KR101876201B1 - Composition for preventing, improving or treating disorder associated with androgen receptor comprising extract of Lithospermi Radix as effective component - Google Patents
Composition for preventing, improving or treating disorder associated with androgen receptor comprising extract of Lithospermi Radix as effective component Download PDFInfo
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- KR101876201B1 KR101876201B1 KR1020170049238A KR20170049238A KR101876201B1 KR 101876201 B1 KR101876201 B1 KR 101876201B1 KR 1020170049238 A KR1020170049238 A KR 1020170049238A KR 20170049238 A KR20170049238 A KR 20170049238A KR 101876201 B1 KR101876201 B1 KR 101876201B1
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- androgen
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- androgen receptor
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Abstract
Description
본 발명은 자근 추출물을 유효성분으로 포함하는 안드로겐 수용체 관련 질환의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, ameliorating or treating an androgen receptor-related disease comprising an extract of rice bran as an active ingredient.
안드로겐(androgen)은 남성 생식계 성장과 발달에 영향을 미치는 호르몬의 총칭으로, 남성호르몬이라고도 하며, 남성호르몬의 작용을 나타내는 모든 물질을 일컫는 말이다. 남성의 2차 성징 발달에 작용하는 호르몬으로 주로 남성의 정소에서 분비되며 일부는 부신피질과 여성의 난소에서도 분비되는데, 탄소원자 19개를 가진 스테로이드로서 고환에서 분비되는 테스토스테론을 비롯하여 세포에서 환원되어 생성되는 디히드로테스토스테론(dehydrotestosterone), 그것이 변하여 오줌 속에 배설되는 안드로스테론이나 디히드로에피안드로스테론(dehydroepiandrosterone) 등과 부신피질에서 분비되는 아드레노스테론 등이 포함된다. Androgen is a generic term for hormones that affect the growth and development of the male reproductive system. It is also referred to as the male hormone. It refers to all substances that act as male hormones. It is a hormone that acts on the development of secondary males in men. It is mainly secreted from male testes. It is also secreted from adrenal cortex and female ovary. It is a steroid with 19 carbon atoms, including testosterone secreted by testis, Dihydrotestosterone, which is changed and excreted in the urine such as androsterone, dehydroepiandrosterone, etc., and adrenocorticotropic adrenocorticosterone.
이들은 생식기관이나 그 밖의 성적 특징의 발육이나 유지 및 기능을 관장한다. 특히 뼈 조직에서 단백질의 증가, 신장의 무게와 크기 증가, 땀과 피지샘의 활동 증가, 적혈구 세포의 재생 등에 관여하고, 피부에 작용하면 표피의 각질층이 두꺼워져 피지가 증가하므로, 사춘기의 청소년들에게 발생하는 여드름의 원인이 되기도 한다. 또한 체모와도 관계가 있는데, 남성의 수염의 경우는 안드로겐이 증가할수록 증가하는 경향을 보이지만, 이마나 정수리부위의 털이 줄어드는 탈모를 진행시키기도 한다. They control the development, maintenance and function of reproductive organs and other sexual characteristics. In particular, it is involved in the increase of protein in bone tissue, the increase in the weight and size of the kidney, the activity of sweat and sebaceous glands, and the regeneration of red blood cells. When the skin is applied to the skin, the epidermis becomes thicker and sebum increases, It is also the cause of acne. There is also a relationship with hair. Male beard tends to increase as the androgen increases, but it also causes hair loss, which reduces the hair on the forehead and crown.
이와 같이 안드로겐이 비정상적으로 증가하여 발생하는 안드로겐 의존성 질환 중에서 전립선 비대증(Benign prostatic hyperplasia, BPH)은 과거에는 전립선이 비대해져 방광 하부의 소변이 나오는 통로를 막아 요도 폐색을 일으켜 소변의 흐름이 감소된 상태로 정의하였고, 조직학적으로는 전립선 간질이나 전립선의 상피조직 세포가 증식된 것으로 정의하였다. 하지만, 최근에는 이와 같은 정의나 개념으로 설명하기에는 질병의 병태 생리가 너무 복잡하여, 현재는 50세 이상의 남성에서 하루 8회 이상 소변을 보는 빈뇨, 야간 빈뇨, 강하고 갑작스런 요의(오줌이 마려운 느낌)를 느끼면서 소변이 마려우면 참을 수 없는 절박뇨 등의 방광 저장 증상과 지연뇨(소변을 볼 때 뜸을 들여야 소변이 나오는 현상), 단절뇨(소변의 흐름이 끊기는 현상), 배뇨 시 힘을 주어야 하는 현상 등 방광의 배출 장애를 나타내는 증상을 통칭한 하부 요로증상의 호소로 전립선 비대증을 정의하고 있다.Among the androgen-dependent diseases caused by abnormal increase of androgens, benign prostatic hyperplasia (BPH) is caused by enlargement of the prostate in the past, blocking the passage of urine under the bladder, resulting in urethral obstruction and decreasing the flow of urine , And histologically defined as proliferating epithelial cells of prostate epilepsy or prostate. In recent years, however, the pathophysiology of the disease is too complex to be explained by such definition or concept. Currently, men over 50 years old urinate more than 8 times a day, nighttime urine, strong and sudden urination (feeling urine) (Urine discharge), urinary incontinence (urine discharge), urinary incontinence, urinary incontinence, urinary incontinence, urinary incontinence, urinary incontinence, The symptom of lower urinary tract symptom, which refers to the symptom of discharge obstruction of the bladder, is defined as enlargement of the prostate.
