KR101932906B1 - Composition for preventing, improving or treating disease caused by side effect of anticancer agent comprising Rumecis Radix extract as effective component - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of diseases caused by side effects of anticancer drugs containing an extract of Rumecis Radix as an active ingredient. The present invention relates to a pharmaceutical composition for preventing or treating disease caused by an anticancer drug- It was confirmed that the inhibition of bone marrow suppression by the anticancer drug was remarkably restored in the animal model in which the reduction of the colonial group was remarkably restored and the bone marrow suppression was induced by intraperitoneal injection of the anticancer drug.
Therefore, the herbal composition extract of the present invention can be usefully used as a composition for prevention, improvement and treatment of diseases caused by side effects of anticancer drugs, and it is possible to increase the effect of anticancer drugs by using anticancer drugs in combination with anticancer drugs.

Description

TECHNICAL FIELD [0001] The present invention relates to a composition for preventing, ameliorating or treating diseases caused by side effects of anticancer drugs containing an extract of Aspergillus oryzae as an active ingredient.

The present invention relates to a composition for preventing, ameliorating or treating a disease caused by an anticancer drug adverse effect containing an amygdala root extract as an active ingredient.

Cancer is one of the top two causes of death in Korea, and 30% of deaths in the 50s and 60s in Korea are dying of cancer. Surgical surgery, radiation therapy, and chemotherapy are most commonly used for the treatment of these cancers. Among them, the development of anti-cancer drugs as chemotherapy has been tried variously, but to date, anti-cancer drugs have not been developed as genuine therapeutic drugs, and they are only helping with adjuvant therapy or short-term life extension.

An anticancer drug used in chemotherapy intervenes in the metabolic pathway of cancer cells to directly interfere with DNA to block the replication, transcription and translation of DNA, inhibit the synthesis of nucleic acid precursors, inhibit cell division, . However, the present anticancer drug has no specific selectivity for cancer, and exhibits therapeutic effect and toxic effect at the same time. Toxicity due to the administration of anticancer drug is caused by hemocyte depletion of white blood cells, platelets, red blood cells, Hair loss, dyspepsia and diarrhea, diarrhea, renal toxicity due to tubulo-necrosis, nervous system, nausea and vomiting due to adverse effects of hair loss, menstrual irregularities and male infertility due to hair loss symptoms, ovarian and testicular side effects, Various side effects such as peripheral neuritis and weakness caused by the disorder, vascular disorders such as vascular pain and rash, skin and nail discoloration occur. Therefore, it is urgent to develop a medicament that can increase the effectiveness of chemotherapy while minimizing side effects caused by the anticancer drug.

On the other hand, Yangjegun refers to the root of Rumex japonicus Houttuyn. The yin-yi is the name of a root-like hoof-like name, and the tongue (牛 舌) is the name of the leaf. It can be used as a sardine if it is slightly dipped, but it is soft and delicious. This medicine has a peculiar smell, it is tasteless, it is temperate and a little poisonous. It has the effect of turning off the blood and stopping the hemorrhage by acting on the blood, and it is used for the nose, hematemesis, fecal bleeding, hemorrhage, uterine bleeding, numbness, Pharmacological actions have been reported to reduce blood clotting time, inhibit skin fungi, prevent colds, inhibit leukemia and mild diarrhea. It is long cylindrical shape with horizontal wrinkles and thin branch roots. The roots of the stem have remnants of stalk, the outer surface is yellowish yellow or yellowish brown, the folded surface is relatively flat, and the tan brownish brown line is concentric with the ring.

Korean Patent Publication No. 2009-0131971 discloses a pharmaceutical composition for prevention and treatment of cancer, which contains a compound isolated from Yangyangjang as an active ingredient, and Korean Patent No. 0742189 discloses a pharmaceutical composition for preventing or treating cancer, Although a composition for treating atopic dermatitis is disclosed, a composition for preventing, ameliorating, or treating diseases caused by side effects of an anticancer agent containing an extract of the present invention as an active ingredient has not been disclosed.

