KR20210011692A - Composition for preventing and treating inflammatory bowel disease comprising rifaximin and niclosamide - Google Patents
Composition for preventing and treating inflammatory bowel disease comprising rifaximin and niclosamide Download PDFInfo
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- KR20210011692A KR20210011692A KR1020190088898A KR20190088898A KR20210011692A KR 20210011692 A KR20210011692 A KR 20210011692A KR 1020190088898 A KR1020190088898 A KR 1020190088898A KR 20190088898 A KR20190088898 A KR 20190088898A KR 20210011692 A KR20210011692 A KR 20210011692A
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- South Korea
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- rifaximin
- niclosamide
- inflammatory bowel
- bowel disease
- composition
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Abstract
Description
본 발명은 리팍시민(Rifaximin) 및 니클로사마이드(niclosamide)를 포함하는, 염증성 장 질환(IBD; inflammatory bowel disease)의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the prevention or treatment of inflammatory bowel disease (IBD), comprising rifaximin and niclosamide.
염증성 장 질환 (Inflammatory bowel disease, IBD)은 위장관 내에 만성적인 염증을 유발하는 질환으로, 비교적 청년층부터 발병하며 복통, 발열, 설사, 하혈 등의 증상을 수반하는 질병이다. 일반적으로 염증성 장 질환은 궤양성 대장염 (Ulcerative colitis, UC)과 크론병 (Cron's disease, CD)의 2가지 형태로 분류된다. 상기 궤양성 대장염은 주로 점막을 침범하여, 문드러짐이나 궤양을 형성하는 확산성 비특이성 염증 (diffuse nonspecific inflammation)의 일종으로서, 그 원인이 명확하게 밝혀져 있지 않으며, 혈성 설사를 비롯하여 다양한 전신 증상을 유발한다. 상기 크론병은 구강에서 항문까지 이르는 전 소화관의 점막에서 궤양, 섬유화, 협착, 병변(病變)을 비연속적으로 유발하는 육아종성 염증성 병변으로, 복통, 만성 설사, 발열, 영양장애 등의 전신 증상을 수반한다.Inflammatory bowel disease (IBD) is a disease that causes chronic inflammation in the gastrointestinal tract, and it occurs in relatively young people and is accompanied by symptoms such as abdominal pain, fever, diarrhea, and bleeding. In general, inflammatory bowel disease is classified into two types: ulcerative colitis (UC) and Crohn's disease (CD). The ulcerative colitis is a type of diffuse nonspecific inflammation that mainly invades the mucous membrane and forms pats or ulcers, the cause of which is not clearly identified, and causes various systemic symptoms including bloody diarrhea. do. The Crohn's disease is a granulomatous inflammatory lesion that causes discontinuous ulcers, fibrosis, narrowing, and lesions in the mucous membrane of the entire digestive tract from the mouth to the anus, and systemic symptoms such as abdominal pain, chronic diarrhea, fever, and nutritional disorders. Entails.
상기 염증성 장 질환의 발병원인은 아직까지 구체적으로 밝혀져 있지 않으나, 면역기능의 이상이 관여하는 것으로 알려져 있으며, 이에 관여하는 면역학적 요인으로는 선천적 면역성, 사이토카인(Cytokine)의 생성, CD4의 활성화 등이 알려져 있다. 특히, 사이토카인이 중요한 역할을 수행하는 것으로 알려져 있으며, 특히 염증 부위에서 종양괴사인자(Tumor nerosis cytokine; TNF-α), 인터루킨(Interluekin; IL)-1, IL-6, IL-8 생성이 궤양성 대장염과 크론병 환자에게 현저하게 증가되는 것이 확인되었다.The cause of the inflammatory bowel disease has not been specifically identified yet, but it is known that abnormalities of immune function are involved, and immunological factors involved in this include innate immunity, production of cytokines, activation of CD4, etc. This is known. In particular, it is known that cytokines play an important role, and in particular, the production of Tumor Necrosis Factor (TNF-α), Interluekin (IL)-1, IL-6, and IL-8 at the site of inflammation It was found to be significantly increased in patients with sexual colitis and Crohn's disease.