주요한 임상적 특징으로는 전립선 확대(prostate enlargement) 및 하부 요로(lower urinary tract) 징후가 있다. 전립선 확대는 안드로겐의 존재 하에서 일어나고, 단백동화 스테로이드들(anabolic steroids)이 전립선의 용량을 증가시키며 요류 속도(urine flow)를 감소시켜 증가된 배뇨 빈도(urinary frequency)를 유발한다고 알려져 있다. The main clinical features are prostate enlargement and lower urinary tract symptoms. Prostate enlargement occurs in the presence of androgens, and anabolic steroids are known to increase the prostate volume and reduce urine flow, resulting in increased urinary frequency.
전립선은 테스토스테론 및 이의 고환 외부 기원 전구체들(extratesticular origin)이 더욱 강력한 DHT(dihydrotestosterone)로 활성화되는 안드로겐-의존성 기관이다. 통상적으로, 전립선은 DHT 형성의 중요한 기관으로, 전립선의 내분비 활성의 전반적인 효과(systemic effect)는 주로 DHT 형성 및 순환(circulation)을 위한 이의 배출에 관여된다. DHT의 생산은 나이가 듦에 따라 증가하여 전립선 성장의 증대 및 비대증을 유발한다. DHT의 중요성은 5α-환원효소(5α-reductase) 억제제가 BPH 남성 환자에 적용된 임상 연구들에 의해 확인된다. 많은 경우에, 5α-환원효소 억제제를 이용한 치료법은 전립선의 DHT 레벨과 전립선 크기를 현저하게 감소시킨다는 것이 알려져 있다. 피나스테라이드(finasteride)는 안드로겐-의존성 질환들, 예를 들어 남성형 대머리, 전립선 비대증(BPH) 및 전립선암의 치료에 폭넓게 이용되고 있다. 피나스테라이드는 5α-환원효소의 경쟁적 및 특이적 억제제로, 전립선, 모낭세포(hair follicles) 및 다른 안드로겐-민감성 조직에서 테스토스테론의 DHT 전환을 차단하여 혈청 및 전립선 내 DHT 농도의 억제를 초래한다. 피나스테라이드 및 두타스테라이드(dutasteride) 같은 종래에 이용된 약물들은 BPH의 효과적인 치료 방법이라는 것이 증명되었지만, 이들의 사용은 발기 부전(erectile dysfunction), 성욕감퇴(loss of libido), 현기증(dizziness) 및 상기도 감염(upper respiratory tract infection) 같은 부작용들로 인하여 엄격하게 제한되고 있다.The prostate is an androgen-dependent organ in which testosterone and its extratesticular origin are activated by the more potent DHT (dihydrotestosterone). Typically, the prostate is an important organ of DHT formation, and the systemic effect of the endocrine activity of the prostate is mainly involved in its release for DHT formation and circulation. The production of DHT increases with age, resulting in increased prostatic hyperplasia and hypertrophy. The importance of DHT is confirmed by clinical studies in which 5α-reductase inhibitors are applied in BPH male patients. In many cases, it is known that treatment with a 5-reductase inhibitor significantly decreases the DHT level and prostate size of the prostate. Finasteride is widely used for the treatment of androgen-dependent diseases such as baldness of men, benign prostatic hyperplasia (BPH) and prostate cancer. Finasteride is a competitive and specific inhibitor of 5α-reductase, blocking DHT conversion of testosterone in prostate, hair follicles and other androgen-sensitive tissues, resulting in the inhibition of serum and prostate DHT levels. While conventionally used drugs such as finasteride and dutasteride have proven to be effective treatments for BPH, their use has been limited by their use for erectile dysfunction, loss of libido, dizziness, But are severely limited by side effects such as upper respiratory tract infection.
한편, 자근 (Lithospermi Radix)은 자초(紫草), 자단(紫丹), 자부(紫芙)라고도 하며 지치(Lithospermum erythrorhizon Siebold et Zuccarini)(지치과 Boraginaceae)의 뿌리를 건조한 것으로, 한의학적으로 혈분(血分)에서 열사(熱邪)를 없애고 해독하며 발진을 순조롭게 한다. 또한 혈액 순환을 촉진하고 대변을 잘 나오게 하며 새살이 빨리 돋아나게 하는 것으로 알려져 있다. On the other hand, Lithospermi Radix is also called Zosu, Zaden, Zubu, Lithospermum erythrorhizon Siebold et Zuccarini (Boraginaceae) is a dry root of the medicine, blood medicine (blood) to remove the heat (heat 邪) and decode and smooth the rash. It is also known to promote blood circulation, improve bowel movements, and encourage newborns to develop quickly.
