WO2014025192A1 - Composition pharmaceutique comprenant un extrait de paeonia japonica en tant que principe actif pour le traitement d'un léiomyome utérin - Google Patents

Composition pharmaceutique comprenant un extrait de paeonia japonica en tant que principe actif pour le traitement d'un léiomyome utérin Download PDF

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Publication number
WO2014025192A1
WO2014025192A1 PCT/KR2013/007084 KR2013007084W WO2014025192A1 WO 2014025192 A1 WO2014025192 A1 WO 2014025192A1 KR 2013007084 W KR2013007084 W KR 2013007084W WO 2014025192 A1 WO2014025192 A1 WO 2014025192A1
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WIPO (PCT)
Prior art keywords
extract
myoma
pharmaceutical composition
cells
earl
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PCT/KR2013/007084
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English (en)
Korean (ko)
Inventor
최인호
이은주
전상식
오영은
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영남대학교 산학협력단
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Publication of WO2014025192A1 publication Critical patent/WO2014025192A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • composition for treating myoma of uterus containing earl extract as an active ingredient
  • the present invention relates to a pharmaceutical composition for treating myoma of the uterus containing Baekjak extract as an active ingredient.
  • Leiomyoma is one of the most frequent tumors in women, it is reported that one of the cells of the smooth muscle of the uterus abnormally proliferate to form a uterine myoma, and is a major cause of hysterectomy. It is estimated that 20% of women aged 30 years or older have such tumors, and in fact, 77% of patients who have had hysterectomy due to other diseases have uterine fibroids. About half of the cases are asymptomatic, and if there are symptoms, various symptoms may occur depending on the location or size of the fibroids. Excessive menstruation is the most common symptom and may include pelvic pain, dysmenorrhea, pain during intercourse, pelvic pressure, and frequent urination.
  • Baekjak is a perennial herb from mountainous regions of Korea. The growing environment grows in high soil fertility, half shade and good drainage. The height is 40 ⁇ 50cni, the leaves are 5 ⁇ 12cm long, 3 ⁇ 7cm wide, the front is green, but the back is white, and 3-4 dogs run alternately and are long oval. Flowers are white, 4 ⁇ 5cni in diameter, hang one by one on the main stem. Calyxes are sweet, 3, petals are upside down, 5-7. There are several surgeries with three to four ovaries. Fruits run in long oval about 2-3cm long in August, and seeds are dark. It is used for ornamental purposes and the root is medicinal for analgesic, dysmenorrhea, and gynecological diseases ([Naver Encyclopedia]).
  • Korean Patent No. 1103481 to which the present inventors have registered a patent discloses a pharmaceutical composition for treating uterine myoma, which contains the herb extract as an active ingredient, but there is no reference to the Earl extract of the present invention.
  • An object of the present invention is to provide a pharmaceutical composition for treating myoma of the uterus containing Baekjak extract as an active ingredient.
  • the present inventors have confirmed that the earl extract is effective in myoma and completed the present invention.
  • the present invention provides a pharmaceutical composition for treating myoma of the uterus containing Baekjak extract as an active ingredient.
  • the extract of Paekjak is characterized in that it is extracted from water, lower alcohols of C1 to C4 or their mixed solvents. More specifically, the earl extract is (i) extracting the earl with alcohol; ( ⁇ ) suspending the bacterium alcohol extract by adding ' alcoholic (containing 3-8% by weight of alcohol) water and then adding nucleic acid; And ⁇ ) is a chloroform fractionation layer obtained by adding chloroform to the water layer containing the remaining alcohol after separating the nucleic acid layer, separating the chloroform layer, and concentrating under reduced pressure.
  • the ear extract extract is a progesterone receptor (PR), ⁇ 4 (tropomyosin), IGFBP5 (insulin like growth factor binding protein 5), IGF-1R (insulin like growth factor 1 receptor) and C0L4a2 (collagen type) 4 alpha 2) characterized by inhibiting the expression of the gene.
  • the genes are those expressed higher in myoma cells than in normal cells. ⁇ .
  • the present invention provides a use for the preparation of a pharmaceutical composition for the treatment of uterine myoma of the active ingredient.
  • the present invention also provides a method of treating uterine myoma, comprising administering to the subject a therapeutically effective amount of a currant extract.
  • the 'subject' may be a mammal including a human, but is not limited thereto.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the earl extract, such a pharmaceutically acceptable carrier is commonly used in pharmaceutical preparations, such as lactose, dextrose, sucrose, Solbi, Manni, Starch, Acacia Rubber, Calcium Phosphate, Alginate, Gelatin, Silicate Sims, Microcrystalline Salose, Polyvinylpyridone, Cellulose, Water, Syrup, Methyl Salose, Methylhydroxybenzo Ate, propylhydroxybenzoate, talc, stearic acid magnesium, mineral oil, and the like, but is not limited thereto.