이러한 염증성 장 질환을 치료하기 위하여 사용되는 약물로는 스테로이드성 면역억제제, 프로스타글란딘(prostaglandins)의 생성을 차단하는 5-아미노살리실산 (5-aminosalicylic acid; 5-ASA) 계통 약물(예, 설파살라진 등), 메살라진 등이 사용되고 있으나, 이들은 염증성 장 질환의 치료효과가 미미할 뿐만 아니라 복부허실(fullness), 두통, 발진, 간질환, 백혈구 감소증, 무과립구증, 남성 불임 등의 심각한 부작용을 유발하기 때문에, 상기와 같은 치료제의 사용이 제한되고 있다.Drugs used to treat such inflammatory bowel disease include steroidal immunosuppressants, 5-aminosalicylic acid (5-ASA) drugs that block the production of prostaglandins (e.g., sulfasalazine), Mesalazine, etc., are used, but they have insignificant therapeutic effect on inflammatory bowel disease and cause serious side effects such as fullness, headache, rash, liver disease, leukopenia, agranulocytosis, and male infertility. The use of therapeutic agents is limited.
또한, 스테로이드류의 면역억제제는 부신피질 스테로이드로서, 단기적인 효과는 인정받고 있지만, 장기적인 예후를 향상시킬 수는 없으며, 유도된 감염성 질환, 2차 부신피질 부전증, 소화성 궤양, 당뇨병, 정신장애, 스테로이드성 신장병 등과 같은 부작용의 측면에서 단지 급성인 경우에만 사용되어야 하는 한계가 있다.In addition, steroid-like immunosuppressants are adrenal cortical steroids, which are recognized for short-term effects, but cannot improve long-term prognosis, and induced infectious diseases, secondary adrenal insufficiency, peptic ulcers, diabetes, mental disorders, and steroids. In terms of side effects such as kidney disease, there is a limit that should be used only in acute cases.
현재까지 염증성 장 질환에 대해 신뢰할 만한 치료요법이 부재한 것으로 평가되고 있으며, 이에 따라 효과적인 치료제의 개발이 요구되고 있다.Until now, it is evaluated that there is no reliable therapy for inflammatory bowel disease, and accordingly, the development of an effective therapeutic agent is required.
본 발명의 목적은 리팍시민 및 니클로사마이드를 포함하는, 염증성 장 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. An object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory bowel disease, comprising rifaximin and niclosamide.
본 발명의 다른 목적은 리팍시민 및 니클로사마이드를 투여하는 단계를 포함하는, 염증성 장 질환의 치료방법을 제공하는 것이다.Another object of the present invention is to provide a method for treating inflammatory bowel disease, comprising administering rifaximin and niclosamide.
본 발명의 또 다른 목적은 리팍시민 및 니클로사마이드를 포함하는, 염증성 장 질환의 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving inflammatory bowel disease, comprising rifaximin and niclosamide.
상기와 같은 목적을 달성하기 위한 본 발명의 일 측면은 리팍시민(Rifaximin) 및 니클로사마이드(niclosamide)를 포함하는, 염증성 장 질환(IBD; inflammatory bowel disease)의 예방 또는 치료용 약학적 조성물에 관한 것이다.One aspect of the present invention for achieving the above object relates to a pharmaceutical composition for the prevention or treatment of inflammatory bowel disease (IBD), comprising rifaximin and niclosamide will be.
본 발명에서, “리팍시민(Rifaximin)”은 반합성 리파마이신 유래의 비-전신성 항생제로서, (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-펜타히드록시-27-메톡시-2,4,11,16,20,22,24,26-옥타메틸-2,7-(에톡시펜타데카-[1,11,13]트리엔이미노)벤조퓨로[4,5-e]피리도[1,2-a]-벤즈이미다-졸-1,15(2H)-디온,25-아세테이트로 명명된다. 구조는 하기 화학식 1에 나타난 바와 같다.In the present invention, "Rifaximin" is a non-systemic antibiotic derived from semi-synthetic rifamycin, (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5 ,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(ethoxypentadeca-[1, 11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-a]-benzimida-zol-1,15(2H)-dione,25-acetate . The structure is as shown in Formula 1 below.