The present invention provides a composition for preventing, ameliorating or treating diseases caused by the side effects of anticancer drugs containing an extract of Yangyangmae root as an active ingredient. The present invention provides a composition for preventing or ameliorating disease by administering docetaxel extract of the present invention to docetaxel To treat the bone marrow cells of the mice in which the hematopoietic stem cells were reduced by the above-described methods, thereby remarkably restoring the survival of the hematopoietic stem cells.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating diseases caused by side effects of anticancer drugs containing Rumecis Radix extract as an active ingredient.

The present invention also provides a health functional food composition for preventing or ameliorating diseases caused by side effects of anticancer drugs containing Rumecis Radix extract as an active ingredient.

The present invention also provides an anticancer adjuvant containing an extract of Rumecis Radix as an active ingredient.

The present invention relates to a pharmaceutical composition for preventing or treating diseases caused by side effects of anticancer drugs containing an extract of Rumecis Radix as an active ingredient. It not only remarkably reduces the reduction of hematopoietic stem cell colonies caused by anticancer agents, The bone marrow extract of the present invention can be utilized as a pharmaceutical composition for the prevention or treatment of diseases caused by side effects of anticancer drugs, a health functional food, or an anti-cancer adjuvant.

1 is a graph showing the effect of suppressing the reduction of bone marrow cells in mice by treatment with docetaxel and the inhibition of hematopoietic stem cell colony reduction induced by anticancer drugs by treating the docetaxel with the 25, 50 and 100 μg / .
FIG. 2 shows the results of confirming the effect of suppressing the reduction of hematopoietic stem cell colonies induced by anticancer drugs by treating docetaxel and hot-water extracts of the noodle root according to the concentration at the concentration (50, 100 and 200 μg / ml) (A) is a Chinese noodle root, (B) is a domestic noodle root produced in Chungbuk Cheongwon, (C) is a domestic noodle root produced in Sancheong in Kyungnam Province, and (D) is a domestic noodle root produced in Boseong in Jeonnam Province.
FIG. 3 shows the results of confirming the effect of suppressing the reduction of hematopoietic stem cell colony induced by anticancer drugs by treating docetaxel and partly extracted hot-water extracts at concentrations of 50, 100 and 200 μg / ml. (A) The root of the Yangjemun root (root), and (B) the root of the Yangjemang (leaf and stem).
FIG. 4 shows the effect of suppressing the decrease of bone marrow cells by treatment of docetaxel with mouse bone marrow cells and the combination treatment of 15 nM docetaxel with 125 μg / kg and 250 μg / kg of farinacea hydrothermal extract according to the present invention The result is confirmed. Control was a control group with no treatment, Vehicle treated with docetaxel, and docetaxel + nasopharyngeal-125 and docetaxel + zyphocyte-250 administered with docetaxel in combination with 125 and 250 μg / kg natus muscle hydrothermal extract. # Indicates that the number of bone marrow cells of the vehicle treated with docetaxel was statistically different from that of control not treated with docetaxel (p = 0.05), * and ** indicate docetaxel The number of bone marrow lengths in the group treated with docetaxel and nasal root extract was statistically significantly different from that of treated group, * means that the p value is less than 0.05, and ** means that the p value is less than 0.01.

The present invention relates to a method The present invention relates to a pharmaceutical composition for preventing or treating diseases caused by the side effects of anticancer drugs containing Radix extract as an active ingredient.

The somatic root extract may be produced by a method including, but not limited to, the following steps:

1) extracting the nasal muscle by adding an extraction solvent;

2) filtering the extract of step 1); And

3) Concentrating the filtrate obtained in step 2) under reduced pressure and drying to prepare an extract.

In the step 1), the extraction solvent is preferably water, a C ₁ -C ₄ lower alcohol, or a mixture thereof, but is not limited thereto.

