JP3178763B2 - Simanol sulfate manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing simnol sulfate and a composition containing the simnol sulfate obtained therefrom, such as pharmaceuticals, cosmetics and foods.

[0002]

2. Description of the Related Art It has long been known that bile of fish has a so-called blood-vibrating effect, and it has already been known that the medicinal component thereof is simanol sulfate.
It has been widely used as a folk medicine to aid digestive and tonic drugs.

[0003] When this fish bile is used as a medicine, it is common to drink the hot water extract, but the hot bile extract of fish bile contains a phenolic substance in addition to simanol sulfate, which is a medicinal ingredient. Since it contains a large amount, it is difficult to use continuously for a long time due to strong bitterness and astringency. In addition, when the polar solvent extract of fish bile is transdermally administered, the phenolic substance has local irritation, and thus has a problem in terms of safety.

[0004] Therefore, from the polar solvent extract of fish bile,
Attempts have been made to remove the phenolic substance to obtain a simnosulfate, but a method for efficiently obtaining a simnosulfate has not yet been reported. For example, it has been difficult to purify by ordinary means, such as column chromatography, because the polarities of phenolic substances and simnol sulfate are very similar. In addition, since phenolic substances form insoluble salts with iron, attempts have been made to remove phenolic substances by adding iron salts.However, since iron salts hydrolyze simnol sulfate, the yield is extremely low. It was not practical.

[0005]

SUMMARY OF THE INVENTION The present invention has been made in view of the above, and provides a method for efficiently obtaining a simnol sulfate from which a phenolic substance has been removed from a polar solvent extract of fish bile. An object of the present invention is to provide a composition such as a drug, a cosmetic, a food, etc., containing the simnol sulfate obtained by the method.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventor has found that a polar solvent extract of fish bile is added with an iron salt solution whose pH has been adjusted to neutral. The present inventors have found that a phenolic substance can be precipitated by converting it into an iron salt, and by removing the iron salt, the phenolic substance in the fish bile extract can be efficiently removed without hydrolyzing the simanol sulfate. Reached.

That is, the present invention is characterized in that fish bile is extracted with a polar solvent, and the resulting extract is treated with an iron salt solution having a neutral pH to remove phenolic substances. The present invention relates to a method for producing simnol sulfate, and a composition containing simnol sulfate obtained by this method.

Hereinafter, the present invention will be described in detail.

<1> Method for producing simnol sulfate of the present invention A method for producing simnol sulfate of the present invention comprises treating a polar solvent extract of fish bile with an iron salt solution having a neutral pH. Removes phenolic substances in the extract.

[0010] The type of fish bile is not particularly limited, but bile of large fish, for example, fish such as whale shark and blue shark, is preferable because bile can be easily collected. These bile can be obtained by using a method such as taking out the gall bladder from the fish and squeezing it. Moreover, you may use what is marketed.

The method of extracting fish bile with a polar solvent may be carried out in a conventional manner, and may be carried out continuously or batchwise. For example, after bile collected from fish as it is or freeze-dried, in addition to a polar solvent in an amount of 1 to 100 times the amount of bile, for several days at room temperature, or for several hours at a temperature near the boiling point, if immersed while stirring Good. This is filtered to remove insolubles, and if necessary, the solvent can be removed by vacuum concentration or the like.

Examples of the polar solvent used for the extraction include alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, water, and the like. One of these solvents may be used alone, or two or more thereof may be used. May be used in combination.

[0013] In the method for producing simnol sulfate of the present invention, the polar solvent extract of fish bile obtained as described above is dissolved again in a polar solvent, and an iron salt solution adjusted to a neutral pH is added thereto. The mixture is stirred at room temperature for a sufficient time, and the iron salt of the phenolic substance precipitated thereby is removed by filtration or the like. Further, if necessary, the solvent can be removed by concentration under reduced pressure or the like. According to this production method, the phenolic substance alone can be removed without hydrolyzing the simnol sulfate, and the phenolic substance-free simnol sulfate can be efficiently obtained.

