KR102343976B1 - Composition for inhibiting ovotoxicity caused by anticancer drug comprising herbal medicine mixture extract as effective component - Google Patents

Abstract

The present invention relates to a composition for inhibiting ovarian toxicity by an anticancer agent comprising an herbal medicine mixture extract as an active ingredient. It has a deterrent effect. Therefore, the herbal medicine mixture extract of the present invention can be usefully used as an adjuvant for anticancer drugs, characterized in that it restores the reduced number of eggs or the quality of eggs due to the administration of anticancer drugs.

Description

Composition for inhibiting ovotoxicity caused by anticancer drug comprising herbal medicine mixture extract as effective component

The present invention relates to a composition for inhibiting ovarian toxicity by an anticancer agent comprising an herbal medicine mixed extract as an active ingredient.

Cancer is a disease that causes about 7 million deaths a year worldwide. In particular, in Korea, according to the 2000 Statistical Yearbook of Causes of Death by the National Statistical Office (the result of analysis of death data in 2000), cancer deaths are As it ranks first among the causes of death, national cancer control measures are required. Currently, various methods such as surgery, radiation therapy, and gene therapy are used as a method of treating cancer, but one of the most used treatment methods is chemotherapy, which administers an anticancer agent. Chemotherapy is a systemic treatment. In most cases, when chemotherapy is administered by injection or orally, it spreads throughout the body along the bloodstream. Therefore, it is a treatment that acts on micrometastasis spread throughout the body rather than a local effect. Therefore, there are many systemic side effects and the degree is very severe compared to surgery or radiation therapy. Chemotherapy, but most anticancer drugs cannot differentiate between normal cells and cancer cells, so that anticancer drugs act selectively on cancer cells by using the difference in drug sensitivity between normal cells and cancer cells, resulting in dose-limiting toxicity. There is that problem.

In particular, alkylation-based anticancer drugs have the ability to substitute an alkyl group for hydrogen atoms in DNA, and when DNA is alkylated, DNA replication and transcription are not possible. In other words, it is an anticancer drug that prevents the growth, division and differentiation of cancer cells by preventing cells from dividing. It is used for breast cancer, leukemia or ovarian cancer, and various side effects appear due to anticancer drug prescription. Among the side effects caused by the anticancer drug prescription, ovotoxicity, which is toxic to ovarian tissue and ovarian germ cells, is known as one of the serious side effects.

On the other hand, Sukjihwang is a herbal medicine made by steaming and drying the root of Rehmannia. Rehmannia ginseng is a perennial medicinal plant belonging to the ginseng family, and its roots are used as medicinal herbs in oriental medicine. Take the medicinal effect first. It has a sweet and bitter taste and has a warm nature, so it has the effect of treating soreness and pain in the lower back and knees, menstrual abnormalities, dizziness, and blackening of the hair.

The peony is the root of hambak flower, a perennial plant of the buttercup family, and is widely used medicinally, but it is also cultivated for ornamental purposes because of its strong fragrance and beautiful flowers. Peony contains paeoniflorin, paeonel, paeonin, tannin, β-sitosterol, triterpenoid, essential oil, fatty oil, resin, etc. Since it contains a large amount of ingredients, it is used for the prevention and treatment of various diseases as it has antioxidant, anti-inflammatory, analgesic, blood-reinforcing, and immune-enhancing effects.

Chrysanthemum is a perennial plant of the dicotyledonous plant Dicotyledonous family, Umbilicalaceae, and contains alkyloids including tetramethylpyrazine and perolyrine, chrysophanoll, and sedanonic acid. Contains a large amount of ingredients such as phenolic components, lactones, and vitamin E, which have excellent antioxidant properties used

Angelica is the dried root of Angelica basil belonging to the Umbrella family, and various types of coumarin ( Coumarin) component has excellent antioxidant action, and it is used for the prevention and treatment of various diseases as it improves blood circulation, analgesic effect, blood retention, and anti-inflammatory action. In particular, deckercin contained in Angelica is a coumarin derivative, which removes free radicals and acts as an excellent antioxidant to protect cells and activate bodily functions.

As a prior art related to anti-cancer drug side effects or herbal medicine mixture extract, Korean Patent No. 0501039 discloses a side effect inhibitor of the chemotherapy anticancer drug cisplatin, which includes a leaf mushroom extract, and Korean Patent No. 1787337 discloses fermentation with antioxidant and immune effects. Although a method for producing a mixed herbal medicine extract and a fermented herbal medicine mixture extract thereof are disclosed, there is no disclosure of a composition for inhibiting ovarian toxicity by an anticancer agent comprising the herbal medicine mixture extract of the present invention as an active ingredient.