In the above production method, the extract of the left and right muscles can be extracted by any conventional method known in the art such as filtration, hot water extraction, immersion extraction, reflux cooling extraction and ultrasonic extraction. It is preferable that the extraction solvent is added by 1 to 20 times the volume of the dried muscle, more preferably 3 to 10 times. The extraction temperature is preferably 20 to 50 DEG C, but is not limited thereto. The extraction time is preferably 10 to 100 hours, more preferably 24 to 96 hours, most preferably 72 hours. In the above method, it is preferable to use a vacuum decompression concentrator or a vacuum rotary evaporator for the decompression concentration in step 3), but it is not limited thereto. The drying is preferably performed under reduced pressure, vacuum drying, boiling, spray drying or freeze drying, but not always limited thereto.

It is preferable that the cancer is any one selected from lung cancer, breast cancer, liver cancer, stomach cancer, colon cancer, colon cancer, skin cancer, bladder cancer, prostate cancer, ovarian cancer, cervical cancer, thyroid cancer, kidney cancer, fibrosarcoma, melanoma and blood cancer However, the present invention is not limited thereto, and any cancer that can be diagnosed is not limited.

The anticancer agent is preferably antitumor antibiotics, topoisomerase inhibitor, or taxane anticancer agent, but is not limited thereto and includes all anticancer drugs that can be used clinically, pharmacologically, or biomedically .

The antineoplastic antibiotic may be selected from the group consisting of actinomycin D, bleomycin sulfate, daunomycin, daunorubicin, doxorubicin, epirubicin, But is not limited to, at least one selected from the group consisting of idarubicin, mitomycin, mitomycin-C and mitramycin.

The topoisomerase inhibitor may be selected from the group consisting of irinotecan, camptothecin, novobiocin, epirubicin, dactinomycin, amsacrine, and at least one selected from the group consisting of teniposide and etoposide, but is not limited thereto.

Preferably, the taxane-based anticancer agent is one or both of paclitaxel and docetaxel, and most preferred is docetaxel according to a preferred embodiment of the present invention.

The disease caused by the side effect of the anticancer agent is preferably at least one selected from hematopoietic toxicity, anemia and neutropenia, but is not limited thereto.

The composition of the present invention may contain 0.1 to 99.9% by weight of the extract of the present invention as an active ingredient, based on the total weight of the composition, and may include a pharmaceutically acceptable carrier, excipient or diluent.

The compositions of the present invention may be of various oral or parenteral formulations. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.

The composition of the present invention may be administered orally or parenterally, and it is preferable to select the intraperitoneal, rectal, rectal, intravenous, intramuscular, subcutaneous, intrauterine or intracerebral injection methods for parenteral administration, It is used for external skin.

The 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 effective dose level will depend on the type of disease, severity, , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention may be administered as an individual therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal 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 body weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of the disease, , Preferably 30 to 500 mg / kg, more preferably 50 to 300 mg / kg, and may be administered 1 to 6 times a day. 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.

The present invention also relates to a health functional food for preventing or ameliorating a disease caused by the side effect of an anticancer agent containing a nasal root extract as an active ingredient. The extraction solvent of the crude muscle root extract is preferably water, a C ₁ -C ₄ lower alcohol or a mixture thereof, but is not limited thereto. The anticancer agent includes all anticancer agents that can be used clinically, pharmacologically, or biomedically, including, but not limited to, antitumor antibiotics, phagosomal enzyme inhibitors or taxane anticancer agents. The disease caused by the side effect of the anticancer agent is characterized in that it is at least one selected from the group consisting of hematopoietic toxicity, anemia and neutropenia.

The health functional food composition of the present invention can be used as it is or in combination with other food or food ingredients, and can be suitably used according to conventional methods. There is no particular limitation on the kind of the health food. Examples of the food to which the Yangmyung root extract can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen and other noodles, gums and ice cream, various soups, drinks, tea, , An alcoholic beverage and a vitamin complex, and includes all the health foods in a conventional sense. The health drink containing the composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as a conventional beverage. Such natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The ratio 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 health food of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin , Alcohols, carbonating agents used in carbonated drinks, and the like. And may further contain flesh for the production of fruit juice or vegetable beverages. These components may be used independently or in combination. The proportion of such additives is not critical, but is generally selected in the range of 0.01 to 2 parts by weight based on 100 parts by weight of the composition of the present invention.

