JPH0641415B2 - Method of manufacturing herbal medicine extract - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention relates to a method for producing a herbal medicine extract in the pharmaceutical industry.

[Conventional technology]

Since ancient times, crude drugs have been used as Kampo medicines, and their Kampo prescriptions have been described in many classics as a collection of many years of experience (Shokan theory, Kimbyo summary, etc.). According to the classics, however, the decoction, in which the crude drug is cut each time and decocted with water to extract the ingredients in the herbal medicine, is not only difficult to take due to its unique medicinal odor and taste, but also a lot of trouble. And takes time.

Currently, in the field of ethical drugs and the like, Chinese herbal medicine extracts that do not require the above-mentioned work and are easy to take are used, and for the sick, from the aspects of storage, portability, and ease of administration. It is very convenient. This herbal medicine extract is usually prepared by extracting a crude herb that has been cut with water or alcohol, and then directly or concentrating the extract and drying it to obtain a herbal medicine powder, which is a suitable excipient (lactose, corn starch, crystalline cellulose, etc.). ) Is added and mixed to prepare various dosage forms (tablets, capsules, powders, fine granules, granules, etc.).

[Problems to be solved by the invention]

Originally, when a drug is orally administered to a living body, it is absorbed by the disintegration in the body and exerts a medicinal effect, so if the administered drug does not disintegrate in the body, the intended purpose as a drug is It will not be possible.

The Chinese herbal medicine extract obtained as described above cannot be said to be sufficiently satisfactory in terms of disintegration. Therefore, the present invention solves the problem of producing a Chinese herbal medicine extract having good disintegration.

[Means for solving problems]

The inventors of the present invention conducted extensive research in search of a method for producing a herbal medicine extract having good disintegration, and extracted the herbal medicine with an extraction solvent and contacting the extract or its concentrate with immobilized amylase to carry out the reaction. Then, the powder obtained by drying the reaction solution is used as it is or mixed with one or more excipients selected from sugars, starches, dextrins, silicic acid compounds, celluloses and natural gums. Then, it was found that a Chinese herbal medicine extract having various disintegration forms can be obtained, and the present invention has been completed.

Hereinafter, the present invention will be described in detail.

The herbal medicines used in the present invention include not only the herbal medicines referred to in traditional Chinese medicine but also so-called herbal medicines or herbal preparations comprising one or a mixture of two or more herbal medicines. As a specific example of Kampo medicine, a guide to general Kampo prescriptions (supervised by the Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare, published by Yakuji Jikhosha, 4th edition, January 8, 1983)
Printing) and Tsumura Medical Kampo Preparations (Comprehensive Catalog). Hachimijiogan, Saiko Keishito, Saiko Keishikanbiyu, Hangeishinshinto, Goreisan, Keishikajutsuyu, Shoseiryuto, Tokishakuyakusan, Kamishoharusan, Keishibukuryogan, Keishika Ryutsu Oyokeyu, Maoyu, Kihomiyu, Toki Shigyakaku Goyu Ginger Keishika-shakuyakuto, Tokokujokito, Hofutsushosan, Gojakusan, Shurikanzoto, Megamisan, Kososan, Keishijinjinto, Yokukansanka-Chen-Shin-Natsu, Kuchiwa, meanwhile, small Kenchu-to, Toki-to, Onkei-to, Goshisha-Kenki-maru, Sairei-to, Gyorei-to, Keirei-Iihan Specific examples of the original color Japanese and Chinese medicine encyclopedia (first volume, second volume, Tsuneo Namba, published by Hoikusha Co., Ltd. on April 1, 1980) and the 10th revised Japanese Pharmacy Law [supervised by the Japanese Official Book Association, published by Hirokawa Shoten (p .863-p.1278)].

Examples of the extraction solvent for Chinese herbs include water or an aqueous ethanol solution having an ethanol concentration of 25% or less,
It can be extracted hot or cold, especially with water.
A method of hot extraction at 0 to 100 ° C is preferable.

Concentration of the extract is generally performed under reduced pressure. Specifically, the degree of vacuum is 30 to 760 mmHg, and the evaporation temperature is 100 ° C.
Hereinafter, vacuum concentration is performed preferably under the condition of 30 to 50 ° C.