본 발명의 안드로겐 수용체 결합 저해제 관련 종래기술로는 일본등록특허 제2655646호에 쓴풀, 지치 쓴풀, 황금, 죽절인삼, 얼룩조릿대 및 진피에서 선택된 적어도 일종의 생약의 추출 엑기스를 유효성분으로 함유하는 안드로겐 수용체 결합 저해제가 알려져 있으나, 본 발명의 자근 추출물을 유효성분으로 포함하는 안드로겐 수용체 관련 질환의 예방, 개선 또는 치료용 조성물에 대해서는 알려진 바 없다.In the prior art related to the androgen receptor-binding inhibitor of the present invention, Japanese Patent Registration No. 2655646 discloses an androgen receptor-binding compound which contains, as an active ingredient, an extract of at least one kind of herbal medicine selected from the group consisting of Sphinx, An inhibitor is known, but a composition for preventing, improving or treating an androgen receptor-related disease which contains the extract of the present invention as an active ingredient is not known.
본 발명은 상기와 같은 요구에 의해 도출된 것으로서, 본 발명은 자근 추출물을 유효성분으로 포함하는 안드로겐 수용체 관련 질환의 예방, 개선 또는 치료용 조성물을 제공하고, 본 발명의 유효성분인 자근 추출물은 항안드로겐 활성이 있으며, DHT(Dihydrotestosterone)의 AR(androgen receptor) 결합을 억제하는 효과가 있다는 것을 확인함으로써, 본 발명을 완성하였다.The present invention provides a composition for preventing, ameliorating, or treating an androgen receptor-related disease comprising an extract of Aspergillus oryzae as an active ingredient. Has an androgenic activity, and has an effect of inhibiting AR (androgen receptor) binding of DHT (dihydrotestosterone), thereby completing the present invention.
상기 목적을 달성하기 위하여, 본 발명은 자근 추출물을 유효성분으로 포함하는 안드로겐 수용체 관련 질환의 예방 또는 치료용 약학 조성물을 제공한다.In order to accomplish the above object, the present invention provides a pharmaceutical composition for preventing or treating an androgen receptor-related disease comprising an extract of Aspergillus oryzae as an active ingredient.
또한, 본 발명은 자근 추출물을 유효성분으로 포함하는 안드로겐 수용체 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or ameliorating an androgen receptor-related disease comprising an extract of rice bran as an active ingredient.
본 발명은 자근 추출물을 유효성분으로 포함하는 안드로겐 수용체 관련 질환의 예방, 개선 또는 치료용 조성물에 관한 것이다. 본 발명의 유효성분인 자근 추출물은 항안드로겐 활성이 있으며, DHT(Dihydrotestosterone)의 AR 결합을 억제하는 효과가 있으므로, 안드로겐 수용체 관련 질환인 전립선비대증, 안드로겐 의존성 탈모, 배뇨장애 및 전립선암 관련 산업에 널리 활용될 수 있다. The present invention relates to a composition for preventing, ameliorating or treating an androgen receptor-related disease comprising an extract of rice bran as an active ingredient. The active ingredient of the present invention is anti-androgenic, and has an effect of inhibiting AR binding of dihydrotestosterone (DHT). Therefore, it is widely used in the industries related with androgen receptor-related diseases such as hyperplasia of prostate, androgen-dependent hair loss, Can be utilized.
도 1은 22Rv1/EE4 세포에서 안드로겐 수용체 전사 활성화 어세이(androgen receptor transcriptional activation (AR-TA) assay)를 이용한 자근 추출물의 항 안드로겐 활성 및 세포 생존률에 대한 1차 스크리닝 결과로, 양성대조군에 대비되는 상대적 활성(%)을 나타낸 것이다.
도 2는 22Rv1/EE4 세포에서 안드로겐 수용체 전사 활성화 어세이(androgen receptor transcriptional activation (AR-TA) assay)를 이용한 자근 추출물의 항 안드로겐 활성 및 세포 생존률에 대한 2차 스크리닝 결과로, 양성대조군에 대비되는 상대적 활성(%)을 나타낸 것이다.
도 3은 본 발명의 자근 추출물의 안드로겐 수용체에 대한 [3H] DHT의 용량-반응 곡선과 cold DHT에 의한 300pM [3H] DHT의 결합 저해를 확인한 결과이다.
도 4는 AR 과발현시킨 Cos7 세포에서 본 발명의 농도별 자근 추출물의 300pM [3H] DHT의 AR 결합 정도를 확인한 것이다.FIG. 1 shows the results of primary screening for anti-androgenic activity and cell viability of root extracts using androgen receptor transcriptional activation assay (AR-TA) assay in 22Rv1 / EE4 cells, Relative activity (%).
FIG. 2 shows the result of secondary screening for anti-androgenic activity and cell viability of root extracts using an androgen receptor transcriptional activation assay (AR-TA) assay in 22Rv1 / EE4 cells, Relative activity (%).
FIG. 3 shows the results of confirming the inhibition of binding of 300 pM [ 3 H] DHT by the dose-response curve of [ 3 H] DHT to the androgen receptor of the extract of the present invention and cold DHT.
FIG. 4 is a graph showing the degree of AR binding of 300 pM [ 3 H] DHT in the concentration-dependent extracts of the present invention in
본 발명은 자근 추출물을 유효성분으로 포함하는 안드로겐 수용체 관련 질환의 예방 또는 치료용 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating an androgen receptor-related disease, which comprises an extract of Aspergillus oryzae as an active ingredient.
