JP2003277278A - Oxytocin antagonist - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine or a food which is safe even when taken for a long time, satisfactorily cures without fail, and is useful for preventing birthpang, for preventing premature birth, and for preventing and curing dysmenorrhea. <P>SOLUTION: An oxytocin antagonist, a birthpang suppressant, a premature birth preventive, and a dysmenorrhea preventive or remedy, all containing propolis or kale or extracts of them are provided; and so are an orally ingestible composition, a food, and a medicine which are safe even when ingested for a long time, satisfactory in curing without fail, and useful for preventing the birthpang and premature birth and for preventing and curing dysmenorrhea. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an agent for suppressing labor, an agent for preventing preterm birth, an agent for preventing or treating dysmenorrhea, which has an oxytocin antagonistic effect, and an oral composition or a food or a drug containing the same.

[0002]

2. Description of the Related Art One of the most important problems in the field of obstetrics is preterm labor pain (preterm birth). During the course of pregnancy, it has been well documented to experience premature labor or premature birth 20 weeks after pregnancy, which
May cause unhealthy newborns or death.

Oxytocin has a peptide structure similar to that of vasopressin. Extensive research in recent years has revealed that oxytocin is a physiological inducer of labor in some mammals, including humans.

Oxytocin has a strong uterine contractile action and is a posterior pituitary hormone consisting of 9 amino acids whose structure was determined in the 1950s. It is widely associated with labor, lactation and sexual behavior. It is used in the field of obstetrics and gynecology for the purpose of inducing and promoting uterine contraction, but it is a problem that careful administration control is necessary because the sensitivity varies greatly among individuals.

Oxytocin also induces uterine contraction, partly by directly contracting the myometrium and partly by promoting the synthesis and release of contractile prostaglandins from the decidua of the endometrium. It is believed to have a contractile effect. Furthermore, these prostaglandins are also important in the cervical maturation process. Due to such processes, the labor process (full-term and pre-full-term) is believed to be caused, in part, by increasing uterine sensitivity as a result of the phenomenon of an increased number of oxytocin receptors for oxytocin.

On the other hand, the oxytocin receptor gives birth (delivery).
It is thought that the expression number controls the onset and promotion of labor. The oxytocin receptors are also found on uterine smooth muscle, and they are also found on myoepithelial cells of the mammary gland, in the central nervous system, and in the kidney.

[0007] This oxytocin receptor-mediated regulatory regulation and increased uterine sensitivity appear to be due to trophic factors that increase cytosolic estrogen levels toward full term pregnancy.

Suppressing the direct (contractile effect) and indirect (prostaglandin synthesis promoting) effects of oxytocin on the uterus is more effective in treating preterm labor (preterm labor) than at rest. Is believed to be.

Dysmenorrhea is also characterized by periodic pain associated with menstruation during the ovulation cycle. This pain is believed to be due to uterine contraction and ischemia through prostaglandin synthesis effects in endometrium secretory cells. Therefore, it is considered that suppressing the direct (contractile effect) and indirect (prostaglandin synthesis promoting) effects of oxytocin on the uterus is more effective in suppressing dysmenorrhea than resting. ing.

On the basis of the above-mentioned idea, in the clinical field of gynecology, it is expected that an oxytocin antagonist has an effect of delaying or reducing the onset of uterine contraction in patients with preterm labor and excessive labor pain. Therefore, it is used as the most ideal obstetric drug, but medicines and foods that are derived from natural products and that are safe enough to be taken for a long period of time and that are sufficiently satisfactory for reliable treatment are currently available. However, it has not been developed at all.

[0011]

The object of the present invention is a natural product-derived component, which has an oxytocin antagonism and can treat or prevent diseases associated with oxytocin, particularly labor, preterm labor, and dysmenorrhea, for a long period of time. It is an object of the present invention to provide a medicine or food which is safe and can be sufficiently satisfied to give reliable treatment.

[0012]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventor has found that it has been used as a dietary supplement in Japan for the purpose of anticancer action and immunostimulatory action. The present invention was completed based on the finding that it has an oxytocin antagonizing effect on propolis or kale of the family Cruciferae. That is, the present invention relates to 1. 1. an oxytocin antagonist containing propolis, kale or an extract thereof; 2. A labor pain suppressant containing propolis, kale, or an extract thereof; 3. A preterm birth inhibitor containing propolis, kale, or an extract thereof; Dysmenorrhea prophylactic or therapeutic agent containing propolis, kale or an extract thereof, oral composition containing any of 5.1 to 4, food containing any of 6.1 to 4, and 7 The present invention relates to a medicine containing any one of 1 to 4.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The propolis used in the present invention is a resin-like black mass collected by bees, and includes any of propolis from Brazil, propolis from China, propolis from Australia, propolis from Uruguay, and propolis from Japan. It may be from a production site and is not particularly limited, but from the viewpoint of versatility, Brazilian propolis and Chinese propolis are preferable.

