KR102608239B1 - 항염증제 - Google Patents
항염증제 Download PDFInfo
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- KR102608239B1 KR102608239B1 KR1020197023135A KR20197023135A KR102608239B1 KR 102608239 B1 KR102608239 B1 KR 102608239B1 KR 1020197023135 A KR1020197023135 A KR 1020197023135A KR 20197023135 A KR20197023135 A KR 20197023135A KR 102608239 B1 KR102608239 B1 KR 102608239B1
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- liver
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Abstract
신규한 항염증제가 제공된다. 간장수해물을 유효성분으로 하는 항염증제가 제공된다.
Description
본 발명은 안전성 높은 항염증제에 관한 것이다.
초고령화 사회로 인해 만성 염증과 관련이 있는 당뇨병, 비만 등 대사성 질환 및 동맥경화 등의 순환기 질환 등 생활 습관병의 예방·치료에 대한 대처의 중요성이 커지고 있다. 실제로 당뇨병에 대하여, IL-1β 신호 저해 및 NF-κB 저해 작용이 개발되고 있다. 류마티스 관절염으로 대표되는 만성 염증성 질환은 TNF-α, IL-1, IL-6 등의 염증성 사이토카인이 비정상적으로 많이 생산, 분비되며, 이러한 염증성 사이토카인 억제제는 우수한 항염증제로서 유용하다. 예를 들어, TNF-α 억제제로는 인플릭시맙 등의 항체 의약이 류마티스 관절염의 치료제로 사용되고 있다 (류마티스 관절염(RA)에 대한 TNF 억제제 가이드라인 (일반사단법인 일본 류마티스 학회)). 또한, IL-6 억제제로는 항체 의약 토실리주맙이 사용되고 있다 (약학회지 129(6) 667-674 (2009)). 또한, IL-1 억제제로는 아나킨라, 릴로나셉트, 카나키누맙 등의 단백질 제제 및 항체 의약이 개발되어 있다 (일본내과학회 잡지 제100권 제10호 p.2985-2990, 평성23년 10월 10일).
그러나, 종래의 염증성 사이토카인 억제제의 대부분은 항체 의약으로 대표되는 생물학적 제제이며, 간 기능 이상, 감염증, 아나필락시 등의 부작용이 생기는 것으로 보고되고 있어, 류마티스 관절염(RA)에 대한 TNF 억제제 가이드라인 (일반사단법인 일본 류마티스 학회) 과 같은 사용 가이드라인이 작성되었다.
따라서, 본 발명의 과제는 안전성이 높고 널리 사용할 수 있는 신규한 염증성 사이토카인 억제에 따른 항염증제를 제공하는 데 있다.
이에, 본 발명자는 여러 성분을 사용하여 염증성 사이토카인의 생산에 대한 작용을 검토해 온 결과, 만성 간질환의 간 기능 개선, 숙취 개선 등에 널리 사용되어온 간장수해물(肝臟水解物)이 강한 IL-1 생산 억제 작용을 갖는 것으로부터, 염증성 사이토카인의 생산을 억제하고, 항염증제로서 유용함을 발견하고, 본 발명을 완성하였다.
즉, 본 발명은 다음의 [1] 내지 [15]를 제공하는 것이다.
[1] 간장수해물을 유효성분으로 하는 항염증제.
[2] 간장수해물을 유효성분으로 하는 염증성 사이토카인 생산 억제제.
[3] 간장수해물을 유효성분으로 하는 IL-1 생산 억제제.
[4] 간장수해물을 유효성분으로 하는 염증개선용 식품조성물.
[5] 간장수해물을 유효성분으로 하는 염증성 사이토카인 생산 억제용 식품조성물.
[6] 간장수해물을 유효성분으로 하는 IL-1 생산 억제용 식품조성물.
[7] 항염증제 제조를 위한 간장수해물의 사용.
[8] 염증성 사이토카인 생산 억제제 제조를 위한 간장수해물의 사용.
