KR20160111354A - Pharmaceutical Composition For Treating Leukopenia Decrease caused by Administrating Anticancer Agent - Google Patents

Abstract

The present invention relates to a pharmaceutical composition which is useful for treating leukopenia induced by administration of anticancer drugs, containing an Angelica gigas Nakai extract as an active ingredient, wherein the content of decursin and decursinol angelate is 70-98% (w/w) by extracting Angelica gigas Nakai using ethanol. As shown in results derived from clinical tests and animal experiments, the composition exhibits effects of preventing reduction in the leucocyte count after anticancer treatment while restoring the reduced the leucocyte count.

Description

[0001] The present invention relates to a pharmaceutical composition useful for treating leukopenia caused by administration of an anticancer agent,

The present invention relates to a pharmaceutical composition useful for the treatment of leukopenia, and more particularly, to a pharmaceutical composition useful for treating leukopenia caused by administration of an anticancer agent using an extract of Angelica gigas Nakai as an active ingredient.

One of the ways to remove cancer cells from the body is chemotherapy (chemotherapy), which is the treatment of cancer by using drugs, ie, cancer drugs, which is a systemic treatment for cancer cells spread throughout the body. Since anticancer drugs are designed to eliminate rapidly growing cancer cells, normal cells can not help but be affected. As a result, after chemotherapy, anemia, white blood cell count and platelet count decrease, mouth drop, nausea, vomiting and diarrhea, hair loss, defective reproductive function, The patient is treated with an anticancer drug and an average rest period of 2 to 3 weeks to wait for the recovery of the normal cells. The next treatment is to be performed.

In this case, the number of white blood cells dropped by chemotherapy often does not recover. However, in this case, G-CSF (granulocyte colony stimulating factor) is administered to increase the leukocyte count. Respectively. However, the administration of G-CSF may cause colds, headache (20%), arthralgia (15%), high fever (12%) and serious side effects such as shortness of breath and temporary shock. If you do not have a limited dose. In addition, despite the administration of G-CSF, white blood cell counts are not recovered, and chemotherapy can not be continued. Therefore, there is a desperate need for the development of effective anti-leukocyte reduction and remedial agents or substances without side effects.

Deccasin is a pyranocoumarin-based natural component originally isolated from ether extracts of Angelica decursiva Fr. et Sav. In Japan. It has a molecular weight of 328.35 and a molecular formula of C ₁₉ H ₂₀ O ₅ (Tetrahedron Letters No 14, 1461-1465, 1966). In particular, Angelica gigas Nakai, which is a Korean angelica gigas Nakai, contains a large amount of decaccine (J. Pharm. Soc. Korea 11, 22-26, 1967) and J. Pharm. Soc. Korea, 13, 47-50, 1969), and a large amount of decaginase was also isolated from the fruit of Peucedanum terebinthaceum Fischeret Turcz. (Journal of Medicine 30, No. 2, 73-78, 1986). In addition, the present inventor has found that a large amount of decaccine is also contained in Angelica gigas Jiri, which is a specialty of Jiri mountain (Korean Patent Publication No. 10-2009-0078267).

Decercinol angelate is a structural isomer having the same molecular weight and the same chemical formula as decacin, and the following molecular structural formula shows the structure of decacin and deacercin angelate.

Decker ginseng and dexacinol angelate can be extracted from Korean ginseng, Angelica gigas, Angelica gigas, body herb, oilseed oil and other plants and can be produced using tissue culture technology and organic synthesis technology.

Chrysanthemum is a Korean wild duckweed called native chrysanthemum or poisonous god. It is native to South Korea. It is a white flower in other country. It has red color, and leaves are large and round. The range of its use has been used as a herbal medicine as a herbal medicine. Recent researches have reported that decursin, an indicator substance of Angelica gigas Nakai, and decursinol, a major component, are improving blood flow and anti-helicobacter activity.

Since the content of decagin and decancinol angelate in the dried product of Angelica angustifolia is very high (about 9% of the dried product) and used in an unpurified state, it can cause hypertension. Therefore, (Korean Patent Registration No. 10-0509843), and a method for extracting dexacin and dexacinol angelate from a genus Chrysanthemum (Korean Patent Registration No. 10-0509843) The extraction method of the extract and the antioxidant effect of the extract using the extract were studied and registered as Korean Patent No. 10-0893779 (invention: extraction method of Angelicae Radix extract having harmful active oxygen scavenging effect) Patented for "True Angelica gigantosa and Angelica gigantus extract and its extraction method", which are effective ingredients of dexacin and dexacinol angelate It has received bar (Republic of Korea Patent No. 10-0995891 call).