The kale used in the present invention (Brassicca Ol
eracea L. var. acephala DC.) include kitchen kale, malo kale, bush kale, tree kale, collard and green algae. Kale is a plant of the family Cruciferae originally originating in Southern Europe and is said to be the original cabbage seed. The leaves may be those normally used for food, and the cultivation method and cultivation place are not particularly limited.

The propolis or kale of the present invention is
Dried product obtained by drying itself, pulverized product, supercritical extract, crude extract with water or organic solvent such as alcohol, ether, acetone, etc., and distribution of crude extract, various chromatography such as column chromatography, etc. It includes all the extract fractions obtained by stepwise purification. These may be used alone or in combination of two or more.

For example, an extract obtained by adding 3 L of 99.5% ethanol extract to 1 kg of a raw product of Brazilian propolis or dried product of kale leaves, stems, flowers and roots, and immersing it overnight at room temperature, It may be used as it is as an oxytocin antagonist, a labor pain inhibitor, a preterm labor preventive agent, a prophylactic / therapeutic agent for dysmenorrhea, or a purified product obtained by combining various chromatographies.

The concentration of the propolis or kale extract in the solution of the extracted propolis or kale extract is not particularly limited, but it is preferably about 15 to 70% by weight, preferably about 20 to 60% by weight. If this concentration is 15% by weight or less, it is necessary to evaporate a large amount of a solution such as ethanol or water during drying, and if it is 70% by weight or more, the viscosity of the solution becomes too high and the processability may be deteriorated.

It has never been known in the past that the dried product or extract of propolis or kale according to the present invention has an oxytocin antagonism, which is a new finding obtained by the present invention.

Propolis or kale or an extract thereof has an excellent oxytocin antagonism and can be used as a food or medicine for the purpose of suppressing labor, preventing preterm birth, preventing or treating dysmenorrhea. . Propolis or kale or an extract thereof can be produced as a food or medicine for oxytocin antagonism, for suppressing labor, for preventing preterm birth, for preventing or treating dysmenorrhea.

Pharmaceuticals such as oxytocin antagonists, labor suppressants, preterm birth inhibitors and prophylactic and therapeutic agents for dysmenorrhea are
Either administration method of oral administration or parenteral administration can be adopted. Upon administration, the active ingredient is orally administered,
It can be administered in the form of a conventional pharmaceutical preparation by mixing with a solid or liquid non-toxic pharmaceutical carrier suitable for administration methods such as rectal administration and injection. Examples of such a preparation include solid preparations such as tablets, granules, powders and capsules,
Examples thereof include solutions, suspensions, liquids such as emulsions, freeze-dried preparations, etc. These preparations can be prepared by conventional means for preparation. The above-mentioned non-toxic pharmaceutical carrier,
For example, glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester,
Amino acids, gelatin, albumin, water, physiological saline and the like can be mentioned. Further, if necessary, conventional additives such as a stabilizer, a wetting agent, an emulsifier, a binder and a tonicity agent can be appropriately added.

As the food, as it is, or by adding various nutritional components or by including it in foods and drinks, it is useful for suppressing labor, preventing preterm birth, and treating and preventing dysmenorrhea. It is eaten as a material. For example, after adding a suitable auxiliary agent such as starch, lactose, maltose, vegetable oil and fat powder, cocoa butter powder, stearic acid, etc., using a conventional means, an edible form, for example, granules, granules, tablets , Capsules, may be formed into a paste or the like and provided for edible foods, and various foods, for example, processed meat products such as ham and sausage, processed fish products such as kamaboko and chikuwa, bread, confectionery, butter, milk powder, fermentation It may be added to dairy products and used, or added to water, fruit juice, milk, tea, soft drinks and other beverages.

The effective dose of the propolis or kale of the present invention is appropriately selected and determined according to the age, body weight, symptom of the patient, degree of the patient, administration route, administration schedule, formulation form, strength of inhibitory activity of the material and the like. For example, in the case of oral administration, it is generally about 10 to 500 mg / kg body weight per day, preferably about 150 to 350 mg / kg body weight per day, and may be administered in several divided doses per day. .

The propolis or kale of the present invention has a low toxicity. For example, even if an ethanol extract of Brazilian propolis is orally administered to rats at a daily dose of 1000 mg / kg for a long period of 100 days, death cases are observed. And no change in body weight was observed.

[Embodiment] The present invention will be specifically described below with reference to an embodiment, but the present invention is not limited to this.

Production Example 1 [Production of Propolis Extract] 3 g of 99.5% ethanol was added to 10 g of each of the original propolis blocks from Brazil and China, and the mixture was immersed at 50 ° C. overnight, and then ethanol was removed by a rotary evaporator. By doing so, each of the propolis extracts was 324 m
g, 216 mg were obtained.