[9] IL-1 생산 억제제 제조를 위한 간장수해물의 사용.
[10] 염증성 질환을 치료하기 위한 간장수해물.
[11] 염증성 사이토카인의 생산을 억제하기 위한 간장수해물.
[12] IL-1의 생산을 억제하기 위한 간장수해물.
[13] 간장수해물의 유효량을 투여하는 것을 특징으로 하는 염증성 질환의 치료 방법.
[14] 간장수해물의 유효량을 투여하는 것을 특징으로 하는 염증성 사이토카인의 생산 억제 방법.
[15] 간장수해물의 유효량을 투여하는 것을 특징으로 하는 IL-1의 생산 억제 방법.
간장수해물은 강한 IL-1 생산 억제 작용을 갖기 때문에, 염증성 사이토카인의 생산을 억제하고 항염증제로서 유용하다. 또한, 간장수해물은 경구 투여 가능하며, 부작용이 거의 없고, 안전성, 사용성도 우수하기 때문에 식품조성물로도 사용할 수 있다.
도 1은 간장수해물의 IL-1β 생산에 대한 작용을 나타내는 도면이다.
본 발명의 항염증제의 유효성분은 간장수해물이다. 간장수해물은 간 가수분해물, 간 추출물, 간 분해 추출물, 간 수해물이라고도 불리지만, 간을 소화 효소 등으로 가수분해하여 얻은 것이며, 간 기능 개선약으로 이용되고 있는 것이다. 원료인 간장은, 소, 돼지, 가다랭이, 고래 등의 신선한 간이 사용된다. 얻어진 가수분해물은 농축해서 사용하는 것이 바람직하다. 바람직하게는, 상기 의약품으로 정해져있는 간장수해물을 들 수 있다.
간장수해물에는 저분자 펩타이드를 주성분으로 각종 아미노산, 뉴클레오타이드, 비타민, 미네랄 등을 포함한다. 보다 상세하게는, 아미노산 19 내지 78 질량%, 펩타이드 및 단백 17 내지 73 질량%, 당류 1.8 내지 11 질량%, 지질 0.005 내지 0.04 질량%, 핵산 0.7 내지 2.5 질량%, 무기물 1.6 내지 5.4 질량%, 비타민 0.03 내지 0.2 질량%, 글루타티온 0.8 질량% 이하를 포함하는 것이 바람직하다. 또한, 아미노산 23 내지 65 질량%, 펩타이드 및 단백 20 내지 61 질량%, 당류 2.2 내지 8.6 질량%, 지질 0.006 내지 0.035 질량%, 핵산 0.9 내지 2.1 질량%, 무기물 1.9 내지 4.5 질량%, 비타민 0.04 내지 0.15 질량%, 글루타티온 0.7 질량% 이하를 포함하는 것이 보다 바람직하고, 아미노산 29 내지 52 질량%, 펩타이드 및 단백 25 내지 49 질량%, 당류 2.8 내지 6.9 질량%, 지질 0.008 내지 0.03 질량%, 핵산 1.1 내지 1.7 질량%, 무기물 2.4 내지 3.6 질량%, 비타민 0.05 내지 0.12 질량%, 글루타티온 0.6 질량% 이하를 포함하는 것이 더욱 바람직하다.