The present invention has been derived from the above needs, and the present invention provides a composition for inhibiting ovarian toxicity by an anticancer agent comprising an herbal medicine mixed extract as an active ingredient, and the number of eggs by administration of an anticancer agent (cyclophosphamide) In contrast to the reduced control group, the present invention was completed by confirming that the number of healthy mature eggs was increased by co-administration of the herbal medicine mixture extract of the present invention with an anticancer agent.

In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention or treatment of ovarian toxicity by administration of an anticancer agent, which contains a mixed extract of herbal medicines consisting of Sukjihwang, peony, cheongung and angelica as an active ingredient.

In addition, the present invention provides a health functional food composition for the prevention or improvement of ovarian toxicity by administration of an anticancer agent containing as an active ingredient a mixed extract of medicinal herbs consisting of Sukhumihuang, peony, cheongung and angelica.

In addition, the present invention provides an anticancer adjuvant for preventing or improving ovarian toxicity by administering an anticancer agent containing a mixed extract of herbal medicines consisting of sukjihwang, peony, cheongung and angelica as an active ingredient.

The present invention relates to a composition for inhibiting ovarian toxicity by an anticancer agent comprising an herbal medicine mixed extract as an active ingredient. By suppressing this decrease, it has the effect of restoring the number and quality of eggs.

1 shows the composition ratio (%) of the initial follicle among the total follicles in the ovarian tissue at the 1st week after cyclophosphamide (Cy) intraperitoneal administration and oral administration of herbal mixed extract (SM) were combined (Cy + SM). is the result Con is the initial follicle (%) of the normal group untreated, and Cy75 is the initial follicle (%) of the group administered intraperitoneally with cyclophosphamide.
Figure 2 is the result of confirming the composition ratio (%) of mature follicles among all follicles in the ovarian tissue at week 1 after cyclophosphamide (Cy) intraperitoneal administration and oral administration of herbal mixed extract (SM) were combined (Cy + SM) to be. Con is the mature follicle (%) of the untreated normal group, and Cy75 is the mature follicle (%) of the group administered intraperitoneally with cyclophosphamide.
3 is a photomicrograph of oocytes collected at 5 weeks after intraperitoneal administration of cyclophosphamide (Cy) and oral administration of herbal mixed extract (SM) combined (Cy+SM). Con is a photograph of a normal group untreated, and Cy75 is a photograph of a group administered intraperitoneally with cyclophosphamide.
4 is a result confirming the number of oocytes collected at 5 weeks after intraperitoneal administration of cyclophosphamide (Cy) and oral administration of herbal mixed extract (SM) combined (Cy+SM). Con is the number of eggs in the normal group untreated, and Cy75 is the number of eggs in the group administered intraperitoneally with cyclophosphamide.
Figure 5 is the result of confirming the number of mature oocytes in fertilized MII cleavage state collected at 5 weeks after intraperitoneal administration of cyclophosphamide (Cy) and oral administration of herbal mixed extract (SM) combined (Cy+SM) to be. Con is the number of mature eggs in the untreated normal group, and Cy75 is the number of mature eggs in the group administered intraperitoneally with cyclophosphamide.
6 is a result confirming the number of mature oocytes with normal spindles in the MII cleavage state collected after intraperitoneal administration of cyclophosphamide (Cy) and oral administration of herbal mixed extract (SM) together (Cy+SM). Con is the number of mature eggs in the untreated normal group, and Cy75 is the number of mature eggs in the group administered intraperitoneally with cyclophosphamide.

The present invention relates to a pharmaceutical composition for the prevention or treatment of ovarian toxicity by administration of an anticancer agent containing a mixed extract of oriental medicinal herbs consisting of sukjihwang, peony, cheongung and angelica as an active ingredient.

The herbal medicine mixture extract is obtained by extracting a mixture of Sukhuanghwang, peony, cheongung and Angelica, and the herbal medicine mixture extract may be prepared by a method comprising the following steps, but is not limited thereto:

(1) extracting by adding an extraction solvent to a mixture of Sukjihwang, peony, cheongung and Angelica;

(2) filtering the extract of step (1); and

(3) Concentrating the filtered extract of step (2) under reduced pressure and drying to prepare an extract.

The extraction solvent in step (1) _{is preferably selected from water, C 1} to C ₄ lower alcohols and mixtures thereof, and more preferably water, but is not limited thereto.

In the above preparation method, the extraction method may use all conventional methods known in the art, such as filtration, hot water extraction, immersion extraction, reflux cooling extraction, and ultrasonic extraction. The extraction solvent is preferably extracted by adding 1 to 20 times the weight of the dried herbal medicine mixed extract, and more preferably adding 5 to 15 times. The extraction temperature is preferably 4 ~ 110 ℃, but is not limited thereto. In addition, the extraction time is preferably 0.5 to 10 hours, more preferably 0.5 to 5 hours, but is not limited thereto. In the above method, the vacuum concentration in step (3) is preferably, but not limited to, a vacuum vacuum concentrator or a vacuum rotary evaporator. In addition, drying under reduced pressure, vacuum drying, boiling drying, spray drying or freeze drying is preferable, but is not limited thereto.

