JPH0867634A - Agent for stimulating secretion of cholecystokinin - Google Patents

Abstract

PURPOSE: To obtain a cholecystokinin secretion-stimulating agent useful for treating diseases such as pancreatitis and cystic dyskinesia and having a cholagogic action. CONSTITUTION: The cholecystokinin secretion-stimulating agent contains one or more kinds of Glycyrrhiza glabra L., Platycodon grandiflorum DC., platycodin D and glycyrrhizin as active ingredients. The agent is used in a form such as an extract obtained by extracting the materials or a powder obtained by grinding the materials, but may also be used in any form. The extract includes various hydrocarbon solvent extracts, but are preferably water extracts. The platycodin D and the glycyrrhizin are obtained by extracting and isolating from the Platycodon grandiflorum DC., and the Glycyrrhiza glabra L., respectively. When used as the active ingredients, the Glycyrrhiza glabra L., and Platycodon grandiflorum DC. are preferably used in amounts of 2.5-3.5 pts.wt. and 1.5-2.5 pts.wt., respectively.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a cholecystokinin secretagogue, which is useful for treating pancreatitis and has a choleretic action.

[0002]

BACKGROUND OF THE INVENTION Cholecystokinin is a polypeptide hormone secreted in the duodenum and promotes secretion of pancreatic juice and bile. Pancreatic juice contains proteolytic enzymes such as trypsin, chymotrypsin and elastase, and an increase in pancreatic juice secretion promotes digestion. On the other hand, bile indirectly acts on digestion and absorption of fat by bile salts, and is involved in excretion of biological components and foreign substances. Further, cholecystokinin has an action of promoting proliferation / regeneration of pancreatic cells and a gastrin lowering action, and is therefore useful for amelioration and treatment of chronic pancreatitis.

At present, anti-enzyme agents and the like are used as oral therapeutic agents for pancreatitis, but these agents have been difficult to treat because they do not have a sufficient effect on patients with chronic pancreatitis.

Cerulein is known as a substance having a pancreatic juice secretagogue action, but this substance has a problem that it is difficult to administer for a long period of time because it is only an administration route by intravenous injection and it causes pain to a patient. Was.

Under the circumstances described above, it has been desired to develop new useful drugs in these fields.

[0006]

[Means for Solving the Problems] In view of the above circumstances, the present inventors have conducted extensive research to find a drug having a cholecystokinin secretagogue action, and as a result, selected from licorice, bellflower, platichodin D or glycyrrhizin. The inventors have found that a drug containing one or more kinds as an active ingredient (hereinafter, referred to as “active ingredient of the present invention”) has an effect of promoting secretion of cholecystokinin, and completed the present invention. .

That is, the present invention is

(1) A cholecystokinin secretagogue containing one or more selected from licorice, bellflower, platycodin D or glycyrrhizin as an active ingredient,

(2) The cholecystokinin secretagogue according to (1), wherein the active ingredients are licorice and bellflower.

The cholecystokinin secretagogue of the present invention refers to a drug used for the purpose of promoting the secretion of cholecystokinin, and refers to a drug effective for treating diseases such as pancreatitis and gallbladder dyskinesia. Say.

Platicodin D which is the active ingredient of the present invention
Is obtained by extraction and isolation from Kikyo, and glycyrrhizin is obtained by extraction and isolation from licorice, but it is commercially available and can be purchased from Wako Pure Chemical Industries, Ltd., for example.

Further, when the active ingredient of the present invention is licorice and bellflower, the mixing ratio of each component is preferably 1 to 4 parts by weight of licorice and 1 to 3 parts by weight of bellflower, and particularly preferably 2.5 to 3.5 of licorice. Parts by weight and bellflower 1.5 to 2.5 parts by weight. When the mixing ratio of licorice and Kikyo is a particularly preferable ratio, it corresponds to Kikyoto, which is a remedy for tonsillitis and the like, which is a classic of Kampo medicine (Kinbyo etc.).

Licorice and bellflower, which are the active ingredients of the present invention,
It may be used in the form of an extract obtained by extracting them or a powder obtained by crushing them, but may be in any other form.

Examples of the extract of licorice and Chinese bellflower include various aqueous solvent extracts, and it is preferable to use an aqueous extract.

A specific example of preparation of the extract is a method in which licorice and / or bellflowers are extracted with 10 to 20 times the amount of hot water and the resulting extract is filtered. This extract is
If necessary, it may be dried to obtain a dry powder.

The active ingredients of the present invention are oral agents, injectable agents,
It can be administered by any of parenteral agents such as instillation agents.