Here, examples of the polar solvent include the same solvents as the polar solvent used in the above-mentioned extraction, and a solvent having a property of dissolving simnol sulfate and not dissolving an iron salt of a phenolic substance. For example, hydrous alcohol and the like are preferably used.

The iron salts used in the present invention include inorganic iron salts such as ferrous chloride, ferric chloride, iron sulfate and iron nitrate, and organic acid iron salts such as iron citrate, iron tartrate and iron gluconate. Salts and the like can be exemplified, but an iron salt which has high reactivity with the phenolic substance and easily precipitates an iron salt of the phenolic substance in the solution, such as ferric chloride, is preferably used.

Further, as the reagent for adjusting the pH of the solution to neutral in the present invention, a weak base such as aqueous ammonia can be exemplified. In the method for producing simnol sulfate of the present invention, the phenolic substance-free simnol sulfate obtained as described above is further purified by column chromatography using a styrenedivinylbenzene-based resin as a carrier. preferable.

Many styrene-divinylbenzene resins for column chromatography are commercially available, and in the present invention, these commercially available products, for example, Diaion HP-20 (manufactured by Mitsubishi Kasei Co., Ltd.) are used. You can also.

<2> Composition of the present invention The composition of the present invention contains the simnol sulfate obtained by the above-mentioned production method.
Cosmetics, foods, and the like.

Here, simnol sulfate obtained by the production method of the present invention refers to a solution of simnol sulfate obtained by removing a phenolic substance from the polar solvent extract of fish bile and a concentrate thereof. Further, it refers to a purified product of simnol sulfate obtained by purifying a solution or concentrate of this simnol sulfate by column chromatography using a styrene divinylbenzene-based carrier.When these are added to the composition, they are used alone. Also,
Alternatively, they may be used as a mixture.

(1) Pharmaceutical The dosage form of the pharmaceutical of the present invention is not particularly limited, but is generally one of harmless one or several kinds of vehicles, carriers, excipients, binders, preservatives which are pharmaceutically acceptable. , Stabilizers, flavoring agents, admixed with coatings, etc., tablets, powders, granules,
Capsules, oral preparations such as drenches, ointments, creams, external preparations such as solutions, injections such as sterile solutions and suspensions can be prepared. These can be manufactured using a conventionally known technique.

For example, the above-mentioned Simnol sulfate and binders such as corn starch and gelatin, excipients such as microcrystalline cellulose, leavening agents such as potato starch and sodium alginate, and sweeteners such as lactose and sucrose are distributed. Into powders, tablets, granules and capsules. In the case of an injection, distilled water for injection, polyethylene glycol, or the like is used as a solvent, or a dispersant, a buffer, a preservative, an antioxidant, and the like may be added as necessary. Good. When used as an external preparation, petrolatum, paraffin, oils and fats, lanolin and the like are used as bases.

The dosage varies depending on the use, purpose, symptoms, age, body weight, etc., but generally, the amount of simanol sulfate per adult per day is 10-500 mg for oral administration and 1-500 mg for injection. By using in the range of 100 mg, and with respect to the external preparation, the compounding amount of simnol sulfate is 0.1% based on the total amount of the external preparation.
The expected effect can be expected by administering as 10 to 10% by weight.

(2) Cosmetic The dosage form of the cosmetic of the present invention is not particularly limited.
For example, besides basic cosmetics (including hair cosmetics) such as lotions, emulsions, creams, and aqueous gels, finishes such as foundations and control colors can be mentioned. These cosmetics can be produced in the same manner as ordinary cosmetics, except that they contain simnol sulfate.

The cosmetic of the present invention contains various components generally used in cosmetics, that is, an aqueous component, an oil component,
Powder ingredients, surfactants, humectants, thickeners, coloring agents, fragrances,
An antioxidant, a pH adjuster, a chelating agent, a preservative, or an ultraviolet protective agent, an anti-inflammatory agent, a whitening agent, and the like can be added.

(3) Food In the case where the above-mentioned simnol sulfate is blended into a food, the required amount of the simnol sulfate may be added to each food material as a general food, and processed and produced by a usual production method. As for the amount of the compound, it may be mixed with each food so that 10 to 500 mg of Simulnosulfate per adult per day can be ingested.