이들 성분 중, 아미노산 조성으로는 Ala 17 내지 68 mg/g, Arg 0.6 내지 4.4 mg/g, Asp 9 내지 48 mg/g, 시스틴 5 mg/g 이하, Glu 18 내지 63 mg/g, Gly 10 내지 39 mg/g, His 3 내지 17 mg/g, Ile 14 내지 56 mg/g, Leu 26 내지 98 mg/g, Lys 15 내지 65 mg/g, Met 0.3 내지 20 mg/g, Phe 13 내지 46 mg/g, Pro 10 내지 48 mg/g, Ser 12 내지 49 mg/g, Thr 12 내지 45 mg/g, Trp 3 내지 13 mg/g, Tyr 1.6 내지 41 mg/g, Val 18 내지 71 mg/g가 바람직하다. 또한, Ala 21 내지 57 mg/g, Arg 0.8 내지 3.6 mg/g, Asp 11 내지 40 mg/g, 시스틴 4 mg/g 이하, Glu 22 내지 53 mg/g, Gly 13 내지 32 mg/g, His 4 내지 14 mg/g, Ile 17 내지 47 mg/g, Leu 32 내지 82 mg/g, Lys 18 내지 54 mg/g, Met 0.4 내지 17 mg/g, Phe 15 내지 38 mg/g, Pro 12 내지 40 mg/g, Ser 15 내지 41 mg/g, Thr 14 내지 38 mg/g, Trp 3.8 내지 11 mg/g, Tyr 1.9 내지 34 mg/g, Val 21 내지 59 mg/g이 보다 바람직하고, Ala 26 내지 45 mg/g, Arg 1 내지 2.9 mg/g, Asp 14 내지 32 mg/g, 시스틴 3 mg/g 이하, Glu 27 내지 42 mg/g, Gly 16 내지 26 mg/g, His 5 내지 11 mg/g, Ile 21 내지 40 mg/g, Leu 4 내지 66 mg/g, Lys 22 내지 43 mg/g, Met 0.5 내지 14 mg/g, Phe 19 내지 31 mg/g, Pro 15 내지 32 mg/g, Ser 18 내지 33 mg/g, Thr 18 내지 30 mg/g, Trp 4.8 내지 8.4 mg/g, Tyr 2.4 내지 27 mg/g, Val 27 내지 48 mg/g이 더욱 바람직하다.
또한, 본 발명에서는 간장수해물의 저분자량 분획을 이용할 수도 있다. 당해 간장수해물의 저분자량 분획으로는 분자량 3000 이하의 분획, 예를 들어, 상기 간장수해물로부터 한외여과막 등으로 분자량 3000 이하의 분획을 채취한 것을 사용할 수 있다.
후술의 실시예에 나타난 바와 같이, 간장수해물 및 이의 저분자 분획은 염증성 사이토카인의 일종인 IL-1β의 생산을 강력하게 억제하는 작용 및 IL-1β의 mRNA 발현을 억제하는 작용을 갖는다. 따라서 간장수해물은 IL-1로 대표되는 염증성 사이토카인의 생산을 억제하고, 염증성 사이토카인이 관여하는 염증성 질환의 치료제 및 염증개선용 음식품조성물로서 유용하다. 여기에서, IL-1 등의 염증성 사이토카인이 관여하는 질환으로는, 류마티스 관절염, 변형성 관절염, 염증성 장질환, 패혈증, 급성 및 만성 골수성 백혈병, 골다공증, 생활 습관병 등을 들 수 있다.
본 발명의 항염증제는, 경구 투여, 경피 투여, 경장 투여, 경정맥 투여 등으로 투여될 수 있으나, 경구 투여가 보다 바람직하다. 경구 투여용 제제로서는, 액제, 정제, 산제, 세립제, 과립제, 캡슐제 등을 들 수 있지만, 액제, 정제가 바람직하고, 액제가 보다 바람직하다.
이러한 경구 투여 제제로 하는데는, 젖당, 만니톨, 옥수수 전분, 결정 셀룰로스 등의 부형제, 셀룰로스 유도체, 아라비아 고무, 젤라틴 등의 결합제, 카르복시메틸셀룰로스 칼슘 등의 붕해제, 탈크, 스테아린산 마그네슘 등의 활택제, 비이온 계면활성제 등의 용해 보조제, 교미제, 감미제, 안정화제, pH 조정제, 물, 에탄올, 프로필렌 글리콜, 글리세린 등을 사용할 수 있다. 또한, 히드록시메틸 셀룰로스 프탈레이트, 히드록시프로필 메틸 셀룰로스 아세테이트 숙시네이트, 셀룰로스 아세테이트 프탈레이트, 메타크릴레이트 공중합체 등의 피복제를 사용할 수 있다.