[화학식 1][Formula 1]
리팍시민은 위장관 흡수가 매우 낮으나 넓은 항균 활성 스펙트럼을 보인다. 위장관의 생체 이용률은 사실상 흡수되지 않아 병원성 장내 세균에 대한 최소 저해 농도를 크게 상회하고, 대장 내 생체 이용률이 높으며 위장 내 외장 부위에 미치는 영향이 제한되어 항생제 내성과 전신 이상반응의 위험을 최소화한다. 리팍시민의 사용은 위장관 감염, 간장 뇌증, 소장 세균성 과증식(SIBO), 염증성 장 질환 및 결장 게실 질환으로 확대되었다.Rifaximin has very low gastrointestinal absorption but shows a broad spectrum of antibacterial activity. Since the bioavailability of the gastrointestinal tract is virtually not absorbed, it greatly exceeds the minimum inhibitory concentration for pathogenic intestinal bacteria, has high bioavailability in the large intestine, and has limited effects on the internal and external areas of the gastrointestinal tract, minimizing the risk of antibiotic resistance and systemic adverse reactions. The use of rifaximin has been extended to gastrointestinal infections, hepatic encephalopathy, small intestinal bacterial hyperplasia (SIBO), inflammatory bowel disease and colon diverticulum disease.
본 발명에서, “니클로사마이드(niclosamide)”는 1960년 FDA 승인을 받아 50년 가까이 다양한 기생충 감염 치료에 사용되는 경구형 살리실 아닐리드 유도체로, 최근에는 다양한 종류의 암에 대한 항암 요법에 사용될 수 있다는 내용이 보고된 바 있다. In the present invention, “niclosamide” is an oral salicylanilide derivative that has been approved by the FDA in 1960 and is used for the treatment of various parasitic infections for nearly 50 years. Recently, it can be used in anticancer therapy for various types of cancer. It has been reported that there is.
구체적으로, 상기 리팍시민은 전체 조성물 기준 1 내지 99 중량%; 및 상기 니클로사마이드는 전체 조성물 기준 1 내지 99중량% 포함되는 것일 수 있다. 상기 함량 범위는 대상 환자군, 약효, 구체적인 질환의 특성, 부작용 등을 고려하여 필요에 따라 적절히 변경하여 적용할 수 있다.Specifically, the rifaximin is 1 to 99% by weight based on the total composition; And the niclosamide may be included in 1 to 99% by weight based on the total composition. The content range may be appropriately changed and applied as necessary in consideration of the target patient group, drug efficacy, specific disease characteristics, side effects, and the like.
본 발명에서, “염증성 장 질환(Inflammatory bowel disease, IBD)”은 위장관 내에 만성적인 염증을 유발하는 질환으로, 원인이 명확히 밝혀져 있지는 않으나 유전적 및 환경적 영향을 받으며, 면역학적 이상에 의해 매개되는 것으로 알려져 있다. In the present invention, “Inflammatory bowel disease (IBD)” is a disease that causes chronic inflammation in the gastrointestinal tract, and the cause is not clearly identified, but is affected by genetic and environmental effects, and is mediated by immunological abnormalities. It is known.
염증성 장 질환의 증상은 구체적인 질병에 따라 차이는 있으나, 일반적으로 복통, 하복부 불쾌감, 결장의 단축(shortening of colon), 체중감소, 출혈지수 상승(출혈) 또는 배변지수 상승(설사)의 증상을 나타낼 수 있으며, 동일한 질병이라도 병변의 범위나 위치 또는 중증도에 따라 다른 양상을 나타낼 수 있다. Symptoms of inflammatory bowel disease vary depending on the specific disease, but generally indicate symptoms of abdominal pain, lower abdominal discomfort, shortening of colon, weight loss, increased bleeding index (bleeding) or increased defecation index (diarrhea). In addition, even the same disease may exhibit different aspects depending on the extent, location, or severity of the lesion.
구체적으로, 상기 염증성 장 질환은 궤양성 대장염(ulcerative colitis), 크론병(crohn's disease), 장형 베체트(intestinal behcet's disease), 불확정 대장염(indeterminate colitis), 세균성 장염, 바이러스성 장염, 아메바성 장염, 게실염(diverticulitis) 및 결핵성 장염으로 이루어진 군에서 선택되는 하나 이상인 것일 수 있으며, 상기에 제한되는 것은 아니고 장에서 발생하는 모든 염증성 질환을 포함할 수 있다.Specifically, the inflammatory bowel disease is ulcerative colitis, Crohn's disease, intestinal behcet's disease, indeterminate colitis, bacterial enteritis, viral enteritis, amoebic enteritis, diverticulitis. (diverticulitis) and tuberculous enteritis may be one or more selected from the group consisting of, but is not limited to the above may include all inflammatory diseases occurring in the intestine.