상기 자근 추출물은 하기의 단계를 포함하는 방법에 의해 제조할 수 있으나, 이에 한정하지 않는다:The agar-agar extract may be prepared by a method including, but not limited to, the following steps:
(1) 자근에 추출용매를 가하여 추출하는 단계;(1) extracting the root muscle by adding an extraction solvent;
(2) 단계 (1)의 추출물을 여과하는 단계; 및 (2) filtering the extract of step (1); And
(3) 단계 (2)의 여과한 추출물을 감압 농축하고 건조하여 추출물을 제조하는 단계. (3) The step of extracting the filtered extract of step (2) by concentration under reduced pressure and drying.
상기 단계 (1)에서 추출용매는 물, C1~C4의 저급 알코올 또는 이들의 혼합물 중에서 선택하는 것이 바람직하며, 더 바람직하게는 에탄올이고, 더욱더 바람직하게는 70%(v/v) 에탄올이지만 이에 한정하지 않는다.In step (1), the extraction solvent is preferably selected from water, a C 1 -C 4 lower alcohol or a mixture thereof, more preferably ethanol, even more preferably 70% (v / v) ethanol But is not limited thereto.
상기 제조방법에 있어서, 추출방법은 여과법, 열수 추출, 침지 추출, 환류 냉각 추출 및 초음파 추출 등의 당 업계에 공지된 모든 통상적인 방법을 이용할 수 있다. 상기 추출용매는 건조된 자근 중량의 1~20배 첨가하여 추출하는 것이 바람직하며, 더 바람직하게는 5~15배 첨가하는 것이다. 추출온도는 4 내지 50℃인 것이 바람직하나 이에 한정하지 않는다. 또한, 추출시간은 0.5~10시간인 것이 바람직하며, 0.5~5시간이 더욱 바람직하고, 1시간이 가장 바람직하나 이에 한정하지 않는다. 상기 방법에 있어서, 단계 (3)의 감압농축은 진공 감압 농축기 또는 진공회전증발기를 이용하는 것이 바람직하나 이에 한정하지 않는다. 또한, 건조는 감압건조, 진공건조, 비등건조, 분무 건조 또는 동결 건조하는 것이 바람직하나 이에 한정하지 않는다.In the above production method, any conventional method known in the art such as filtration, hot water extraction, immersion extraction, reflux cooling extraction, and ultrasonic extraction may be used. The extraction solvent is preferably added by 1 to 20 times the weight of the dried root, more preferably 5 to 15 times. The extraction temperature is preferably 4 to 50 DEG C, but is not limited thereto. The extraction time is preferably 0.5 to 10 hours, more preferably 0.5 to 5 hours, most preferably 1 hour, but not always limited thereto. In the above method, it is preferable to use a vacuum decompression concentrator or a vacuum rotary evaporator for the decompression concentration in the 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.
상기 안드로겐 수용체 관련 질환은 전립선비대증, 안드로겐 의존성 탈모, 배뇨장애 및 전립선암 중에서 선택된 하나 이상인 것이 바람직하지만 이에 한정하는 것은 아니다.Preferably, the androgen receptor-related diseases are at least one selected from among benign prostatic hyperplasia, androgen-dependent alopecia, dysuria, and prostate cancer.
상기 자근 추출물 이외에 추가로 약제학적으로 허용가능한 담체, 부형제 또는 희석제를 더 포함할 수 있다.In addition to the dried root extract, the composition may further comprise a pharmaceutically acceptable carrier, excipient or diluent.
본 발명의 약학 조성물은 캡슐제, 산제, 과립제, 정제, 현탁액, 에멀젼, 시럽 및 에어로졸 중에서 선택된 어느 하나의 제형으로 제조될 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition of the present invention may be prepared into any one of formulations selected from capsules, powders, granules, tablets, suspensions, emulsions, syrups and aerosols, but is not limited thereto.
본 발명의 약학 조성물은 경구 또는 비경구로 투여될 수 있으며, 비경구 투여 시 피부 외용 또는 복강 내, 직장, 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사 방식을 선택하는 것이 바람직하며, 가장 바람직하게는 피부 외용으로 사용한다.The pharmaceutical 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 during parenteral administration, It is preferably used for external skin application.
본 발명의 약학 조성물은 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성 용제 및 현탁 용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로 젤라틴 등이 사용될 수 있다.The pharmaceutical composition of the present invention can be prepared using a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, or an excipient. 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.
본 발명에 따른 조성물은 약제학적으로 유효한 양으로 투여한다. 본 발명에 있어서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.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 can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can 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.
본 발명의 조성물의 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도에 따라 그 범위가 다양하게 사용할 수 있다.The dosage of the composition of the present invention may be varied depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease.
또한, 본 발명은 자근 추출물을 유효성분으로 포함하는 안드로겐 수용체 관련 질환의 예방 또는 개선용 건강기능식품 조성물에 관한 것이다.The present invention also relates to a health functional food composition for preventing or ameliorating an androgen receptor-related disease comprising an extract of rice bran as an active ingredient.
상기 안드로겐 수용체 관련 질환은 전립선비대증, 안드로겐 의존성 탈모, 배뇨장애 및 전립선암 중에서 선택된 하나 이상인 것이 바람직하지만 이에 한정하는 것은 아니다.Preferably, the androgen receptor-related diseases are at least one selected from among benign prostatic hyperplasia, androgen-dependent alopecia, dysuria, and prostate cancer.