또한, 본 발명의 항염증제에는 다른 유효성분을 배합할 수도 있다. 다른 유효성분으로는 비타민 B1 류; 티아민, 티아민 질산염, 티아민 염산염, 푸르설티아민, 비스벤티아민, 벤포티아민, 티아민 디설파이드, 디세티아민, 티아민 프로필디설파이드 및 이들의 유도체, 비타민 B2 류; 리보플라빈 및 유도체 및 이들의 염, 비타민 B3 류; 나이아신, 니코틴산, 니코틴산 아미드 및 유도체 및 이들의 염, 비타민 B5 류; 판테놀, 판토텐산 및 유도체 및 이들의 염, 비타민 B6 류; 피리독신 및 유도체 및 이들의 염, 비타민 B12 류; 시아노코발라민 및 유도체 및 이들의 염, 이 외 비타민류; 비타민 A, 비타민 C, 비타민 E, 비타민 K, 비타민 P, 디클로로아세트산 디이소프로필아민, 타우린, 콘드로이틴 황산, 로얄젤리, 카페인, 울금, 밀크시슬, 민들레, 서양 민들레, 우엉, 마늘, 국화, 서양톱풀, 치자나무, 참깨, 삼칠근, 아스파라거스, 양파, 치커리, 약용 사루비아, 조선엉겅퀴 (아티초크), 구기자, 콩과·붓꽃과 식물, 사철란, 엘바·드·파사리뉴 (Erva de passarinho), 세테산구리아 (Sete sangrias), 예덕나무, 홍차, 레스베라트롤, 카테킨류, 베르베린, 로즈마리, 콩 추출물, 메트포민, 브로멜린, 알기닌, 승마(Black cohosh), 아이브라이트(eyebright), 프로폴리스, 샤크 카트리지(Shark Cartilage), 허하운드(horehound), 알팔파, 황기속, 벨라돈나, 홀리티슬, 메리골드, 카모마일, 천수근, 왜당귀, 에키네이샤, 엘더, 유칼립투스 오일, 피버퓨, 생강, 인삼, 골든씰, 병풀, 홉, 카바(kava), 라벤더, 감초, 톱 야자, 스피루리나, 서양고추나물, 티트리오일, 설령쥐오줌풀, 야생마(wild yam) 등을 들 수 있다.
또한, 본 발명의 항염증제는 안전성도 높고 경구 투여 가능하기 때문에, 의약품 외에, 의약외품, 건강기능식품, 스포츠 음료, 재활 음료, 애완동물 식품 등의 기능성 식품 등 식품조성물로도 사용 가능하다.
본 발명의 항염증제의 간장수해물의 함량은 투여 형태에 따라 다르지만, 통상 건조중량으로 0.001 내지 10 질량%가 바람직하고, 0.001 내지 5 질량%가 보다 바람직하다. 또한, 본 발명의 항염증제의 간장수해물의 1일 투여량은 건조중량으로 100 mg 내지 1076 mg이 바람직하고, 383 mg 내지 623 mg이 보다 바람직하고, 351 mg 내지 680 mg이 더욱 바람직하다.
[실시예]
다음 실시예를 들어 본 발명을 상세하게 설명하지만, 본 발명은 이에 한정되는 것은 아니다.
제조예 1
분자량 3000으로 분획 가능한 한외여과막 (MICROCON (등록상표) Centrifugal Devices YM-3)의 필터 부분을 인산 버퍼 (PBS)로 미리 세정하였다. 100 mg/mL의 간장수해물 (제리아 신약 공업 제조) 스톡을 PBS로 12 mg/mL으로 희석 후, 샘플 일부를 세포 첨가용으로 저장해두었다 (분획 전 샘플). 희석한 12 mg/mL의 샘플 500μL를 한외여과막에 분주하고, 12000 rpm, 4℃, 260 min으로 원심하고, 여과액 분획 (간장수해물 저분자 분획 : under Molecular Weight 3000 : uMW3k)을 회수하였다.