The present invention also relates to an anticancer adjuvant containing an amygdalary muscle extract as an active ingredient. The anticancer adjuvant is characterized by inhibiting one or more side effects of anticancer drugs selected from hematopoietic toxicity, anemia and neutropenia induced by administration of an anticancer drug.

The anticancer adjuvant may further contain at least one active ingredient which exhibits the same or similar function to the extract of the root extract. The anticancer adjuvant can be administered orally or parenterally at the time of clinical administration and can be administered orally or parenterally at the time of parenteral administration and can be administered by intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, intrauterine injection, And can be used in the form of a general pharmaceutical preparation.

The anticancer adjuvant may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers. The daily dose of the anticancer adjuvant is about 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg. It is preferable to administer the adjuvant once or several times a day, The range varies depending on diet, time of administration, method of administration, excretion rate, and severity of the disease.

The anticancer adjuvant of the present invention can be administered in various forms of parenteral administration at the time of actual clinical administration. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, It is prepared. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilisers or suppositories. As the non-aqueous solvent or suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like may be used. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are merely illustrative of the present invention and that the scope of the present invention is not limited thereto.

Example  One. Yang Jae-geun  Preparation of extract

(Purchased from Hwang Story Medicines) produced in Chungbuk Cheongwon, domestic products purchased from Herb Story Medicine (purchased from Herb Story Medicines), domestic (purchased from Herb Story Medicine), and Jeonnam (Acquired from Herb Story Medicine) produced by Boseong. 100 g of each of the purchased noodles was pulverized and then mixed with 2 L of water in a round flask. The water bath connected to the reflux condenser equipped with a cooling tube was heated and repeated twice for 2 hours each time. The extracted extract was filtered under reduced pressure using a paper filter paper (Whatman No. 2) and a vacuum pump (Vacuum pump, GAST). The filtered liquid extract was concentrated under reduced pressure using a rotary evaporator (EYELA), the concentrated extract was lyophilized, and then homogenized with a mortar to obtain a two-component hot-water extract. This was stored in a sealed plastic container at 4 ° C in a low temperature storage tank until the experiment.

Example  2. Docetaxel  Check hematopoietic toxicity

To examine the hematopoietic effect of docetaxel, an anticancer drug currently in clinical use, the effect of docetaxel on the growth and differentiation of hematopoietic stem cells in mouse bone marrow cells was examined using ex vivo experiments.

One) In bone marrow cells of mice, Hematopoietic toxicity  Effect verification ( ex vivo )

Bone marrow cells were isolated from mouse femurs. The recombinant murine stem cell factor, rm IL-3, recombinant human IL-6, and human IL-6 derived from humans, supplemented with docetaxel, And methocult GF M3434 (methocult GF M3434) medium containing rh erythropoietin for 7 to 10 days to induce the growth of hematopoietic stem cells. And the effect of anticancer drugs on growth and differentiation of hematopoietic stem cells was observed by performing a colony forming unit assay (CFU assay).

As a result, as shown in Fig. 1, treatment of 15 nM docetaxel resulted in bone marrow toxicity in mouse bone marrow cells, and the combined treatment of both mouse root extracts of the present invention resulted in a decrease in hematopoietic stem cell population colony counts were recovered statistically and the cell size as well as cell number were restored to some extent.

In addition, the hematopoietic toxicity mitigation effect was confirmed by differentiating the two or three differentiated nematodes by their production sites or regions. As shown in Fig. 2, the effect of the hematopoietic toxicity reduction of the nematodes according to the production sites was excellent in both Chinese and domestic And the domestic nodules produced by Boseong in Jeonnam proved to be effective even at a relatively low concentration of 50 ㎍ / ㎖.