Production Example 2 [Production of Kale Extract] Kale leaves were dried at 90 ° C. to deactivate the enzyme which becomes a bitter and astringent ingredient. While heating and refluxing 4 kg of the pulverized product with an electric water bath, extraction was performed using 20 L of 99.5% ethanol to obtain 80 g of a kale extract.

Test Method The binding test to the oxytocin receptor was evaluated by Douglas J. P.
Method of ettibone et al. (European Journal of Pharmacology
-Molecular Pharmacology Section, 188, 235-24
2, 1990) with some modifications.

That is, 0.3 to 18 mg / day before slaughter
10 mM Tris buffer (pH 7.4) containing 1 mM EDTA and 0.5 mM dithiothreitol from uterine tissue isolated from a rat treated by intravenously injecting kg synthetic estrogen, diethyl vestylbesterol dipropionate. Homogenize using 48000 × g, centrifuge at 4 ° C. for 30 minutes, and precipitate obtained is 50 mM Tris buffer (pH 7.4) containing 5 mM magnesium chloride and 0.1% bovine serum albumin (hereinafter, Reconstitute with buffer solution A) at 48000 xg at 4 ° C
After centrifugation for 30 minutes, a precipitate was obtained. The resulting precipitate was dissolved with buffer A and ice-cooled until analysis.

Next, a competitive test was carried out by using 10 nM [ ³ H] -labeled oxytocin (New England Nuclear, specific activity; 30-6.
0Ci / mmol) and 500 μg / ml of each propolis or kale extract obtained in Production Examples 1 and 2 in Buffer A at 22 ° C. and 60 ° C.
Let react for minutes.

Then, a glass filter (Model 7019,
Skatron Inc.) was used to perform filtration to separate the [ ³ H] -labeled oxytocin-bound membrane preparation.
It was washed once with 5 ml of buffer A. The glass filter was placed in a vial, mixed with aquazole (a cocktail for liquid scintillation), the amount of bound [ ³ H] -labeled oxytocin was measured with a liquid scintillation counter, and the inhibition rate (%) was calculated by the following formula. Inhibition rate (%) = 100 - _{[(C 1 -B) / (C} 0 -
B)] × 100 (In the formula, C ₁ represents the amount of [ ³ H] -labeled oxytocin bound to the membrane in the state where a known amount of the test compound and [ ³ H] -labeled oxytocin coexist, and C ₀ represents the amount of binding of ^[3 H] labeled oxytocin film when excluding the test compound, B is an excess of oxytocin ^{(5 × 10 -6 M) [} 3 H] labeled oxytocin film in the presence of The IC ₅₀ value of oxytocin as a positive control in this assay system was 3.1 nM (0.32 μg / ml).

[0031]

[Table 1]

From Table 1, it can be seen that the propolis or kale of the present invention or its extract has a strong oxytocin antagonism.

Example 1 [Production of tablet] Using the ethanolic extract of Brazilian propolis obtained in Production Example 1, a tablet having the following composition was produced according to a conventional method. (Composition) (Composition: wt%) Brazilian Propolis Extract 24 Lactose 63 Corn Starch 12 Guar Gum 1

Example 2 [Manufacture of juice] Using the ethanolic extract of kale obtained in Manufacturing Example 2, a juice having the following composition was manufactured according to a conventional method. (Composition) (Composition: wt%) Frozen concentrated Unshu mandarin orange juice 5.0 5.0 Fructose glucose liquid sugar 11.0 Citric acid 0.2 L-Ascorbic acid 0.02 Perfume 0.2 Pigment 0.1 Kale extract 0. 2 Water 83.28

[0035]

INDUSTRIAL APPLICABILITY Propolis or kale or an extract thereof has an oxytocin antagonism and can be used as a food or medicine useful for the prevention of labor, the prevention of preterm birth, the prevention and treatment of dysmenorrhea. According to the present invention, it is possible to provide a medicine or food useful for the prevention of labor, the prevention of preterm birth, the prevention of dysmenorrhea, which is sufficiently satisfactory to perform a safe and reliable treatment even if taken for a long period of time. it can.

Front page continuation (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 15/06 A61P 15/06 F term (reference) 4B018 MD53 MD78 ME14 4B041 LK39 LP05 4C087 AA01 AA02 BB22 MA02 MA52 NA14 ZA81 4C088 AB15 AC03 AC05 AC11 CA06 MA02 MA52 ZA81

Claims (7)

[Claims] 1. An oxytocin antagonist containing propolis, kale or an extract thereof. 2. A labor depressant containing propolis, kale or an extract thereof. 3. A preterm birth preventive agent containing propolis, kale, or an extract thereof. 4. A prophylactic or therapeutic agent for dysmenorrhea containing propolis, kale or an extract thereof. 5. An oral composition containing the agent according to claim 1. 6. A food containing the agent according to claim 1. 7. A medicine containing the agent according to any one of claims 1 to 4.