  • a pharmaceutically acceptable carrier is commonly used in pharmaceutical preparations, such as lactose, dextrose, sucrose, Solbi, Manni, Starch, Acacia Rubber, Calcium Phosphate, Alginate, Gelatin, Silicate Sims, Microcrystalline Salose, Polyvinylpyridone, Cellulose, Water, Syrup, Methy
  • the pharmaceutical composition may further include a lubricant, wetting agent, sweetener, flavoring agent, emulsifier, suspending agent, preservative, and the like as an additive.
  • the pharmaceutical composition is determined in accordance with the degree of symptoms of uterine fibroids, it can be administered to various mammals such as rats, mice, livestock, humans. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous intrauterine dural or intracerebroventricular injection.
  • the dosage (the therapeutically effective amount) of the active ingredient in the pharmaceutical composition may vary depending on the route of administration, the severity of the disease, the age, sex, and weight of the patient, and preferably a daily dosage of 0.01 to 1,000. mg / kg, specifically 0.1 to 1,000 mg / kg, more specifically 0.1 to 100 mg / kg. Administration can be administered once a day or divided into several times, thereby not limiting the scope of the invention.
  • the 50% lethal dose (LD50) of the toxicity test has proved to be a safe substance of at least 2 g / kg and its stability is ensured.
  • the pharmaceutical compositions can be prepared in unit dose form or formulated using pharmaceutically acceptable carriers and / or excipients or incorporated into multi-dose containers.
  • the formulation may be in the form of a solution, suspension or emulsion, or may be in the form of an exerciser, extract, powder, granule, tablet, economy, lotion ointment.
  • the present inventors confirmed that the earl extract inhibits the cell proliferation of myoma cells and reduces the expression of genes that are highly expressed in myomas. Therefore, it can be usefully used as a therapeutic agent for fibroids.
  • Figure 1 shows the appearance of myoma cells when treated with Earl extract (1 mg / ml) for 7 days Indicates.
  • Figure 2 is a graph showing the results of the proliferation rate of the cells treated with the white medicinal extract for 7 days using the MTT assay method.
  • the control group was not treated with medicinal herb extracts. When the control value was 100%, the cell proliferation rate in the treatment group was expressed as a relative value (p ⁇ .0001, Tuckey test).
  • Figure 3 is a graph showing the proliferation rate of cells analyzed using MTT assay after incubation for 7 days after treatment with 100 ug / ml, 100 ug / ml, 10 ug / ml.
  • the control group was not treated with medicinal herb extracts, and when the control value was 100%, the cell proliferation in the treatment group was expressed as a relative value ( ⁇ ⁇ 0001, Tuckey test).
  • Figure 4 is a graph showing the proliferation rate of myoblast cell lines C2C12 cells analyzed by ⁇ assay after incubation for 7 days after treatment with 100 ug / ml, 100 ug / ml, 10 ug / ml.
  • the control group was not treated with medicinal herb extracts. When the control group value was 100%, the cell growth rate in the treatment group was expressed as a relative value (p ⁇ .0001, Tuckey test).
  • Figure 5 shows the proliferation rate of human fibroblasts analyzed using ⁇ assay after incubation for 7 days after treatment with 1000 ug / ml Baekje extract. It is a graph.
  • the control group was not treated with medicinal extracts, and when the control value was 100%, the cell proliferation rate in the treatment group was expressed as a relative value (p ⁇ .0001, Tuckey test).
  • Figure 6 is a graph showing the result of analyzing the gene value by processing RNA through extracting the extract of 1 mg / ml of myoma cells and real-time PCR. The relative value of the gene expression value of the treated cells was calculated with the control group value of 1, and ⁇ -act in gene was used for normalization (p ⁇ 0.05, Tuckey test).
  • FIG. 7 is 7 days after treatment with the earl extract Protein expression was observed through immunostaining. Green indicates C0L4a2 ⁇ ⁇ expression and blue indicates nucleus.
  • A) represents normal myoblasts
  • Figure 8 shows the results of treatment of myofibril fraction (ethyl acetate, chloroform, nucleic acid) to the myoma cells for 48 hours.
  • the control group was not treated with medicinal herb extracts, and the results showed the relative cell proliferation rate in the treatment group when the control group was 100% (Tuckey test).
  • Figure 9 shows the appearance of myoma cells when treated with motherwort extract (1 mg / ml) for 7 days.
  • Baekjak extract was prepared at a concentration of 0.1 g / ml, and the Baekjak extract was dissolved in sterile tertiary distilled water, filtered once in a 40 strainer and filtered at 0.2 urn filter and stored frozen at -20 ° C until use.
  • the methanol extract was suspended in 1 liter of 5% methane and then poured into a separatory funnel, followed by pouring 1 liter of nucleic acid (Hexane) and shaking several times. It was then left for 4 hours at room temperature to allow equilibrium between the two solvents. When the nucleic acid layer and the water layer (5% methane is water soluble) were partitioned, the nucleic acid layer was separated and concentrated under reduced pressure to obtain a nucleic acid fraction.