Then, the above-mentioned extract or its concentrate is brought into contact with immobilized amylase to react.

As the amylase to be immobilized, α-amylase, β-
Amylase, saccharified amylase and the like can be used, and specific examples of α-amylase include α-amylase (manufactured by Wako Pure Chemical Industries, Ltd.), klyase (manufactured by Daiwa Kasei Co., Ltd.), etc. Specific examples of the α-amylase include Neospitase PG (manufactured by Nagase Sangyo Co., Ltd.) and spitase CP-3 (manufactured by Nagase Sangyo Co., Ltd.). Specific examples of β-amylase include “β-amylase # 1500” (manufactured by Nagase & Co., Ltd.), Zeozyme M (manufactured by Amano Pharmaceutical Co., Ltd.) and the like, and specific examples of saccharified amylase include glucozyme (Nagase & Co., Ltd. Manufactured by Nagase & Co., Ltd., and the like.

In order to obtain a solid amylase by immobilizing these amylases, a commonly used enzyme immobilization method [for example, 198
July 21, 1st, Tokyo Kagaku Dojin, "Biochemistry Experiment Course, Enzyme Research Method (below)" p. 644 to 660]. In addition, commercially available immobilized α
-Amylase [eg A-5386 manufactured by SIGMA] can also be used.

Here, a specific example of the production of the immobilized amylase is as follows.

Specific Example 10 mg of α-amylase (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in 0.1 M Tris-hydrochloric acid buffer solution to obtain acrylamide 7
50 mg and 40 mg of N, N fraction-methylenebisacrylamide (manufactured by Tokyo Kasei) were added. To this mixed solution, 0.5 m of a 5% dimethylaminopropionitrile aqueous solution and 0.5 m of a 1% potassium persulfate aqueous solution were added, and the mixture was allowed to stand at 37 ° C. for 30 minutes. The gel thus obtained was washed with a 0.2 M sodium phosphate buffer, lyophilized, and then sieved through a 40-80 mesh sieve to obtain immobilized α-amylase.

In order to bring the extract or concentrated solution of the above herbal medicine into contact with the immobilized amylase to react with it, any means capable of bringing the extract or concentrated solution into contact with the immobilized amylase may be used. For example, an immobilized amylase is directly added to the above extract or concentrate to bring them into contact with each other to cause a reaction,
After completion of the reaction, a separation operation usually used, for example, 30 to 4
Examples include a method of obtaining a reaction solution by separating the immobilized amylase by treatment with a vibrating screen of about 50 mesh, centrifugation, and suction.

At this time, the reaction temperature is 20 ° C to 50 ° C, particularly 30 ° C to 40 ° C.
℃ is preferred, and the pH of the reaction solution is preferably 6 to 8. Therefore, if necessary, add an alkali such as calcium carbonate, calcium hydroxide, sodium carbonate or sodium hydroxide.
It is better to adjust the pH. The reaction time depends on the amount of alkali to be added or the reaction temperature, but is completed in about 1 to 48 hours, and it is more effective if the reaction is carried out with stirring using a commonly used stirring device or the like. The amount of immobilized amylase added is 0.05% or more, particularly 0.1% to 100%, relative to the weight of starch contained in the extract or its concentrate.
Is preferred.

Alternatively, the immobilized amylase may be packed in a suitable reactor, for example, a column, and the extract or concentrate may be passed through and contacted therewith to obtain a reaction solution. In this case, 30
It is desirable to set the reactor, for example, the diameter and length of the column, the outflow rate of the reaction solution, etc. so that the above-mentioned extract or concentrate may contact the immobilized amylase for 30 minutes or more under a temperature condition of ˜70 ° C. .