In addition, the present inventor has registered an invention patent for an increase in the number of spermatozoa of a true angelica angelica extract containing decursin, decursinol angelate as a main component (Korean Patent Registration No. 10-1144715) Single toxicity and repeated toxicity of this purified product (Molecular & Cellular Toxicology, 5 (2) 153-159), Genotoxicity (Molecular & Cellular Toxicology 5 (1), 83-87), Pharmacokinetics (absorption, distribution, metabolism, excretion) (JOURNAL OF MICROBIOLOGY AND BIOTECHNOLOGY 19 (12), 1569-1572), and published the results of a study on standardization (Journal of the Korean Society of Food Science and Nutrition, 38 (5), 653 ~ 656).

The inventors of the present invention conducted various studies on the efficacy of Angelica gigas Nakai extract as described above, and found that Angelica gigas Nakai extract has excellent effects on the reduction and recovery of leukocyte caused by administration of anticancer drugs, and compared with the conventional drugs such as G-CSF It is effective and has no side effects. Thus, the present invention has been completed.

Disclosure of the Invention The present invention has been made to solve the above-mentioned problems of the prior art. It is an object of the present invention to provide a pharmaceutical composition useful for treating leukopenia caused by administration of an anticancer agent, The purpose is to provide.

In order to achieve the above object, the present invention is implemented by the following means.

The present invention relates to an extract of Angelica gigas Nakai which is extracted from Angelica gigas Nakai with ethanol and contains 70% (w / w) to 98% (w / w) of decaccin and decascinol angelate as an active ingredient, A pharmaceutical composition useful for treating leukopenia is provided.

The present invention has the following effects with the above-described configuration.

The pharmaceutical compositions useful for the treatment of leukopenia induced by the administration of anticancer drugs using the true Angelica giganta extract of the present invention as an active ingredient can prevent the decrease in leukocyte count after chemotherapy and show a decrease in leukocyte count It has an excellent effect of recovering the heat.

Fig. 1 is a photograph of granules prepared by using the purified Angelica edulis extract in an airtight container. The refined product per gram of granule contains 166.7 mg of dexacin and dexycinol angelate content of 120 mg and a purity of 72%.
FIG. 2 is a graph showing the results of experiments in which blood leukocyte count reduction and restoration effects of the present invention are reduced by administering benzene to blood vessels.
FIG. 3 is a graph showing the results of experiments in which leukocyte count reduction and restorative effects of the present invention in blood are reduced by administering benzene orally.

The Applicant hereunder explains in detail the means for solving the foregoing problem. The detailed description of known technology that may unnecessarily obscure the gist of the present invention will be omitted and will be described in detail with reference to the embodiments. The following examples illustrate the invention in more detail but do not limit the scope of the invention.

The present invention relates to a pharmaceutical composition useful for treating leukopenia caused by the administration of an anticancer agent, comprising an Angelica gigantosa extract as an active ingredient.

The contents of this example are deckacin and decoxynol angelate extracted by the method using ethanol extracted by the method of Korean Patent Registration No. 10-0893779 registered by the present inventor and specifically deckacin and decker It is the result of studying the cytochrome c Angelate. If the content of dexacin and decoxynol angelate are low and the impurities are high, there is a side effect of blood pressure increase. Therefore, the purity of the extracts having a purity from 70% to 98% Respectively.

The pharmaceutical composition of the present invention is prepared by a method that can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. The pharmaceutical composition of the present invention can be used in the form of sucrose, lactose mannose, dextrose, fructose, starch , Mannitol, xylitol, lactitol, ribitol, etc., and surfactants such as polysorbitan and Triton X-100 as polyhydric alcohols in order to prevent aggregation when they are made into liquids. And may include acacia rubber, pectin, xanthan gum, agar, etc. as the thickening agent. In addition, stabilizers, preservatives, flavors, sweeteners, lubricants and the like can be further added,

Citric acid, succinic acid, tartaric acid, succinic acid, malic acid, boric acid, acetic acid, hydrochloric acid, ascorbic acid and the like can be used as an acidity controlling agent for preventing decomposition.