In the preparation of the herbal medicine mixture extract, it is preferable to extract by mixing a mixture of Sukjihwang, peony, cheongung and angelica in a weight ratio of 1:1:1:1, but the present invention is not limited thereto.

The ovarian toxicity by administration of the anticancer agent means a decrease in the quality of eggs or the number of eggs, and the anticancer agent is preferably an alkylated anticancer agent, and the alkylated anticancer agent is cyclophosphamide, mechlorethamine. (mechlorethamine), ifosfamide, chlorambucil, thiotepa, altretamine, procarbazine, busulfan, streptozocin, Carmustine (carmustine), iomustine (iomustine), dacarbazine (dacabazine), cisplatin (cisplatin), carboplatin (carboplatin) and any one selected from oxaliplatin (oxaliplatin), but is not limited thereto.

The anti-cancer is preferably anti-cancer for breast cancer, leukemia or ovarian cancer, but is not limited thereto.

The composition of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent in addition to the active ingredient, and may be in various oral or parenteral formulations. In the case of formulation, it is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include capsules, powders, granules, tablets, pills, etc., and such solid preparations include one or more compounds and at least one excipient, for example, starch, calcium carbonate, sucrose or lactose ( lactose), gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral administration include suspensions, emulsions, syrups, aerosols, etc., and various excipients such as wetting agents, sweetening agents, fragrances, preservatives, etc. in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilisates, and suppositories. As the non-aqueous solvent and the suspending solvent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycero gelatin, etc. may be used. For parenteral administration, it is preferable to select external or intraperitoneal, rectal, intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection.

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the level of the effective amount is determined by the type, severity, and drug activity of the patient. , can be determined according to factors including sensitivity to drug, administration time, administration route and excretion rate, duration of treatment, concurrent drugs, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.

The dosage of the composition of the present invention varies depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and severity of disease. The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

In addition, the present invention relates to a health functional food composition for the prevention or improvement of ovarian toxicity by administration of an anticancer agent containing a mixed extract of oriental medicinal herbs comprising as an active ingredient, sukjihwang, peony, cheongung and angelica.

The composition is preferably prepared in any one formulation selected from powder, granules, pills, tablets, capsules, candy, syrup, and beverages, but is not limited thereto.

When the health functional food composition of the present invention is used as a food additive, the herbal medicine mixed extract may be added as it is or may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined according to the purpose of its use (prevention, health or therapeutic treatment). In general, in the production of food or beverage, the composition of the present invention is added in an amount of 15 parts by weight or less, preferably 10 parts by weight or less, based on the raw material. However, in the case of long-term intake for health and hygiene or health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

There is no particular limitation on the type of the food. Examples of foods to which the herbal mixture extract can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, There are drinks, alcoholic beverages, vitamin complexes, etc., and includes all health functional foods in the ordinary sense.

When the composition of the present invention is used as a health drink, it may contain various flavoring agents or natural carbohydrates as an additional component like a conventional drink. The above-mentioned natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclotenstrin, and sugar alcohols such as xylitol, sorbitol and erythritol. As the sweetener, natural sweeteners such as taumarin and stevia extract, synthetic sweeteners such as saccharin or aspartame, and the like can be used. The proportion of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 g of the composition of the present invention. The composition of the present invention contains various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal agents, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonic acid It may contain a carbonation agent used in beverages, and the like. In addition, the composition of the present invention may contain the pulp for the production of natural fruit juice, fruit juice beverage, and vegetable beverage. These components may be used independently or in combination. Although the proportion of these additives is not very important, the composition of the present invention is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight.

In addition, the present invention relates to an anticancer adjuvant for preventing or improving ovarian toxicity by administration of an anticancer agent containing a mixed extract of oriental medicinal herbs comprising as an active ingredient sukjihwang, peony, cheongung and angelica.

The anti-cancer adjuvant may contain at least one active ingredient exhibiting the same or similar function in addition to the herbal medicine mixture extract. The anticancer adjuvant can be administered orally or parenterally during clinical administration, and when administered parenterally, intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, intrauterine dural injection, intracerebrovascular injection, or chest It can be administered by internal injection, and can be used in the form of general pharmaceutical preparations.

The anticancer adjuvant of the present invention may be administered in various parenteral formulations during actual clinical administration. When formulated, a diluent or excipient such as a commonly used filler, extender, binder, wetting agent, disintegrant, surfactant, etc. is prepared Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.

Hereinafter, the present invention will be described in more detail using examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited thereto.