  • the Baekja extract fractions thus obtained were prepared at a concentration of 0.2 g / ml, each fraction was dissolved in DMS0 and refrigerated at 4 ° C.
  • the myoma tissue removed after surgery on the day was soaked in saline and transported. Dip the tissue once again into saline, wash it, cut the tissue into a size of about 3-5m, and then cut the tissue into type I collagenase / KRB (rebs-ringer bicarbonate buffer)]. Put and incubate at 37 ° C for about 30-40 minutes. At this time, the incubation time and the amount of Krebs-Ringer bicarbonate buffer should be changed little by little depending on the state and amount of the sample.
  • the tissues were cultured as they were until they adhered to the culture plate, and the cells emerged from the digested tissues.
  • the cells were filled in the cell culture dish, passage culture was performed, and passage culture was performed with trypsin EDTA.
  • the same cells were dispensed into 6 well culture dishes by cell count measurement before dispensing the cells into the culture dishes.
  • the ⁇ assay method was used to measure the cell proliferation according to the extract treatment, and after 3 hours after the addition of the ⁇ reagent, 500 ⁇ l of DMS0 was added and the cell proliferation was measured at 590 nm. As a result of the measurement, it was observed that the proliferation rate of the cells treated with Baekjak extract was lower than that of the myoma cells of the control group which were not treated with anything. The relative value of the treated cells was obtained with the cell proliferation value of the control group at 100%: in the case of white peony, only 63% of the cells proliferated (FIG. 2).
  • Example 4 Observation of Cell Proliferation According to Concentration of Baek-Pak Extract
  • 1000 ug / ml, 100 ug / ml, and 10 ug / ml were treated. After incubation for 7 days and the growth rate was measured by MTT assay. The results showed that 1000 ug / ml Baekja extract treatment was the most effective in inhibiting cell proliferation compared to control group, and 100 ug / ml and 10 ug / ml treatment did not affect cell proliferation inhibition.
  • Figure 3 Observation of Cell Proliferation According to Concentration of Baek-Pak Extract
  • C2C12 cells which are myoblasts, were used for the toxicity test of the extract. After growing more than about 70% of the cells, the White Pear extract was treated with 1000 ug / ml, 100 ug / ml and 10 ug / ml and incubated for 3 days. After 3 days, the proliferation of cells was measured by MTT assay, and the cells were treated with 100% of untreated cells. As a result of obtaining the relative value, the extract of Baekjak had no significant effect on the proliferation of C2C12 cells (FIG. 4). In addition, human fibroblasts were treated with 1000 ug / ml of Baekja extract for 7 days, and then the proliferation of the cells was observed. As a result of treatment, only 67% of the cells of the Baekjak extract survived the comparison with the control group (FIG. 5).
  • the extract of Pear vulgaris is a gene that is expressed higher in myoma cells than in normal cells, such as PR (progesterone receptor), TPM4 (tropomyosin), IGFBP5 (insulin like growth factor binding protein 5), IGF-1R (insulin like growth factor 1 receptor) and It was confirmed that C0L4a2 (collagen type 4 al ha 2) gene is effective in suppressing the expression.
  • PR progesterone receptor
  • TPM4 tropomyosin
  • IGFBP5 insulin like growth factor binding protein 5
  • IGF-1R insulin like growth factor 1 receptor
  • the following figure shows the expression of C0L4 a 2 exon in normal uterine myoblasts and myoma cells, and high expression in myoma cells can be observed. After treatment, the decrease in C0L4 a 2 protein expression was observed The earl extract was effective in inhibiting the expression of C0L4 a 2 protein in myoma cells (FIG. 7).
  • motherwort herb which is widely used as a blood-treatment medicine in oriental medicine
  • Fig. 9 there was no significant difference in the proliferation comparison with the cells without the motherwort treatment, and the results of comparing the growth of normal myometrial cells and myoma cells with the motherwort treatment did not show any significant difference. Therefore, it can be seen that the suppression of the proliferation of fibroids is a peculiar effect on the extract of the present invention.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un extrait de Paeonia japonica en tant que principe actif pour le traitement d'un léiomyome utérin. Plus particulièrement, la présente invention concerne une composition pharmaceutique comprenant un extrait de Paeonia japonica en tant que principe actif qui peut présenter des effets thérapeutiques sur un léiomyome utérin. L'herbe médicinale peut inhiber la prolifération de tissu de myome et de cellules de myome tout en induisant moins d'effets secondaires, et par conséquent, peut être utilisée en tant que médicament sûr pour un léiomyome utérin.
PCT/KR2013/007084 2012-08-07 2013-08-06 Composition pharmaceutique comprenant un extrait de paeonia japonica en tant que principe actif pour le traitement d'un léiomyome utérin WO2014025192A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20120086362 2012-08-07
KR10-2012-0086362 2012-08-07