상기 자근 추출물을 유효성분으로 포함하는 안드로겐 수용체 관련 질환의 예방 또는 개선용 건강기능식품 조성물은 분말, 과립, 환, 정제, 캡슐, 캔디, 시럽 및 음료 중에서 선택된 어느 하나의 제형으로 제조하거나, 식품의 성분으로 첨가하여 제조될 수 있으며, 통상적인 방법에 따라 적절하게 제조될 수 있다. The health functional food composition for prevention or amelioration of the androgen receptor-related diseases containing the dried root extract as an active ingredient may be prepared into any one form of powder, granule, ring, tablet, capsule, candy, syrup and beverage, And may be suitably prepared according to a conventional method.
본 발명의 자근 추출물을 첨가할 수 있는 식품의 일례로는 육류, 소시지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 중에서 선택된 어느 하나의 형태일 수 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.Examples of foods to which the extract of the present invention can be added include meat products, sausages, breads, chocolate, candies, snacks, confectionery, pizza, ramen noodles, other noodles, dairy products including ice- A tea, a drink, an alcoholic beverage, and a vitamin complex, all of which include health functional foods in a conventional sense.
상기 건강기능식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 및 천연 풍미제, 착색제 및 증진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알킨산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일 주스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. The health functional foods include various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, colorants and enhancers (cheese, chocolate etc.), pectic acid and its salts, alkynic acid and its salts, , pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. It may also contain flesh for the production of natural fruit juices and vegetable drinks. These components may be used independently or in combination.
본 발명의 건강기능식품 조성물은 여러가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상기 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 슈크로스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다.
The health functional food composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient. The natural carbohydrates are sugar saccharides such as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, 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.
이하, 실시예를 이용하여 본 발명을 더욱 상세하게 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로 본 발명의 범위가 이들에 의해 제한되지 않는다는 것은 당해 기술분야에서 통상의 지식을 가진 자에게 있어 자명한 것이다.
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.
1. 시료 및 실험방법1. Samples and Experimental Methods
본 발명의 일 실시예에서 사용하는 자근은 옴니허브(주)으로부터 구입하여 사용하였다. In the embodiment of the present invention, the rhizome root was purchased from Omni Hub Co., Ltd. and used.
1) One) 자근Thigh 추출물의 제조 Preparation of extract
건조한 자근 970g에 대하여, 70%(v/v) 에탄올 10ℓ를 가하고, 3시간 동안 환류 추출하였다. 상기 추출액을 여과한 후, 냉각 콘덴서가 장착된 농축 장치로 40℃에서 감압 농축하였다. 감압 농축된 추출물의 용매를 완전히 제거하기 위하여 정제수 500㎖를 넣어 현탁시킨 후, 동결건조기를 이용하여 동결건조하였다. 자근의 동결건조된 70% 에탄올 추출물의 수득률은 38.30%였다.
To 970 g of dry root, 10 L of 70% (v / v) ethanol was added and the mixture was refluxed for 3 hours. The extract was filtered, and then concentrated under reduced pressure at 40 DEG C with a condenser equipped with a cooling condenser. In order to completely remove the solvent of the concentrated extract, 500 ml of purified water was added to suspend the suspension, followed by lyophilization using a freeze dryer. The yield of the lyophilized 70% ethanol extract of wheat germ was 38.30%.
2) 2) 항안드로겐Anti-androgen 활성 스크리닝 Active Screening
본 발명의 일실시예에서는 22Rv1/EE4 세포를 사용하여 인 비트로 안드로겐 수용체 전사 활성화 어세이(in vitro androgen receptor transcriptional activation assay)를 이용하여 자근 추출물의 항안드로겐 활성을 스크리닝하였다. 상기 22Rv1/EE4 세포는 사람 전립선암 세포주인 22Rv1 세포에 안드로겐 반응인자(androgen responsive element)에 의해 발현이 조절되는 루시퍼라아제 수용체 유전자 플라스미드(luciferase reporter gene plasmid)를 함유하고 있으며, 글루코코르티코이드 수용체(glucocorticoid receptor)를 넉다운(knock down)시킨 세포이다.In one embodiment of the present invention, 22Rv1 / EE4 cells were used to screen anti-androgenic activity of the extract from rice bran using an in vitro androgen receptor transcriptional activation assay. The 22Rv1 / EE4 cell contains a luciferase reporter gene plasmid whose expression is regulated by an androgen responsive element in 22Rv1 cell, a human prostate cancer cell line, and a glucocorticoid receptor (glucocorticoid receptor) receptors are knocked down.
1차 스크리닝은 대조군(Control)을 포함하여 4단계의 농도로 나누어 실시하였으며, 1차 스크리닝 후 대략적인 IC50 값을 기준으로 2차 스크리닝 대상을 선별하였으며, 2차 스크리닝은 대조군(Control)을 포함하여 7단계의 농도로 나누어 실시한 후, IC50를 산출하였다.
The primary screening was divided into four concentrations, including control (Control). After the first screening, secondary screening subjects were selected based on the approximate IC 50 values. Secondary screening included control , And the IC 50 was calculated after dividing by the concentration of 7 steps.