시험예 1
RAW264.7 세포의 세포수를 1.5 × 106 세포/dish로 조정하여 분주하고 하룻밤 배양하였다. 분획 전 샘플 또는 여과액 분획을 함께 EMEM 배지로 20배 희석하였다 (최종 농도 약 0.6 mg/mL). 컨트롤에는 샘플 대신 PBS를 EMEM 배지로 20배 희석하였다. 배지로 희석한 상기의 각 샘플 (컨트롤·분획 전·여과액 분획)을 각 dish 군에 첨가하였다. 24시간 배양 후, 리포폴리사카라이드 (LPS)가 최종 농도 1.0 μg/mL가 되도록 첨가하였다. 3시간 정치하고, RNA를 회수하여, 역전사 반응에 의해 cDNA 합성을 실시하였다. 이어서, RT-RCR에 의해 EEF1A1, IL-1β의 측정을 실시하였다.
그 결과를 도 1에 나타낸다.
LPS 자극 RAW 세포에서 간장수해물 군과 간장수해물 대신에 PBS를 첨가한 Cont 군 간에 염증 관련 유전자의 mRNA 발현량을 비교한 결과, IL-1β는 유의하게 저하하여, 간장수해물 (PLH : 분획 전)의 염증 억제 효과가 시사되었다. 또한, 간장수해물 저분자 분획 (uMW3k) 군에서도 마찬가지로, IL-1β mRNA 발현량의 유의한 저하가 보였다.
이상의 결과로부터, 간장수해물은 항염증 효과를 가지며, 간장수해물 중 분자량 3000 이하의 저분자 분획에 항염증 효과를 나타내는 생리활성물질이 존재하고 있음이 시사되었다.
Claims (15)
- 간장수해물의 분자량 3000 이하의 분획을 유효성분으로 하는, 염증성 사이토카인 IL-1의 생산을 억제함으로써 염증을 예방 또는 치료하는 약학 조성물.
- 삭제
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- 간장수해물의 분자량 3000 이하의 분획을 유효성분으로 하는, 염증성 사이토카인 IL-1의 생산을 억제함으로써 염증을 개선하는 식품 조성물.
- 삭제
- 삭제
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US20100136030A1 (en) * | 2007-02-27 | 2010-06-03 | Lamhamedi-Cherradi Salah-Eddine | Antagonist ox40 antibodies and their use in the treatment of inflammatory and autoimmune diseases |
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JP5177901B2 (ja) * | 2009-12-02 | 2013-04-10 | 株式会社明治 | 栄養組成物 |
CN102961404B (zh) * | 2012-12-12 | 2014-05-14 | 青岛亚博生物科技有限公司 | 一种从动物器官提取的组合物的衍生物 |
JP6456833B2 (ja) * | 2013-09-25 | 2019-01-23 | ゼリア新薬工業株式会社 | 肝臓機能及び/又は膵臓機能の改善剤 |
CN103689626A (zh) * | 2013-12-30 | 2014-04-02 | 徐州绿之野生物食品有限公司 | 一种营养食品及其加工方法 |
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JP2002080388A (ja) | 2000-09-04 | 2002-03-19 | Takeda Food Products Ltd | 肝機能賦活剤 |
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SG10202108899XA (en) | 2021-09-29 |
TW201834670A (zh) | 2018-10-01 |
JPWO2018155525A1 (ja) | 2019-12-12 |
CN110198723A (zh) | 2019-09-03 |
CN110198723B (zh) | 2024-03-05 |
TWI794210B (zh) | 2023-03-01 |
JP7216966B2 (ja) | 2023-02-02 |
KR20190119039A (ko) | 2019-10-21 |
WO2018155525A1 (ja) | 2018-08-30 |
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