The hematopoietic toxicity reduction effect of the nodule root of each nodule was divided into the upper part (leaf and stem) and the lower part (root), and the combined extracts of the nodule root (50, 100 and 200 ㎍ / And the degree of inhibition of hematopoietic stem cell colony reduction was confirmed. As a result, as shown in FIG. 3, the amniotic sac was found to have hematopoietic mitigation effect both in the upper part and the lower part, and it was confirmed that the hematopoietic mitigation effect was superior in the underground part than in the upper part.

Example  3. Yang Jae-geun Heat number  Extract Doclex  Bone marrow suppression in guided myelosuppressive animal models Mitigability  Confirm

To investigate whether the extract of Yangjemun hydrothermal extract showed hematopoietic mitigation effect in the animal model of bone marrow suppression, bone marrow suppression was induced by intraperitoneal injection of docetaxel in the mouse,

Specifically, C57BL / 6 mice were divided into four groups: Group 1 was treated with physiological saline containing 5% ethanol and 2% polysorbate 80 as a control, Group 2 was treated with 30 mg / kg And docetaxel treated with docetaxel 3 times a day. In group 3, 125 mg / kg of a root extract was forcibly administered once a day for two days before dosing with docetaxel, and once daily for 3 days with docetaxel, And group 4 was administered with 250 mg / kg of the root extract twice a day for two days before the administration of docetaxel in the same manner as the group 3, and the administration of docetaxel The dose of 250mg / kg of both muscle extracts was administered once daily for 3 days.

Thereafter, the mice were weighed daily for weight change in the control group, the docetaxel-treated group, the docetaxel-treated group (125 mg / kg) and the docetaxel-treated group (250 mg / kg) On day 6, the mouse was dissected and the weight of spleen and thymus, which plays an important role in changes in myelosome number and hematopoiesis, were measured.

As shown in Table 1, mice injected with docetaxel had an organ index due to a sudden decrease in weight due to abnormalities of spleen and thymus, which are internal organs involved in hematopoiesis, . However, it was confirmed that decrease in the index of the organ is alleviated in the group administered with docetaxel and nasal root extract.

Organ index (mg / g) = weight of the organ (mg) / weight of the individual (g)

The organ index, which confirmed the changes in the spleen and thymus weight of the docetaxel group, docetaxel group, Spleen index (mg / g) Thymus index (mg / g) Control group 3.111 ± 0.58 2.360 0.28 Doclex 2.366 ± 0.22 0.911 0.22 Docetaxel + soy sauce-125 3.376 + 0.78 1.048 ± 0.51 Docetaxel + yangjemun-250 2.594 + 0.084 1.303 + - 0.30

Bone marrow mononuclear cells were collected from the femurs of Groups 1 to 4 (control group, docetaxel group, docetaxel + amniotic fluid-125 and docetaxel + amniotic fluid-250) The number of bone marrow cells was rapidly decreased in the docetaxel alone group but the decrease in the number of bone marrow cells in the group treated with the succinylcholine extract was statistically significantly restored (FIG. 4).

Claims (10)

A pharmaceutical composition for preventing or treating at least one disease selected from hematopoietic toxicity, anemia and neutropenia induced by docetaxel or paclitaxel containing Rumecis Radix extract as an active ingredient. 2. The method according to claim 1, wherein the crude muscle root extract is selected from the group consisting of hematopoietic toxin, anemia and neutropenia induced by docetaxel or paclitaxel, which is extracted with water, a lower alcohol of C ₁ -C ₄ or a mixture thereof. ≪ / RTI > or a pharmaceutically acceptable salt thereof. delete delete delete delete delete A health functional food composition for preventing or ameliorating at least one disease selected from hematopoietic toxicity, anemia and neutropenia induced by docetaxel or paclitaxel containing Rumecis Radix extract as an active ingredient. Characterized in that the disease is caused by one or more anticancer drug side effects selected from hematopoietic toxicity, anemia and neutropenia caused by administration of docetaxel or paclitaxel containing Rumecis Radix extract as an active ingredient Cancer adjuvant.
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