3) 3) in vitroin vitro 항안드로겐Anti-androgen 활성 검색 조건 Active search criteria
- 시험 재료: 70%(v/v) 에탄올 자근 추출물이 100mg/㎖의 농도가 되도록 DMSO에 용해하여 준비하였다. Test material: 70% (v / v) ethanol dried root extract was prepared by dissolving in DMSO to a concentration of 100 mg / ml.
- 시험 세포주: 22Rv1/EE4 세포(안드로겐 수용체 반응인자(androgen receptor responsive element)를 함유한 리포터 유전자와 GR 넉다운(knock down) 플라스미드(plasmid)를 영구 함유하는 사람의 전립선암 세포주)Test cell lines: 22Rv1 / EE4 cells (human prostate cancer cell lines that permanently contain reporter genes containing androgen receptor responsive elements and GR knock down plasmids)
- 시험 조건: 96웰 플레이트에 charcoal stripped FBS (Sigma)를 5% 첨가한 페놀-레드 프리 RPMI-1640 배지에 3×104개의 세포를 분주하고, 세포를 유지했던 배지에 의한 안드로겐 작용이 최소화되도록 48시간 동안 인큐베이션하였다. 그 후, 300pM R1881과 여러 농도의 자근 추출물을 동시에 24시간 동안 처리한 후 세포를 수득하여 프로메가(Promega) 사의 루시퍼라아제 어세이 시스템(luciferase assay system)을 이용하여 루시퍼라아제(luciferase) 활성을 측정하였다. 실험의 검증을 위하여 0.13% DMSO 및 20μM의 비칼루타마이드(bicalutamide; anti-androgen compound), 300pM R1881, 300pM R1881+20μM 비칼루타마이드(bicalutamide)를 양성 및 음성 대조군으로 사용하여 매 플레이트마다 실험하였다. Test conditions: 3 × 10 4 cells were dispensed into phenol-red-free RPMI-1640 medium supplemented with 5% charcoal stripped FBS (Sigma) to a 96-well plate, and the culture medium was used to minimize the androgen action And incubated for 48 hours. Then, the cells were treated with 300 pM R1881 and various concentration of root extract for 24 hours, and luciferase activity was measured using a luciferase assay system of Promega Co., Were measured. For the purpose of the experiment, experiments were carried out for each plate using 0.13% DMSO and bicalutamide (anti-androgen compound), 300 pM R1881, 300 pM R1881 + 20 μM bicalutamide as positive and negative controls, Respectively.
- 항안드로겐 작용이 세포독성에 의할 수 있으므로 항안드로겐 시험과 동일한 조건으로 세포 플레이팅 및 시료 처리 후, MTS 어세이를 이용하여 세포독성을 확인하였다.- Since anti-androgen action can be attributed to cytotoxicity, cytotoxicity was confirmed by MTS assay after cell plating and sample treatment under the same conditions as antiandrogen test.
- 양성 대조군 및 결과 분석: 항안드로겐 작용의 양성대조군은 300pM R1881을 사용하였으며, 양성대조군 300pM R1881의 활성을 100%로 기준하여 자근 추출물의 항안드로겐 작용을 나타내었다.
- Positive Control and Result Analysis: 300 pM R1881 was used as a positive control for antiandrogenic action, and the antiandrogenic activity of the extract was determined on the basis of 100% activity of the
% of inhibition = [(자근 추출물 + 300pM R1881의 루시퍼라아제 활성)-(블랭크의 루시퍼라아제 활성)]×100
% of inhibition = [(luciferase activity of leucitol root extract + 300 pM R1881) - (luciferase activity of blank)] × 100
4) 4) 자근Thigh 추출물의 세포 기반 안드로겐 수용체 결합 Cell-based androgen receptor binding of the extract 어세이Assay 조건 Condition
- 시험 세포주: 인간 안드로겐 수용체를 일시적으로 과발현시킨 Cos-7 세포 (ATCC® CRL-1651™).Test cell line: Cos-7 cells (ATCC® CRL-1651 ™) transiently overexpressing human androgen receptor.
- 시험 조건: 24웰 플레이트에 웰당 5×104의 Cos-7 세포를 깔은 후, 24시간 후에 리포펙타민 2000(lipofectamine 2000)을 이용하여 pCMV-hAR 플라스미드를 형질전환시켰다. 호르몬을 고갈시킨 DMEM 배지에 [3H]DHT (Dihydrotestosterone, [1,2,4,5,6,7-3H(N)]-(5αAndrostan-17β-OL-3-One), Cat. no. NET453250UC, PerkinElmer)를 최종 300pM이 되도록 녹인 후, 자근 추출물을 원하는 농도로 용해시킨 시험배지를 제조하여, 형질전환 24시간 후에 배지를 제거한 후 세포를 PBS로 3회 세척한 후 시험배지로 교체하였다. 그 후 90분간 배양한 후 각 웰을 빙-냉 PBS로 3번씩 세척하여 결합되지 않은 [3H]DHT를 완전히 씻어 제거한 후 Passive lysis buffer(PLB; Cat. no. E1941, Promega)를 웰 당 200㎕씩 첨가하여 세포를 용해시켰다. 액체섬광계수기(Liquid Scintillation Counter, LSC) vial에 칵테일 솔루션 3㎖과 cell lysate 150㎕를 넣어 잘 섞은 후, LSC를 이용하여 카운팅하였다.- Test conditions: 5x10 < 4 > cells / well Cos-7 cells were plated, and after 24 hours, pCMV-hAR plasmid was transformed with lipofectamine 2000 (lipofectamine 2000). To the hormone-depleted DMEM medium [ 3 H] DHT (Dihydrotestosterone, [1,2,4,5,6,7-3H (N)] - (5αAndrostan-17β-OL-3-One), Cat. The cells were washed three times with PBS and then replaced with test media. The cells were washed three times with PBS, and the cells were washed three times with PBS. After incubation for 90 minutes, each well was washed three times with ice-cold PBS to completely wash away unbound [ 3 H] DHT, and then passive lysis buffer (PLB; Cat. No. E1941, Promega) And the cells were lysed. Liquid Scintillation Counter (LSC) Vials were mixed with 3 ml of cocktail solution and 150 μl of cell lysate, followed by counting using LSC.