[0026]

The present invention will be described below in detail with reference to examples. First, Examples of the method for producing simnol sulfate of the present invention will be described.

[0027]

Example 1 500 g of a dried shark bile was pulverized, and 2 l of ethanol was added thereto, followed by heating under reflux for 2 hours. After cooling, the resulting solution was filtered to remove insolubles, and concentrated under reduced pressure to dryness. 50% of 1L
Dissolve in ethanol aqueous solution and add 40 g of ferric chloride to 40
A solution dissolved in 0 ml of a 50% aqueous ethanol solution and adjusted to pH 7 with ammonia was added, and the mixture was stirred at room temperature for 12 hours. Thereafter, insolubles were removed from the obtained solution by filtration, and the solid was dried under reduced pressure.

Further, the dried product obtained as described above was dissolved in purified water and charged into a column filled with DIAION HP-20 (manufactured by Mitsubishi Kasei Corporation). Thereafter, purified water was flown to wash the column, and ethanol was further flowed to elute simanol sulfate. The solvent was removed from this solution to obtain 39.6 g of simnol sulfate produced by the production method of the present invention as a pale yellow amorphous.

<Evaluation of Simnol Sulfate> With respect to the simnol sulfate obtained in Example 1 above, the safety and the blood activating effect (blood flow improving effect) were evaluated. As a comparison, the dried shark bile used as a raw material in Example 1 was used.

(1) Local Toxicity Test Three groups of six female Hartley female white guinea pigs were placed on the back of the simnol sulfate obtained in Example 1 in three groups.
0.05 ml of a 1% physiological saline solution, a 1% physiological saline solution of the dried shark bile used in Example 1 as a comparison, and 0.05 ml of a physiological saline as a control were injected intradermally.
Twenty-four hours after the injection, the injection site was observed and judged based on the following Japanese patch test criteria.

-: No reaction ±: False positive reaction +: Positive reaction ++: Reaction with edema The results are shown in the number of guinea pigs judged at each level.
Shown in

[0032]

[Table 1]

From these results, it can be seen that simnol sulfate obtained by the production method of the present invention has higher safety than dried bile. This also indicates that the phenolic substances removed in the purification process of the present invention contribute to local toxicity.

(2) Improving Blood Flow Two groups of 5 Wistar rats (male, body weight 200
g to 250 g) with sodium pentobarbital, and then a cannula for drug administration was attached to the femoral vein and a probe for measuring blood flow was attached to the vertebral artery. The blood flow of each rat was measured before administration of the drug, and thereafter, 10 μg of the blood flow improving agent obtained in Example 1 and the dried shark bile used in Example 1 were added to the rats of each group from the cannula.
The blood flow was measured again 30 minutes after the administration.

The blood flow measurement value before drug administration is subtracted from the blood flow measurement value after drug administration, the result is divided by the blood flow measurement value before drug administration, and the result is multiplied by 100 to obtain a blood flow improvement degree (%). Was used for evaluation. The results are shown in Table 2 as an average of 5 rats.

[0036]

[Table 2]

As is apparent from these results, regarding the blood flow improving effect used as an indicator of the vitality, not only the simnol sulfate obtained by the production method of the present invention but also the dried shark bile were excellent in blood. It has been found to have a flow improving effect.

Furthermore, the results show that the simnol sulfate obtained by the production method of the present invention is more excellent in improving the blood flow rate than the dried shark bile,
In addition, it can be seen that the phenolic substance removed in the purification process of the present invention does not contribute to the efficacy.

Next, examples of the composition of the present invention, such as pharmaceuticals, cosmetics, and foods, containing the simnol sulfate obtained by the production method of Example 1 will be described. The amounts used below are all parts by weight.

[0040]

Example 2 Capsules A component in Table 3 was mixed well, put in a New Marumerizer (manufactured by Fuji Paudal), granulated while spraying a 10% aqueous solution of B component, and dried at 50 ° C. for 6 hours. Thus, coarse granules were obtained. This was placed in a capsule filling machine and encapsulated to obtain a capsule.