The pharmaceutical carrier can be selected according to the above-mentioned administration form and dosage form. In the case of oral preparations, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like are used. It When preparing an oral preparation, a binder, a disintegrant,
Surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents,
Fragrances and the like can be added. Specific examples thereof include the following.

(Binder) Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose,
Ethyl cellulose, polyvinylpyrrolidone, macrogol.

(Disintegrant) Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

(Surfactant) sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 8
0.

(Lubricant) Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

(Flowability accelerator) Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The active ingredient of the present invention can also be administered as an oral liquid preparation such as a suspension, emulsion, syrup, elixir, etc., and in these various dosage forms, flavoring agents, A colorant can be added.

On the other hand, in the case of a parenteral preparation, it is produced according to a conventional method and is generally used as a diluent in distilled water for injection, physiological saline, glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene. Glycol, polyethylene glycol and the like can be used.
Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation may be filled in a vial or the like, frozen, and then water may be removed by an ordinary freeze-drying technique, and a liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, if necessary, an isotonicity agent, a stabilizer, a preservative, a soothing agent and the like can be appropriately added.

The dose of the active ingredient of the present invention depends on the route of administration,
Although it varies depending on the degree of disease, age of the recipient, etc., in general, in the case of oral administration, an amount of about 1 to 10 g per day for an adult may be administered in 1 to 3 divided doses.

The active ingredient used in the present invention has been used as a Kampo prescription for many years, and its safety has been confirmed. Therefore, it can be used with confidence. For example, the dry powder of Kikyoto extract is extremely safe as it is clear from the fact that no death or abnormal findings were observed in mice and rats at the dose limit of 15 g / kg orally. .

The present invention will be described in more detail with reference to Examples, Experimental Examples and Formulation Examples, but the present invention is not limited to these Examples and the like.

Example 1 50 ml of purified water was added to a mixed crude drug (Kikyoto; 5 g) of 3 g of licorice and 2 g of Kikyo, boiled to about half volume, filtered, and the obtained filtrate was concentrated and freeze-dried. Dried extract powder 1.25g
I got

Example 2 500 l of purified water was added to a mixed crude drug (Kikyoto; 5 kg) of licorice 3 kg and Kikyo 2 kg, and the mixture was extracted at 100 ° C. for about 60 minutes and solid-liquid separated. The concentrate was concentrated to 1/10 and the concentrate was spray-dried to obtain 1.25 kg of dry extract powder.

Example 3 20 g of bellflower was extracted by heating with 200 ml of purified water, and the extract was freeze-dried to obtain a bellflower extract powder.

Example 4 20 g of licorice was extracted by heating with 200 ml of purified water, and the extract was freeze-dried to obtain licorice extract powder.

Example 5 2 kg of bellflowers were extracted with 10 l of methanol, 1.3 l of methanol was added to dissolve the extract, and 6.6 l of acetone was added to remove the precipitated insoluble matter, and the supernatant obtained was concentrated. did. The concentrated extract was suspended in water, defatted with ether, butanol extract obtained by extraction with butanol was dissolved again in 133 ml of methanol, and 1.33 l of ether was added to precipitate 17.3 g of insoluble matter. The saponin fraction was used.
Of these, by repeating the normal-phase and reverse-phase column chromatography using 16.45 g of crude saponin fraction,
129 mg of platicodin D was obtained.

Experimental Example 1 Male Wistar rats weighing 280 to 300 g were anesthetized by inhalation, the abdomen was opened, and cannulas were fixed in the bile duct, pancreatic duct, duodenum, and stomach, and the abdomen was introduced from the caudal side of the back to close the abdomen.
Further, the jugular vein was also cannulated, and after waiting 12 hours for recovery for 3 days after surgery, the dried extract powder solution obtained in Example 2 prepared in various concentrations by adding distilled water (test drug)
A), the dry extract powder solution obtained in Example 3 (test drug B),
The dry extract powder solution obtained in Example 4 (test drug C), the praticodine D solution obtained in Example 5 (test drug D) and the commercially available glycyrrhizin solution (test drug E) were intragastrically administered. Pancreatic juice secretion and protein content in pancreatic juice for 30 minutes after administration of the test drug
The value was calculated for 30 minutes before administration as the standard (100%). In addition, 30 minutes before and 30 minutes after the administration of the test drug, it was collected from the jugular vein and
The CCK (cholecystokinin) concentration was measured.

The results of Experimental Example 1 are shown in Tables 1 and 2.