The reaction solution obtained as above is dried as it is or after being concentrated. The reaction liquid can be concentrated in the same manner as the above-mentioned concentration of the extraction liquid. The reaction solution or its concentrated solution is dried by a suitable drying method such as a spray drying method, a vacuum drying method or a freeze-drying method generally used to obtain a powder, that is, a Chinese herb extract powder. For example, in the case of the spray drying method, an atomizer sprays the reaction liquid or its concentrated liquid into a hot air stream in a drying chamber kept at a high temperature of 60 to 300 ° C. to instantaneously evaporate the solvent for drying. In the case of vacuum drying method,
The reaction solution is sufficiently concentrated under reduced pressure and dried under a reduced pressure of 760 mmHg or less at 5 to 100 ° C. In the freeze-drying method, the reaction solution or its concentrated solution is cooled to −80 to 0 ° C. to be frozen, and the solvent is directly sublimed in a vacuum state of 1 mmHg or less for drying.

The Chinese herb extract powder thus obtained may be directly made into various dosage forms (tablets, capsules, powders, fine granules, granules), or mixed with an appropriate excipient to obtain various dosage forms. (Tablets, capsules, powders, fine granules, granules).

Mixing of Chinese herb extract powder and excipients is achieved by ordinary powder mixing using a mixer, etc., and the specific mixing ratio is based on the total weight of Chinese herbal extract powder and excipients. The agent weight is 0.1 to 95%, preferably 5 to 50%.

Specific examples of saccharide excipients include mannitol, sucrose, sorbitol, glucose, fructose, maltose, lactose and the like, and specific examples of starch excipients include corn starch, soluble starch, carboxymethyl starch and the like, Specific examples of the dextrin type excipients include dextrin, cyclodextrin and the like, and specific examples of the silicic acid compound type excipients include porous silicic anhydride, ultrafine silicic acid anhydride and the like,
Specific examples of the cellulose type excipient include crystalline cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium salt, carboxymethyl cellulose sodium salt, and the like, and specific examples of the natural gum type excipient include trangant gum, gum arabic and the like. Is mentioned.

Then, granules, fine granules, powders by subjecting the Chinese herbal extract powder obtained as described above or a mixture of the Chinese herbal extract powder and excipients to operations such as granulation, sizing, and tableting as necessary. , Into capsules, tablets, etc. to make Chinese herbal extract. In this case, if desired, lubricants and binders usually used in preparations may be added. The granulation method includes a general dry granulation method and a wet granulation method, and the dry granulation method is preferable. [Effects of the Invention] The effects of the present invention include the following points.

The Chinese medicine extract obtained according to the present invention has good disintegration property.

Experimental examples showing that the Chinese medicine extract obtained according to the present invention has good disintegration are as follows.

Experimental Example 1 The same procedure as described in Example 1 below was carried out except that the step of adding immobilized α-amylase (A-5386 manufactured by SIGMA) to the concentrated solution and performing the reaction in Example 1 below was not performed. As a result, one tablet of 300 mg was obtained.

The disintegration time of the Romimi-pill tablets produced as described above and the Romi-mi-pill tablets produced in Example 1 below was measured by the disintegration test method of the 10th revised Japanese Pharmacopoeia. That is, the lower end of a glass tube with an inner diameter of 22 mm opened at both ends is closed with a mesh opening of 2.0 mm, one sample tablet is placed on the mesh, and this glass tube is soaked in distilled water to move up and down. Disintegration time was defined as the end of disintegration when no residue was observed above. As a result, the disintegration time of the Rokumi-maru tablet produced in Experimental Example 1 was 52 minutes, whereas the Romimi-maru tablet produced in Example 1 described later disintegrated in 15 minutes and the components were rapidly eluted.

Experimental Example 2 Performed in the same manner as described in Example 2 described below, except that the step of adding immobilized α-amylase (A-5386 manufactured by SIGMA Co., Ltd.) to the concentrated solution and performing the reaction in Example 2 described below was not performed. As a result, one tablet of 300 mg was obtained.

In the disintegration test described in Experimental Example 1, the disintegration time of the Romimi-maru tablet produced as described above was 52 minutes, whereas the Romimi-maru tablet produced in Example 2 described later disintegrated in 7.7 min. The components were quickly eluted.

Experimental Example 3 In Example 3 described below, 1 was performed in the same manner as described in Example 3 described below, except that the step of adding the immobilized α-amylase obtained in the above-described specific example to the extract and causing the reaction was not performed.
A Shigyakusan tablet of 290 mg was obtained.