양성 대조군은 300pM [3H]DHT를 사용하였으며, 이를 100%로 기준하여 자근 추출물에 의한 안드로겐 수용체에 결합된 [3H]DHT의 양을 계산하였다. For the positive control, 300 pM [ 3 H] DHT was used, and the amount of [ 3 H] DHT bound to the androgen receptor by the extract from the root was calculated on the basis of 100%.
% of inhibition = [(자근 추출물+300 pM [3H]DHT counting- Blank cell counting)/(300 pM [3H]DHT counting- Blank cell counting)×100]
% Of inhibition = [(jageun extract +300 pM [3 H] DHT counting- Blank cell counting) / (300 pM [3 H] DHT counting- Blank cell counting) × 100]
실시예Example 1. One. 자근Thigh 추출물의 항 안드로겐 활성 스크리닝 Screening of anti-androgenic activity of extract
자근 추출물에 의한 세포독성에 의해서도 안드로겐 작용이 저해되는 것처럼 나타날 수 있으므로 세포독성 실험을 함께 실시하여 자근 추출물의 세포독성에 의한 안드로겐 작용이 저해되는 것을 배제하였다.The cytotoxicity of extracts from Aspergillus oryzae may appear to be inhibited by androgenic action. Therefore, the inhibition of the androgenic action by the cytotoxicity of the extracts of the extracts was inhibited.
300pM R1881(양성대조군)과 자근 추출물을 0.1, 1, 10 및 100㎍/㎖의 농도로 각각 처리하여 항안드로겐 작용을 1차 스크리닝한 결과, 도 1 및 표 1에 개시한 바와 같이, 0.1~10㎍/㎖의 농도에서 항안드로겐 활성 및 세포생존율이 우수하였으나, 100㎍/㎖의 농도에서 항안드로겐 활성 및 세포생존율이 감소하는 것을 확인하였다. As a result of first screening for anti-androgenic action by treatment with 300 pM R1881 (positive control) and rice bran extract at concentrations of 0.1, 1, 10 and 100 μg / ml, 0.1 to 10 ㎍ / ml, the anti-androgen activity and the cell survival rate were excellent, but the anti-androgen activity and the cell survival rate were decreased at the concentration of 100 μg / ml.
LC30: Lethal Concentration 30 LC 30 : Lethal Concentration 30
이후, 항안드로겐 활성 및 세포 독성에 대한 2차 확인 실험을 수행하였다. 자근 추출물은 100㎍/㎖을 최고 농도로 하여 단계별로 7단계의 농도(0.1, 0.5, 1, 5, 10, 50 및 100㎍/㎖)로 처리하여 자근 추출물의 항안드로겐 작용의 용량 의존성을 확인하였으며, IC50(㎍/㎖) 값을 산출하였다. Subsequently, a secondary confirmation experiment on anti-androgen activity and cytotoxicity was performed. The dose-dependent inhibition of anti-androgenic action of the extracts was determined by treating the extracts with 100 μg / ml of the extract at a concentration of 7 steps (0.1, 0.5, 1, 5, 10, 50 and 100 μg / And the IC 50 (占 퐂 / ml) was calculated.
그 결과, 도 2 및 표 2에 개시한 바와 같이, 자근 추출물의 항안드로겐 작용의 용량 의존성은 IC50이 26.8㎍/㎖인 것으로 나타났고, 50㎍/㎖의 자근 추출물을 처리할 때까지는 세포독성이 거의 없다는 것을 확인하였다.As a result, as shown in Fig. 2 and Table 2, the dose dependency of anti-androgenic action of the agar extract was found to be 26.8 占 퐂 / ml of IC 50 , and until the treatment of 50 쨉 g / .
실시예Example 2. 자근 추출물의 세포 기반 안드로겐 수용체 결합 2. Cell-Based Androgen Receptor Binding of Leaf Extract 어세이Assay
자근 추출물의 안드로겐 수용체(androgen receptor;AR)와의 상호작용을 관찰하기 위하여 세포 기반 안드로겐 수용체 결합 어세이를 실시하였다. A cell - based androgen receptor - binding assay was performed to observe the interaction of the extract with androgen receptor (AR).
