1-9).

In addition, the blending ratio of glycyrrhizic acid and paeoniflorin is preferably 1: 0.5 to 1:10 (Examples 1 to 7), more preferably, in that the antioxidant effect can be enhanced more efficiently and synergistically. It was found to be 1: 3 to 1: 5 (Examples 4 to 6).
Test Example 2: Analgesia test (acetic acid rising test: inflammatory pain model)
In this test example, an analgesic test (acetic acid rising test) was performed.

  As a model, a 5-week-old male ddy mouse (purchased from Nippon SLC Co., Ltd.) was used. In the test, mice (6 weeks old) fasted for 18 hours were used as 6 mice per group.

  Specifically, the sole activity prepared such that glycyrrhizic acid and paeoniflorin are in the ratios (1: 0.48, 1: 2.1 and 1: 4.3) shown in the Examples or Comparative Examples in Table 2 below. The kakkonto extract compounding agent was obtained as described above. The obtained compounding agent (sample) was crushed, mixed with 1 ml of distilled water, and orally administered to the mouse using a stomach tube (the dose was as shown in Table 2 and calculated based on the body weight of the mouse). ). 45 minutes after oral administration, 0.7% acetic acid aqueous solution was intraperitoneally administered and left for 5 minutes. The number of risings observed during 15 minutes was then measured. Mice that received only distilled water instead of the sample were not treated (Reference Example 1).

  The analgesic effect was calculated according to the following formula.

  The results are shown in Table 2.

  In this test example, as a representative example of the blending ratio of glycyrrhizic acid and paeoniflorin of Examples 1 to 9 in Test Example 1, the sole activity prepared so that the blending ratio of glycyrrhizic acid and paeoniflorin was Examples 10 and 11 A sample of Kakkonto extract formulation was used.

  From these results, in Example 10 and Example 11 containing paeoniflorin in a ratio of a certain amount or more with respect to glycyrrhizic acid, as compared with the untreated group (Reference Example 1) and Comparative Example 3 which does not satisfy the ratio, Rising It was found that the number of times was significantly reduced. That is, it was found that the analgesic effect was synergistically enhanced by using paeoniflorin in combination with a certain ratio or more with respect to glycyrrhizic acid. Moreover, the immediate effect of the effect was confirmed.

Inflammation amplification usually occurs when intracellular transcription factors are activated by signals from excess reactive oxygen species, resulting in increased expression of inflammatory cytokine mRNA. In this test example, the anti-inflammatory action and analgesic action were remarkably enhanced by the synergistic enhancement of the antioxidant action by glycyrrhizic acid and paeoniflorin resulting from the inclusion of paeoniflorin at a certain ratio or more with respect to glycyrrhizic acid. It was confirmed that
Test Example 3: Subjective Symptom Test In this test example, improvement of subjective symptoms was evaluated.

  In this test example, 12 patients who had pain due to falling asleep were used as subjects. The test subjects were divided into two groups of 6 persons, one group being a “sample administration group” in which the independent kakkonto extract formulation (sample) was administered, and the other group being a “sample non-administration group” in which no sample was administered. .

  As a sample, an independent kakkonto extract compounding agent prepared so that glycyrrhizic acid and paeoniflorin had a ratio (1: 4.3) shown in Example 12 of Table 3 below was obtained as described above.

  The daily doses of glycyrrhizic acid and paeoniflorin in the sample are as shown in Example 12 of Table 3. Specifically, the daily sample of 12 tablets is divided into three times and taken between meals. (4 tablets were administered once).

  In the sample administration group, the degree of pain was examined before taking the sample and 24 hours after the start of taking the sample. In the sample non-administered group, the degree of pain was examined together with the measurement of the sample administered group.

  The degree of pain was examined by filling in a Visual Analogue Scale (hereinafter referred to as VAS) questionnaire with 10 as the pain before taking.

  The results are shown in Table 3 below.

  Also in this test example, as a representative example of the blending ratio of glycyrrhizic acid and paeoniflorin of Examples 1 to 9 in Test Example 1, the independent kuzukuri prepared so that the blending ratio of glycyrrhizic acid and paeoniflorin becomes Example 12. A sample of hot water extract formulation was used.

  From this result, by taking the sample described in Example 12, a markedly excellent pain reduction effect was confirmed. Moreover, the immediate effect of the effect was confirmed.

In this way, it was confirmed that pain was reduced even when sleeping with a higher degree of inflammation than stiff shoulders, so when paeoniflorin was combined with glycyrrhizic acid at a certain ratio or more, it was significantly better than ever It was found that anti-inflammatory action and analgesic effect were exhibited.
Formulation Examples Formulation Examples 1 to 28 are shown in Tables 4 to 7 below. Manufacture of Kokukokuto extract formulation in each formulation example is as follows.

  An independent Kakkonto extract having the following contents of glycyrrhizic acid and paeoniflorin was obtained as described above. Using the obtained extracts (a) to (g), tablets were prepared according to Formulation Examples 1 to 14 and granules were prepared according to Formulation Examples 15 to 28 by a conventional method. When these preparations were also tested in the same manner as in Test Example 3, an excellent pain reduction effect was confirmed. Moreover, the immediate effect of the effect was confirmed.

Extract (a) Glycyrrhizic acid: 5.0 mg / g
Paeoniflorin: 5.0mg / g
Extract (b) Glycyrrhizic acid: 5.0 mg / g
Paeoniflorin: 10.0mg / g
Extract (c) Glycyrrhizic acid: 5.0 mg / g
Paeoniflorin: 15.0mg / g
Extract (d) Glycyrrhizic acid: 5.0 mg / g
Paeoniflorin: 20.0mg / g
Extract (e) Glycyrrhizic acid: 5.0 mg / g
Paeoniflorin: 25.0mg / g
Extract (f) Glycyrrhizic acid: 5.0 mg / g
Paeoniflorin: 35.0mg / g
Extract (g) Glycyrrhizic acid: 5.0 mg / g
Paeoniflorin: 50.0mg / g

Claims (2)

An independent kakkonto extract compounding agent containing 2 to 50 parts by weight of paeoniflorin with respect to 1 part by weight of a total amount of glycyrrhizic acid and a salt thereof, and containing 30 to 90% by weight of the independent kakkonto extract in a dry weight total amount. The sole active kakkonto extract compounding agent of Claim 1 which contains 5-15 mg of total amounts of glycyrrhizic acid and its salt per daily dosage unit.