In the disintegration test described in Experimental Example 1, the disintegration time of the Shigyakusan tablet produced as described above was 63.5 minutes, whereas that of the Shigyakusan tablet produced in Example 3 described later was 12.5. It disintegrated in minutes and the components were quickly eluted.

Experimental Example 4 Obtained in the same manner as described in Example 3 below, except that the step of adding the immobilized α-amylase obtained in the above-described specific example to the extract and reacting it in Example 3 described below was not performed. The dried extract powder was compacted, crushed, and classified to obtain a four-reverse-dispersion granule having a diameter of 1.19 to 0.36 mm.

The disintegration time of the Shigyakusan granules produced as described above and the Shigyakusan granules produced in Example 4 below were measured by the disintegration test method of the 10th revised Japanese Pharmacopoeia. That is, inner diameter 12
mm, 20 mm in length of a plastic auxiliary cylinder is closed with a mesh opening of 0.42 mm, and 0.1 g of Shigyakusan granule is put in this auxiliary cylinder. The tablet was fixed at the bottom of the glass tube used in the tablet disintegration test described above, immersed in distilled water and moved up and down, and when no residue was observed in the auxiliary cylinder, the disintegration was completed and the disintegration time was determined. As a result, the disintegration time of the Shigyakusan granule produced in Experimental Example 4 was 16
In contrast to this, the Shigyakusan granules produced in Example 4 described later disintegrated in 2 minutes and quickly eluted the components.

Experimental Example 5 In Example 5 described later, the same procedure as described in Example 5 described below was performed except that the step of adding immobilized α-amylase (A-5386 manufactured by SIGMA Co., Ltd.) to the concentrated solution and performing the reaction was not performed. One ginseng tablet of 210 mg was obtained.

In the disintegration test described in Experimental Example 1, the disintegration time of the ginseng tablet produced as described above was 44.5 minutes, whereas that of the ginseng tablet produced in Example 5 described later was 9.5 minutes. It disintegrated and the components were quickly eluted.

Experimental Example 6 In Example 6 described later, the same procedure as described in Example 6 described below was performed except that the step of adding immobilized α-amylase (A-5386 manufactured by SIGMA Co., Ltd.) to the concentrated solution and performing the reaction was not performed. As a result, ginseng granules with a diameter of 1.18 to 0.36 mm were obtained.

In the disintegration test described in Experimental Example 4, the disintegration time of the ginseng granules produced as described above was 30 minutes or longer, whereas the ginseng granules produced in Example 6 described later disintegrated in 1 minute. Then, the components were quickly eluted.

Experimental Example 7 The ginseng granules obtained in Experimental Example 6 were pulverized with a pulverizer to give 42
The powder of the following powder was filled into No. 1 gelatin capsule (450 mg per capsule) to obtain a ginseng hard capsule.

The disintegration time of the ginseng hard capsules produced as described above and the ginseng capsules produced in Example 7 below was measured by the disintegration test method of the 10th revised Japanese Pharmacopoeia.
That is, the lower end of a glass tube having an inner diameter of 22 mm and both ends opened was closed with a mesh having a mesh opening of 2.0 mm, a sample capsule was placed on the mesh, and this glass tube was used as a test solution (sodium chloride 2. The disintegration time was defined as the disintegration time when the solution was immersed in 0 g of dilute hydrochloric acid (24.0 m) and water to a volume of 1000 m to a pH of about 1.2) and was then moved up and down until no residue was observed on the net.

As a result, while the disintegration time of the ginseng hard capsules produced in Experimental Example 7 was 18 minutes, the ginseng hard capsules produced in Example 7 described later disintegrated in 3 minutes and the components were rapidly eluted. .

Experimental Example 8 In Example 9 described below, the same procedure as described in Example 9 described below was performed except that the step of adding the immobilized α-amylase obtained in the above-described specific example to the extract and reacting it was not performed. One tablet of 250 mg was obtained.

In the disintegration test described in Experimental Example 1, the disintegration time of the Nichinto tablet produced as described above was 60 minutes or longer, whereas the Nichinoto tablet produced in Example 9 described later disintegrated in 12 minutes. Then, the components were quickly eluted.