또한 구체적으로, 상기 약학적 조성물은 리팍시민 및 니클로사마이드가 동시, 순차적 또는 역순으로 병용 투여되는 것을 특징으로 하는 것일 수 있다. 또한 리팍시민 및 니클로사마이드의 복합제 형태일 수 있다.In addition, specifically, the pharmaceutical composition may be characterized in that rifaximin and niclosamide are administered simultaneously, sequentially or in reverse order. It may also be in the form of a combination of rifaximin and niclosamide.
본 발명 일 실시예에서는 2,4,6-트리니트로벤젠술폰산(2,4,6-trinitrobenzene sulfonic acid, TNBS)을 투여하여 염증성 장 질환을 유발한 마우스 모델에 있어서, 리팍시민 및 니클로사마이드를 함께 투여한 경우 체중, 배변지수 및 출혈지수의 회복을 통해 마크로스코픽 스코어가(macroscopic score)가 현저히 개선되었는 바, 우수한 치료 효과를 나타냄을 확인하였다(도 1). In one embodiment of the present invention, in a mouse model in which inflammatory bowel disease was induced by administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS), rifaximin and niclosamide were used together. In the case of administration, the macroscopic score was remarkably improved through the recovery of body weight, defecation index, and bleeding index, and it was confirmed that an excellent treatment effect was shown (FIG. 1).
특히, 기존 적용되던 치료제인 리팍시민 단독 처리 군에 비해 현저히 우수한 치료 효과를 나타내었으며, 스테로이드 제제인 프레드니솔론 수준의 치료 및 개선 효과를 나타내었다. 스테로이드 제제의 경우, 염증성 장 질환 치료에 있어 관해 유도에는 효과적이나, 관해 유지에는 효과적이지 않은 것으로 알려져 있으며, 부작용이 따름에 따라 단기간 내에 중단을 해야 하는 문제가 있다.In particular, it exhibited remarkably superior therapeutic effect compared to the group treated with rifaximin alone, the previously applied treatment, and showed treatment and improvement effects at the level of prednisolone, a steroid formulation. In the case of steroid preparations, it is known to be effective in inducing remission in the treatment of inflammatory bowel disease, but not effective in maintaining remission, and there is a problem that it must be stopped within a short period of time due to side effects.
본 발명의 리팍시민 및 니클로사마이드의 병용투여 또는 복합제 형태의 제공은 스테로이드의 부작용 문제를 해결하고, 장기 투여가 가능함으로써 지속적인 약효 유지까지 가능하게 할 수 있는 바, 만성 질환으로 이어질 수 있는 염증성 장 질환에 대한 치료 효과를 더욱 높일 수 있다. The combination or combination of rifaximin and niclosamide of the present invention solves the problem of side effects of steroids and enables long-term administration, thereby enabling sustained medicinal efficacy. Inflammatory bowels that can lead to chronic diseases It can further increase the therapeutic effect for the disease.
본 발명의 약학적 조성물은 투여를 위하여, 상기 본 발명의 리팍시민 및 니클로사마이드 외에 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 포함할 수 있다. 상기 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier, excipient, or diluent in addition to rifaximin and niclosamide of the present invention for administration. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oils.
또한, 본 발명의 약학적 조성물은 어떠한 제형으로도 적용가능하며, 보다 구체적으로 경구용 제형일 수 있다. In addition, the pharmaceutical composition of the present invention can be applied in any formulation, and more specifically, may be an oral formulation.
또한 비경구용 제형으로도 적용될 수 있으며, 비경구형 제형으로는 주사용, 도포용, 에어로졸 등의 스프레이 형일 수 있다. 더욱 구체적으로는 주사제 형태일 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성 용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.In addition, it may be applied as a parenteral formulation, and the parenteral formulation may be a spray type such as injection, application, or aerosol. More specifically, it may be in the form of an injection. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.