Table 1

Table 2

From the results of Experimental Example 1 and Experimental Example 2, it was proved that the active ingredient of the present invention increases the amount of pancreatic juice, the amount of protein secretion and the blood CCK concentration, and promotes the secretion of pancreatic juice.

From the results of Experimental Example 1, it was proved that the active ingredient of the present invention increases the amount of pancreatic juice, the amount of protein secreted and the blood CCK concentration, and promotes the secretion of pancreatic juice.

Formulation Example 1 Preparation of granules: dry extract powder 20 obtained according to Example 1
0g was mixed with lactose 89g and magnesium stearate 1g, the mixture was tabletted with a single-shot tableting machine, diameter 20mm,
A slug tablet weighing about 2.3 g was obtained. This slug tablet was crushed with an oscillator, sized and sieved to obtain a granule having a particle size of 20 to 50 mesh.

Formulation Example 2 Preparation of tablets: 200 mg of the dried extract powder obtained in Example 2 was mixed with 20 g of microcrystalline cellulose and 5 g of magnesium stearate, and this mixture was tabletted with a single-shot tableting machine to give a diameter of 7 m.
A tablet having a weight of 225 mg was produced. One tablet of the present invention contains 200 mg of the dry extract powder obtained in Example 2.

Formulation Example 3 Preparation of capsule: 500 mg of dry extract powder obtained in Example 1
Was filled in a hard capsule to prepare a capsule.

Formulation Example 4 Preparation of injection: 300 g of alanine (without pyrogen) is added to 20 l of the filtrate obtained in Example 1, dissolved and lyophilized. The freeze-dried product was poured into 900 vials to obtain an injection.
This injection 1 vial contained lyophilized product 406 mg, and was easily dissolved in 10 ml of purified water. In addition, the solution after injection had a permeability of 92% (550 nm), which was compatible with the test method for pyrogenic substances of the Japanese Pharmacopoeia.

Formulation Example 5 Preparation of tablets: Corn starch 44 g Crystalline cellulose 40 g Carboxymethyl cellulose calcium 5 g Light anhydrous silicic acid 0.5 g Magnesium stearate 0.5 g Dry extract powder obtained in Example 1 10 g Total 100 g

According to the above formulation, the ingredients (1) to (2) were uniformly mixed and compression-molded with a tableting machine to give tablets (200 mg each).

Each tablet contains 20 mg of the dry extract obtained in Example 1, and 10 to 25 tablets for adults are to be taken in several divided doses per day.

Formulation Example 6 Preparation of Granules: Dry extract powder 20 obtained according to Example 3
0g was mixed with lactose 89g and magnesium stearate 1g, the mixture was tabletted with a single-shot tableting machine, diameter 20mm,
A slug tablet weighing about 2.3 g was obtained. This slug tablet was crushed with an oscillator, sized and sieved to obtain a granule having a particle size of 20 to 50 mesh.

Formulation Example 7 Preparation of tablets: 200 mg of the dry extract powder obtained in Example 4 was mixed with 20 of microcrystalline cellulose and 5 g of magnesium stearate, and the mixture was tableted with a single-shot tableting machine to give a diameter of 7 m.
A tablet having a weight of 225 mg was produced. One tablet of the present invention contains 200 mg of the dry extract powder obtained in Example 4.

Formulation Example 8 Preparation of Capsule: Hard capsules were filled with 500 mg of platicodin D obtained in Example 5 to prepare capsules.

Formulation Example 9 Preparation of tablets: Glycyrrhizin 200 mg and microcrystalline cellulose 20
And 5 g of magnesium stearate were mixed, and this mixture was tabletted with a single-shot tableting machine to produce tablets having a diameter of 7 mm and a weight of 225 mg. Glycyrrhizin is added to 200 tablets in this tablet.
Contains mg.

[0050]

INDUSTRIAL APPLICABILITY The cholecystokinin secretagogue according to the present invention has few side effects and can be administered for a long period of time because the desired effect can be obtained in oral administration. Conventionally,
Although there was no drug for treating diseases such as pancreatitis and gallbladder dyskinesia by promoting the secretion of cholecystokinin, the drug of the present invention treats these diseases by promoting the secretion of cholecystokinin. Made it possible. that's all

Claims (2)

[Claims] 1. A cholecystokinin secretagogue comprising, as an active ingredient, one or more selected from licorice, bellflower, platycodin D and glycyrrhizin. 2. The method according to claim 1, wherein the active ingredients are licorice and bellflower.
The cholecystokinin secretagogue as described.