Experimental Example 9 In Example 11, which will be described later, except that the extract was not passed through a column packed with immobilized α-amylase, the same procedure as described in Example 11, which was described later, was performed. I got an agent.

In the disintegration test described in Experimental Example 4, the disintegration time of Hangekabokuto granules produced as described above was 30 minutes or longer, whereas that of Hangekabokuto granules produced in Example 11 described later was 2 minutes.
It disintegrated in minutes and the components were quickly eluted.

〔Example〕

Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.

Example 1 Rokumi Maru (5 parts of Sioux, 3 parts of Sanyuyu, 3 parts of Sanyaku,
Water (10 kg) was added to 1 kg of a prescription crude drug consisting of Takushia (3 parts, Bucurio 3 parts, and button pie 3 parts), and the mixture was extracted by heating at 100 ° C. After the extraction was completed, solid-liquid separation was performed during heating to obtain an extract. The extract was concentrated to 2 and 500 m of this concentrate was collected and sodium hydroxide was added to adjust the pH to 6.9. The immobilized α-amylase (SIG
0.7 g of A-5386 manufactured by MA Co., Ltd. was added, and 2 at 30 ° C.
The reaction was carried out with stirring for 4 hours. After completion of the reaction, immobilize with a sieve with a mesh of 150 mesh stainless steel α-
Amylase was separated and collected.

The reaction solution thus obtained was freeze-dried (freezing temperature -40
C., vacuum degree 0.1 mmHg, shelf temperature 20.degree. C.) to obtain 90 g of dry extract powder. This dry extract powder 49.75
Magnesium starate [manufactured by Ohira Chemical Industry Co., Ltd.]
0.25 g was added, mixed well in a vinyl bag, and compression-molded so that one tablet was 300 mg to obtain a Rokumi round tablet.

Example 2 α-amylase immobilized on a concentrated solution (A-5 manufactured by SIGMA)
386) 0.7 g was added, and each tablet was obtained in the same manner as described in Example 1 except that the reaction was carried out at 30 ° C. for 48 hours with stirring to give a Rokumi-maru tablet (300 mg each).

Example 3 Shigyakusan (consisting of 5 parts of psycho, 4 parts of peony, 2 parts of pheasant and 1.5 parts of licorice) 30 kg of prescription crude drug and 300 parts of water
Was added and the mixture was heated and extracted at 100 ° C. After the extraction was completed, solid-liquid separation was performed while hot to obtain an extract. 200 of the extract was collected and concentrated under reduced pressure at 40 ° C. until it reached 40. From this concentrated solution, 5 were collected, calcium hydroxide was added thereto to adjust the pH to 6.0, and 200 g of the immobilized α-amylase obtained in the above-mentioned specific example was added to the concentrated solution, which was stirred at 37 ° C. for 10 hours. It was made to react. Then, the immobilized α-amylase was recovered by a centrifuge with a wire mesh of 100 mesh.

The reaction solution thus obtained was spray-dried (blast temperature 160
(° C., exhaust air temperature 110 ° C.) to obtain 800 g of dry extract powder. This powder was compression-molded to obtain a Shigyakusan tablet of 290 mg each.

Example 4 A dry extract powder obtained as described in Example 3 was compressed, crushed and classified to a diameter of 1.19-0.36 mm.
To obtain Shigyakusan granules.

Example 5 90 kg of water was added to 6 kg of ginseng, and the mixture was heated and extracted at 100 ° C. After the extraction was completed, solid-liquid separation was performed during heating to obtain an extract.
The extract was concentrated to 14 at 40 ° C. under reduced pressure. Of this concentrated solution, take 2 parts and add sodium carbonate to it
It was adjusted to 6.0, immobilized α-amylase (A-5386 manufactured by SIGMA) was added, and the mixture was reacted at 30 ° C. for 12 hours with stirring. Then, suction filtration was carried out using a sieve with a mesh of 150 mesh to separate and collect the immobilized α-amylase.