In the present invention, the preparations can be administered orally or non-oral, and the oral preparations can be administered in the form of tablets, capsules, solutions, granules, powders, and the like. The dose of the preparation may be from 0.5 mg / kg to 10 mg / kg.

The following example confirms the effect of preventing and decreasing the decrease of leukocyte count by using the Angelica gigantosa extract containing 70% by weight or more of Decker's and Decker's angelate.

Purified Angelica extract

This study was carried out to separate and concentrate deckrin and decercinol angelate from. In the case of Chinese origin, Japanese origin, and Vietnamese origin, the content is not economically valuable.

For use in food and medicine, phytotoxic ethanol and ethanol were used as extraction solvents and purified water was used for water. The raw Angelica gigas cormum was ground finely to a size of 40 mesh or less, dried to a moisture content of 5% or less, and added with 2 to 4 times of crushed Angelica angelica as a weak alcohol or alcohol (hereinafter referred to as ethanol) Extracted for more than 12 hours and quantitated by filtration. In this case, the concentration of decaccine and decancinol angelate contained in the concentrate was 33%.

The concentrate was evaporated to dryness to obtain a viscous material. One liter of ethanol was added per kilogram of this material to dissolve the main component and left at -20 ° C for 10 hours. The resulting precipitate was removed by centrifugation and the supernatant was obtained. The supernatant was evaporated to dryness to give a concentrate.

The concentrate was eluted with 50 liters of 60% ethanol (diluted ethanol). In this case, the concentration of decaccine and decascinol angelate contained in the concentrate was 330 grams, and the amount of the main ingredient capable of dissolving in 50 liters of 60% ethanol was 330 grams.

After elution and centrifugation, only 60% ethanol layer was obtained. This was evaporated to dryness to obtain a concentrate. This was dissolved in 99% alcohol and the supernatant was taken to yield the final concentrate.

Representative results of this analysis by liquid chromatography (HPLC) showed that the contents were 54.52% deckacin, 41.26% deacercinolate and 0.299% deacercinol, and the total content was 96%.

Granule manufacturing

The purified Angelica gigantis extract was weighed 12.5% and dissolved in 10 times ethanol. The mixture was mixed with 0.0522% of sucralose, 1.11% of citric acid, 1% of magnesium stearate, 2% of silicon dioxide, 38.75% of mannitol and 44.59% of corn starch, Of particle size. The prepared granules were dried at 80 DEG C for 4 hours or more and stored in an airtight container (refer to FIG. 1, and FIG. 1 shows the granules prepared using the purified Angelica gigantosum radix). mg).

The results of administration on female cancer patients (clinical results of granular administration of Angelica gigantea extract purified according to Example 2)

The patient in Example 3 was a female patient with colon cancer who was living in Busan. She was admitted to the hospital of Seoul National University Hospital and was treated with amitriptyline three times. Respectively. The female patient was given G-CSF for leukocyte growth, but the leukocyte count was not recovered and she was discharged from the hospital with 0 cell / ul. This female patient was then given granules of Angelica gigas Nakai extract for 3 weeks. One gram of granule once a day (120 mg as an extracted tablet) was administered and the efficacy of the leukocyte was increased to 1800 cells / ul after 3 weeks of administration. After that, the patient was admitted to the hospital for the 4th and 5th anticancer drugs. At that time, granules of Angelica gigas Nakai extract were administered once a day. The leukocyte count of this patient after 5th cancer treatment was 2,800 cells / ul.

Results of administration to male patients (Clinical results of granular administration of Angelica gigas Rinse extract)

The patient in Example 4 was a 50-year-old male patient with a lymphocytic lymphoma in Busan. She was admitted to Pusan National University Hospital and was treated with hamam. Respectively. To increase leukocyte count in this male patient, granules of Angelica gigas Nakai extract were administered from the first chemotherapy. One gram of granule (120 mg as an extracted tablet) was taken once a day and showed remarkable efficacy with a leukocyte count elevated to 1100 cells / ul after 3 weeks of dosing. During the subsequent chemotherapy, 1 g of granules of Angelica gigas Nakai extract was continuously administered once a day. The leukocyte level before the third treatment was 1,600 cells / ul, and it was more than 7,000 cells / ul before the fourth treatment. Approximately one week after the fourth treatment, the male patient had a leukocyte count of 10,000 cells / ul, and the leukocyte count after receiving the chemotherapy until the sixth was 15,000 cells / ul. In addition, a liver function test and a renal function test were performed on this patient at Pusan National University Hospital. Blood tests and biochemical tests showed no functional impairment.