안드로겐 수용체 결합 어세이는 AR이 발현되지 않은 Cos7 세포에 AR을 일시적으로 과발현시킨 후 [3H] DHT가 AR에 결합되는 것을 AR에 친화력이 있는 물질이 저해하는 것을 관찰하는 시험으로, 본 실시예 2에서는 [3H] DHT의 농도를 항안드로겐 시험에서 사용한 300pM로 사용하였으며, 최대 CPM은 약 10,000~11,000 정도였으며, 아무것도 처리하지 않은 세포는 100 이하로, cold DHT 10μM을 처리한 세포에서는 100~150 정도가 측정되어 실험에 적정할 것으로 판단하였다. 우선적으로 [3H] DHT의 용량-반응 곡선을 위하여 다양한 농도의 [3H] DHT를 처리한 후 방사능(radioactivity)를 측정한 결과, 도 3에 개시한 바와 같이, 용량 의존적으로 CPM이 증가되는 양상을 확인할 수 있었다. The Androgen Receptor Binding Assay is a test for observing that an AR-affinity substance inhibits the binding of [ 3 H] DHT to AR after transiently overexpressing AR in Cos7 cells in which AR is not expressed, 2, the concentration of [ 3 H] DHT was used as 300 pM in the antiandrogen test. The maximum CPM was about 10,000 to 11,000, the number of untreated cells was 100 or less, 150 were measured and determined to be suitable for the experiment. Preferentially [3 H] amount of DHT - after processing the [3 H] DHT at various concentrations to a reaction curve was measured for radioactivity (radioactivity), as disclosed in Figure 3, in a dose-dependent manner that CPM is increased I could confirm the aspect.
아울러 300 pM [3H] DHT와 cold DHT를 다양한 농도로 처리하였을 때 cold DHT가 용량 의존적으로 [3H] DHT의 AR 결합을 저해하였으며, IC50 값을 산출하였을 때 1.9×10-8 M로 나타났다. In addition, 300 pM [3 H] DHT was cold that inhibit the AR binding of [3 H] DHT in a dose-dependent manner by treatment with a DHT cold DHT in various concentrations, IC 50 The value was 1.9 × 10 -8 M when calculated.
또한, AR을 일시적으로 과발현시킨 Cos7 세포에 300pM [3H] DHT와 자근 추출물(500㎍/㎖을 최대농도로 하여 공비 1/2로 희석하여 최소 15.6㎍/㎖)을 6단계의 농도로 처리한 후 방사능을 측정하여 용량-반응 관계 확인 및 IC50 값을 산출하였다.Cos7 cells transiently overexpressing AR were treated with 300 pM [ 3 H] DHT and rice bran extract (at least 15.6 μg / ml diluted to 1/2 of the azeotrope with a maximum concentration of 500 μg / ml) And the radioactivity was measured to determine the dose-response relationship and calculate the IC 50 value.
그 결과, 도 4 및 표 3에 개시한 바와 같이, 자근 추출물은 용량 의존적으로 300pM [3H] DHT의 결합을 저해하는 것을 확인하였다. As a result, as disclosed in Fig. 4 and Table 3, it was confirmed that the agar extracts inhibited binding of 300 pM [ 3 H] DHT in a dose-dependent manner.
(% of [3H] DHT)Min
(% Of [3 H] DHT )
(%)CV
(%)
IC50(㎍/㎖)AR-TA
IC 50 ([mu] g / ml)
Min: 자근 추출물이 500㎍/㎖ 농도 이하에서 최대로 AR 결합을 저해했을 때를 % of [3H] DHT로 나타낸 것이다. Min: shows a when jageun extract inhibit the AR binding to the maximum at the 500㎍ / ㎖ concentration below as% of [3 H] DHT.
CV: Coefficient of Variation으로, 표준편차/평균으로 구하여 10% 이하가 실험의 신뢰성이 받아들여지는 값이다.CV: Coefficient of Variation. The standard deviation / average is 10% or less.
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| KR1020170049238A KR101876201B1 (en) | 2017-04-17 | 2017-04-17 | Composition for preventing, improving or treating disorder associated with androgen receptor comprising extract of Lithospermi Radix as effective component |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220029474A (en) | 2020-08-31 | 2022-03-08 | 건국대학교 글로컬산학협력단 | Pharmaceutical composition for treating disorder associated with androgen receptor comprising Abeliophyllum distichum extract as an active ingredient |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002363085A (en) * | 2001-05-31 | 2002-12-18 | Maruzen Pharmaceut Co Ltd | Antiandrogenic hormone preparation, hair growing cosmetic, inhibitor for sebum secretion and inhibitor for prostatic hypertrophy |
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2017
- 2017-04-17 KR KR1020170049238A patent/KR101876201B1/en active IP Right Grant
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002363085A (en) * | 2001-05-31 | 2002-12-18 | Maruzen Pharmaceut Co Ltd | Antiandrogenic hormone preparation, hair growing cosmetic, inhibitor for sebum secretion and inhibitor for prostatic hypertrophy |
Non-Patent Citations (3)
| Title |
|---|
| International Journal of Oncology, Vol.44, pp.1455-1460 (2014.) * |
| International Journal of Oncology, Vol.44, pp.1455-1460 (2014.). * |
| 비특허문헌 (Int. J. Oncology) * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220029474A (en) | 2020-08-31 | 2022-03-08 | 건국대학교 글로컬산학협력단 | Pharmaceutical composition for treating disorder associated with androgen receptor comprising Abeliophyllum distichum extract as an active ingredient |
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