[0041]

[Table 3]

[0042]

Example 3 Tablets The components shown in Table 4 were uniformly mixed, and granulated while spraying water using a Numalmerizer, followed by hot-air drying.
This was tableted with a tableting machine to obtain tablets.

[0043]

[Table 4]

[0044]

Examples 4 and 5 Lotion The components shown in Table 5 were weighed, stirred at room temperature, and dissolved to prepare a lotion.

[0045]

[Table 5]

[0046]

Example 6 Emulsion The components A, B and C in Table 6 were each dissolved by heating at 80 ° C., the B component was added to the A component, the C component was further added and emulsified. Obtained.

[0047]

[Table 6]

[0048]

Example 7 Cream The components A and B in Table 7 were each dissolved by heating at 80 ° C.
The component A was gradually added to the component A, emulsified, and cooled with stirring to obtain a cream.

[0049]

[Table 7]

[0050]

Example 8 Candy The component A shown in Table 8 was heated and dissolved at 150 ° C., cooled to 120 ° C., added with the component B, stirred, molded, and cooled to obtain a candy. In the same manner, a candy of Comparative Example 1 was prepared, in which the dried shark bile used in Example 1 was replaced with the simnol sulfate obtained in Example 1.

[0051]

[Table 8]

<Evaluation of Food of the Present Invention> The candy obtained in Example 8 and Comparative Example 1 was used to evaluate the taste.

[0053] Ten panelists tasted the candy of Example 8 and the candy of Comparative Example 1,
A questionnaire regarding the overall taste was conducted and evaluated. The results are shown in the bottom column of Table 8 by the number of persons.

Thus, the candy of the example containing the simnol sulfate obtained by the production method of the present invention had a taste better than that of the comparative candy containing the dried shark bile from which the phenolic substance had not been removed. Turned out to be good.

[0055]

Example 9 Gummy The component A in Table 9 was heated and dissolved at 110 ° C., the separately swelled and dissolved component B was added, the component C was further added, and the mixture was poured into a mold.
After standing for one day and night, it was removed from the mold to obtain gummy.

[0056]

[Table 9]

[0057]

According to the method of the present invention for producing simnol sulfate, it is possible to remove phenolic substances more efficiently than the polar solvent extract of fish bile, and to obtain the pharmaceutical, cosmetic, and food products of the present invention. The composition such as, by blending the simnol sulfate obtained by the above production method,
Long-term continuous use is possible without any problems in safety and taste.

Continued on the front page (72) Inventor Toshiyuki Fukuda 560 Paula Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside Totsuka Research Laboratories Co., Ltd. (72) Inventor Hisao Iwabuchi 27-1, Takashimadai, Kanagawa-ku, Yokohama-shi, Kanagawa Pref. (72) Inventor Norie Muramatsu 27-1 Takashimadai, Kanagawa-ku, Yokohama-shi, Kanagawa Prefecture Pola Kasei Kogyo Co., Ltd. Yokohama Institute (72) Inventor Yoshikazu Hirai 27-1, Takashimadai Takashimadai, Kanagawa-ku, Yokohama, Kanagawa (72) Inventor Masayoshi Yagi, Inventor Masaki Yagi, 560 Pola, Kashio-cho, Totsuka-ku, Yokohama, Kanagawa Pref. Inside the Totsuka Research Laboratory (58) Fields investigated (Int. Cl. ⁷ , DB name) C07G 17/00 A23L 1/30 A61K 7/00 A61K 35/60 C07C 37/88 C07C 39/04 BIOSIS (DIALOG) JICST (JOIS) AFIC file (JOIS)

Claims (3)

(57) [Claims] 1. Simulnosulfate, wherein fish bile is extracted with a polar solvent, and the resulting extract is treated with an iron salt solution having a neutral pH to remove phenolic substances. Manufacturing method. 2. The method according to claim 1, wherein the extract treated with the iron salt solution is further purified by column chromatography using a styrenedivinylbenzene-based carrier. Manufacturing method of sulfate. 3. A composition containing simnol sulfate obtained by the method according to claim 1 or 2.