Prevention of leukopenia reduction in animals

1) Preparation of experimental animals

SD rats (SD rats, rats) were purchased for about 200 grams, adapted for 1 week, turned off and turned on at 12-hour intervals. Breeding was carried out using an aseptic animal experiment equipment (SPF chamber manufactured by Dongbang Sincinnati) and humidity was maintained at 50 ± 5% and 24 ℃ ~ 26 ℃. When animals were in stock, they were used for the experiment after 7 days of adaptation.

In the intravenous administration of benzene, 4 SD rats per group were used. In the oral administration of benzene, 3 animals were used in the normal group and the control group (benzene group), and 5 animals were used in the oral administration group.

2) Preparation of suspending agent

A certain amount of Angelica gigantosa L. extract, which contains the main components decagin and dexacinol angelate, was dissolved in ethanol. In addition, xylitol, sucralose, citric acid, D-sorbitol, and Tween-80 were dissolved in water to prepare a solution. Each concentration was made to be 20% xylitol, 0.02% sucralose, 0.025% citric acid, 10% D-sorbitol and 0.05% tween-80, and 1% ethanol.

A specific preparation method was as follows: Tween was added to an ethanol solution containing a main component, uniformly dissolved, mixed with a water-soluble solution in which the remaining materials were dissolved, and the suspension was slowly prepared while stirring to disperse the main components uniformly distributed. We called this the 'Agnex suspension'.

3) Experimental method by intravenous administration of benzene

Benzene was administered intravenously and 0.2 ml / kg was administered at intervals of 2 days for 3 weeks. The true angelically extracted extract was orally administered before and after administration of benzene at a dose of 2 mg / kg.

The control group was a group of free-diet after intravenous administration of benzene. The positive control group was intravenously injected with benzene 0.2 ml / kg every two days for 3 weeks,

The experimental and preventive groups were pre-administered orally with Agnex suspension at a dose of 2 mg / kg for 7 days followed by benzene (0.2 ml / kg intravenously every 2 days) and Agnex suspension (daily oral administration) This group was administered for 3 weeks.

The normal group is a group that has only free diet.

The recovery control group consisted of a group of white rats (white rats) that had been given intravenous injection of benzene 0.2 ml / kg every two days for 3 weeks,

The recovery group was a group of oral administration of Agnex suspension for 7 days to white rats in which white blood cells were decreased by intravenous administration of benzene 0.2 ml / kg every 2 days for 3 weeks.

4) Experimental method by oral administration of benzene

Benzene was administered orally and 200 mg / kg was administered once a day for 2 weeks. Benzene was uniformly mixed with the same amount of corn oil at the time of administration. The Angelica giganta extract (Agnex, Agnex) was mixed with benzene at a dose of 10 mg / kg for 1 day, once for 2 weeks.

The control group is a natural group after oral administration of benzene,

The positive control group was a group of benzene 200 mg / kg orally administered daily for 2 weeks

The oral administration group was a group in which the Agnex suspension was orally administered with benzene (200 mg / kg) for 2 weeks at a dose of 10 mg / kg.

5) Experimental results

(1) Experimental results by intravenous administration of benzene

When white blood cell counts were examined,

The control group (6,500 cells / μl) showed a decrease of about 32% compared to the normal group (9,500 cells / μl)

The experimental group (10,000 cells / ul) showed a slightly higher level of 5.2% than the normal group,

In the recovery group, the recovery control group (6,000 cells / μl) decreased about 8% compared to the control group, while the recovery experimental group (8,700 cells / ul) recovered to 91.6% of the normal group. This results in a 45% increase in leukocyte count compared to the restored control group (see FIG. 2).

(2) Experimental results by oral administration of benzene

When white blood cell counts were examined,

The control group (3,660 cells / μl) showed a decrease of about 56% compared to the normal group (6,460 cells / μl)

The experimental group (4,610 cells / ul) recovered to 71% level compared to the normal group and showed a 26% increase compared to the control group (see FIG. 3).

Claims (1)

The extracts of Angelica gigas Nakai (Angelica gigas Nakai) extracted from Angelica gigas Nakai with ethanol and containing 70% (w / w) ~ 98% (w / w) of Deckersin and Decoxynol Angelate as active ingredients were used as leukopenia treatment ≪ / RTI >

Images