[Animal model and herbal medicine mixed extract administration]

To 10-week-old C57BL/6 mice, 75 mg/kg of cyclophosphamide (Cy) was intraperitoneally administered 3 times for 1 week. A total of 20 herbal medicine mixture extracts were orally administered at 5 g/kg for 4 weeks. The herbal medicine mixture extract was purchased and used as a mixture of Sukjihwang, peony, cheongung and Angelicae sold by Hanpoong Pharmaceutical as 'Samultang'.

Example 1. Evaluation of the distribution of follicle growth stages according to the administration of the herbal medicine mixture extract

After oral administration of the herbal medicine mixture extract, the ovarian tissue was extracted one week after the oral administration, and the distribution of each follicle growth stage in the tissue was evaluated. After burying the ovarian tissue fixed in 4% paraformaldehyde (biosesang) fixative in paraffin, the entire tissue was cut continuously to a thickness of 5 μm. After H&E staining for every fifth section, the microscopic examination was performed. Segmental follicle growth stage was evaluated by classifying them into primordial follicle, primary follicle, secondary follicle, and antral follicle.

As a result, as shown in FIG. 1, the distribution of primordial follicles was statistically significantly reduced by administration of cyclophosphamide, and the group administered with the herbal medicine mixture extract was statistically significantly recovered and cyclophosphamide was administered. It was confirmed that the number of primitive follicles increased compared to the Pamid-administered group.

In addition, as shown in FIG. 2, the distribution of the mature follicle stage in the cyclophosphamide administration group was statistically significantly increased compared to the normal group, and the herbal medicine mixed extract administration group of the present invention compared to the cyclophosphamide administration group showed the mature follicle stage. It was confirmed that the distribution decreased statistically significantly.

Therefore, it was determined that the herbal medicine mixed extract of the present invention can suppress the follicle burnout phenomenon caused by administration of cyclophosphamide.

Example 2. Evaluation of the number and quality of oocytes according to the administration of the herbal medicine mixture extract

The number and quality of oocytes collected by inducing ovulation by injection of 5IU PMSG (Prospec) and 5IU hCG (Prospec) hormones at 5 weeks after oral administration of the herbal medicine mixture extract were evaluated.

The number and maturity of the collected oocytes were evaluated by dividing them into immature oocytes (Germinal vesicle or Metaphase I stage) and mature oocytes (Metapase II stage) according to the maturity of the oocytes.

Using DAPI (vectashield) and 1:200-diluted FITC-a-tubulin antibody (Cell signaling technology), the nucleus and spindle threads of the collected oocytes were stained. quality was evaluated.

As a result, as shown in FIGS. 3 to 6, the number of eggs collected by inducing ovulation (hormonal injection) at the 5th week was statistically significantly increased in the group administered with the herbal medicine mixture extract compared to the group administered with cyclophosphamide. In addition, the number of healthy oocytes most likely to be fertilized (eg MII and normal spindle oocytes) also increased statistically significantly.

Claims (9)

A pharmaceutical composition for the prevention or treatment of ovarian toxicity for a decrease in ova quality or number of eggs induced by the administration of an anticancer drug containing a mixed herbal medicine water extract consisting of sukjihwang, peony, cheongung and angelicae as an active ingredient. delete delete The pharmaceutical composition for preventing or treating ovarian toxicity by administration of an anticancer agent according to claim 1, wherein the anticancer agent is an alkylated anticancer agent. [Claim 5] The method of claim 4, wherein the alkylation-based anticancer agent is cyclophosphamide, mechlorethamine, ifosfamide, chlorambucil, thiotepa, altre. altretamine, procarbazine, busulfan, streptozocin, carmustine, iomustine, dacabazine, cisplatin, carbople A pharmaceutical composition for the prevention or treatment of ovarian toxicity by administration of an anticancer agent, characterized in that any one selected from Latin (carboplatin) and oxaliplatin (oxaliplatin). The pharmaceutical composition for preventing or treating ovarian toxicity by administration of an anticancer agent according to claim 1, further comprising a pharmaceutically acceptable carrier, excipient or diluent in addition to the active ingredient. The pharmaceutical composition for preventing or treating ovarian toxicity by administering an anticancer agent according to claim 1, wherein the anticancer agent is an anticancer agent for breast cancer, leukemia or ovarian cancer. A health functional food composition for the prevention or improvement of ovarian toxicity to the decrease in ova quality or number of eggs induced by the administration of an anticancer drug containing as an active ingredient a water extract of a mixed herbal medicine consisting of sukjihwang, peony, cheongung and angelica. An anticancer adjuvant for the prevention or improvement of ovarian toxicity to the decrease in the number or quality of eggs induced by the administration of an anticancer drug containing a water extract of a mixed herbal medicine consisting of sukjihwang, peony, cheongung and angelicae as an active ingredient.

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