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WO2014025192A1 true WO2014025192A1 (fr) 2014-02-13

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030033473A (ko) * 2001-10-23 2003-05-01 주식회사 바이오딕스 생약 추출물을 포함하는 부인병 개선 및 예방용 조성물
KR100823123B1 (ko) * 2000-09-13 2008-04-18 지앙수 카니온 파마수티컬 씨오., 엘티디. 생약 조성물 및 그의 제조방법
KR100950564B1 (ko) * 2008-03-03 2010-04-01 동아대학교 산학협력단 한약재 추출물을 유효성분으로 함유하는 항암용 조성물
KR20110015172A (ko) * 2009-08-07 2011-02-15 최장현 여성 생리불순 개선용 식물추출 조성물

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100823123B1 (ko) * 2000-09-13 2008-04-18 지앙수 카니온 파마수티컬 씨오., 엘티디. 생약 조성물 및 그의 제조방법
KR20030033473A (ko) * 2001-10-23 2003-05-01 주식회사 바이오딕스 생약 추출물을 포함하는 부인병 개선 및 예방용 조성물
KR100950564B1 (ko) * 2008-03-03 2010-04-01 동아대학교 산학협력단 한약재 추출물을 유효성분으로 함유하는 항암용 조성물
KR20110015172A (ko) * 2009-08-07 2011-02-15 최장현 여성 생리불순 개선용 식물추출 조성물

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PARK, JUN-SIK ET AL.: "Case Reports of 6 Outpatients Complaining of Uterine Myoma", THE JOURNAL OF ORIENTAL OBSTETRICS & GYNECOLOGY, vol. 18, no. 4, 2005, pages 230 - 241 *
PARK, YOUNG SUN ET AL.: "The effect of p-sitosterol proliferation and appoptosis in human uterine leiomyoma cells", THE JOURNAL OF ORIENTAL OBSTETRICS & GYNECOLOGY, vol. 18, no. 1, 2005, pages 181 - 191 *

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