The reaction liquid thus obtained was spray-dried (blast temperature: 150
℃, exhaust air temperature 100 ℃), dried extract powder 360g
Got To 90 g of this dry extract powder, 9.5 g of lactose (manufactured by Megre Co., Ltd.) and 0.5 g of magnesium stearate (manufactured by Ohira Chemical Industry Co., Ltd.) were added and mixed using a mixer,
A ginseng tablet was obtained by compression-molding one tablet to 210 mg.

Example 6 Dry extract powder 8 obtained as described in Example 5
20 g of dextrin [Matsutani Chemical Industry Co., Ltd.] was added to 0 g, and after mixing well, compression molding and sieving were performed.
A ginseng granule with a diameter of 1.18 to 0.36 mm was obtained.

Example 7 The ginseng granules obtained in Example 6 were crushed with a crusher to give 42
No. 1 gelatin capsule was filled as the powder below (450 mg per capsule) to obtain a ginseng hard capsule.

Example 8 Dry extract powder 7 obtained as described in Example 5
To 0 g, 30 g of cornstarch [Matsuya Chemical Co., Ltd.] was added and mixed well to obtain a ginseng extract powder.

Example 9 Prescription crude drug 1 of Nichinto (consisting of 5 parts of Hange, 5 parts of bukuryo, 4 parts of cockpiper, part of licorice and 1 part of citrus fruit)
100 kg of water was added to 0 kg, and the mixture was heated and extracted at 100 ° C. After the extraction was completed, solid-liquid separation was performed while hot to obtain an extract. 10 of this extract was collected, and 100 g of the immobilized α-amylase obtained in the above-mentioned specific example was added to the extract, and the mixture was reacted at 40 ° C. for 8 hours with stirring. Then, the immobilized α-amylase was separated and collected by a sieve with a mesh of 100 mesh stainless steel.

After concentrating the reaction solution thus obtained to 2,5,
It was freeze-dried (freezing temperature -40 ° C, vacuum degree 0.1 mmHg, shelf temperature 20 ° C) to obtain 450 g of dry extract powder. To 80 g of this dried extract powder, 20 g of crystalline cellulose (Avicel [Asahi Kasei Co., Ltd.]) was added, mixed well and compression-molded so that one tablet was 250 mg to obtain Ninin-to tablets.

Example 10 The Nininto tablet obtained in Example 9 was pulverized with a pulverizer and sieved to obtain a 32-150-meshyu Nininto fine granule.

Example 11 Hangekokuboku-to (6 parts Hange, 5 parts bukuriyo, 3 kokuboku)
Water, 1 part of soybean, 2 parts of soybean, and 1 part of Japanese butterbur) was added with water 1 and extracted by heating at 100 ° C. After the extraction was completed, solid-liquid separation was performed during heating to obtain an extract. Next, a mixture of 2 g of immobilized α-amylase (A-5386 manufactured by Sigma) and 8 g of glass powder was packed in a column with a jacket for heat retention (diameter 1 cm, length 5 cm), and the extract was kept at 30 ° C. Meanwhile, the mixture was allowed to pass through at a flow rate of 0.1 m / min for contact to cause a reaction.

The reaction solution thus obtained was freeze-dried (freezing temperature -40
C., vacuum degree 0.1 mmHg, shelf temperature 20.degree. C.) to obtain 11 g of dry extract powder. To 9 g of this dried extract powder, 1 g of D-mannitol (trade name: Mannit, manufactured by Towa Kasei Kogyo Co., Ltd.) was added and mixed, and further 5 g of 10% hydroxypropylcellulose ethanol solution was added, and kneaded and extruded in the usual manner. Granulate, dry and screen 12-4
Hangekobokuto granules of 8 mesh particles were obtained.

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Claims (1)

[Claims] 1. A Chinese herbal medicine is extracted with an extraction solvent, and the extract or concentrated solution thereof is brought into contact with immobilized amylase to cause a reaction, and the reaction solution is dried to obtain a powder as it is, or sugars, starches, Dextrins, silicic acid compounds,
A method for producing a Chinese herbal medicine extract, which comprises mixing with one or more excipients selected from celluloses and natural gums to prepare various Chinese herbal medicine extract agents.