또한, 본 발명의 약학적 조성물은 약학적으로 유효한 양으로 적용될 수 있으며, "약학적으로 유효한 양"은 의학적 치료에 적용가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 성병, 연령, 질병의 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. In addition, the pharmaceutical composition of the present invention may be applied in a pharmaceutically effective amount, and "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and is effective Dosage levels depend on the patient's sexually transmitted disease, age, type of disease, severity, activity of the drug, sensitivity to the drug, time of administration, route of administration and rate of excretion, duration of treatment, factors including concurrent drugs, and other well-known medical fields. It can be determined by factors.
나아가, 본 발명의 약학적 조성물은 또 다른 치료제와 병용하여 투여될 수 있고, 종래의 다른 치료제와 순차적으로 또는 동시에 투여될 수 있다. 또한 본 발명의 약학적 조성물은 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 필요에 따라 용이하게 결정될 수 있다. Furthermore, the pharmaceutical composition of the present invention may be administered in combination with another therapeutic agent, and may be administered sequentially or simultaneously with other conventional therapeutic agents. In addition, the pharmaceutical composition of the present invention may be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all of the above factors, and can be easily determined as needed by a person skilled in the art.
본 발명의 다른 측면은 상기 약학적 조성물을 포함하는 염증성 장 질환의 예방 또는 치료용 키트에 관한 것이다.Another aspect of the present invention relates to a kit for the prevention or treatment of inflammatory bowel disease comprising the pharmaceutical composition.
본 발명의 키트는 그 종류가 특별히 제한되지 않으며, 당해 기술 분야에서 통상적으로 사용되는 형태의 키트를 사용할 수 있다. 본 발명의 키트는 리팍시민 및 니클로사마이드가 각각 개별 용기에 담긴 형태, 또는 하나 이상의 구획으로 나누어진 한 개의 용기 내에 담긴 형태로 포장되어 있을 수 있으며, 상기 리팍시민 및 니클로사마이드는 각각 1회 투여 용량의 단위 용량 형태로 포장되어 있을 수 있으나, 이에 제한되지 않는다.The type of the kit of the present invention is not particularly limited, and a kit of a type commonly used in the art may be used. The kit of the present invention may be packaged in a form in which rifaximin and niclosamide are each contained in individual containers, or in one container divided into one or more compartments, and the rifaximin and niclosamide are each one time. It may be packaged in a unit dosage form of an administered dose, but is not limited thereto.
상기 키트 내의 리팍시민 및 니클로사마이드는 투여 대상 개체의 건강 상태 등에 따라 적절한 시기에 개별적으로 병용 투여될 수 있다. 또한, 리팍시민 및 니클로사마이드는 동시, 순차적, 또는 역순으로 개체에게 병용 투여될 수 있다.Rifaximin and niclosamide in the kit may be separately administered in combination at an appropriate time according to the health condition of the subject to be administered. In addition, rifaximin and niclosamide may be co-administered to a subject in simultaneous, sequential, or reverse order.
본 발명의 또 다른 측면은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는, 염증성 장 질환의 치료방법에 관한 것이다.Another aspect of the present invention relates to a method of treating inflammatory bowel disease, comprising administering the pharmaceutical composition to a subject.
구체적으로, 상기 투여하는 단계는 리팍시민 및 니클로사마이드를 동시, 순차적 또는 역순으로 병용 투여하는 것을 특징으로 하는 것일 수 있다. '염증성 장 질환'은 상기 설명한 바와 같다.Specifically, the administering step may be characterized in that rifaximin and niclosamide are administered simultaneously, sequentially or in reverse order. 'Inflammatory bowel disease' is as described above.
본 발명의 용어 "개체"는 본 발명에 따른 약학적 조성물의 투여에 의해 증상이 호전될 수 있는 염증성 장 질환을 가진 동물 또는 인간을 포함한다. 본 발명에 따른 치료용 조성물을 개체에게 투여함으로써, 염증성 장 질환을 효과적으로 예방 및 치료할 수 있다. The term "subject" of the present invention includes animals or humans with inflammatory bowel disease whose symptoms can be improved by administration of the pharmaceutical composition according to the present invention. By administering the therapeutic composition according to the present invention to an individual, inflammatory bowel disease can be effectively prevented and treated.
본 발명의 용어 "투여"는 어떠한 적절한 방법으로 인간 또는 동물에게 소정의 물질을 도입하는 것을 의미하며, 본 발명에 따른 치료용 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 경구 또는 비경구 투여될 수 있다. 또한, 본 발명에 따른 치료용 조성물은 유효성분이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다. The term "administration" of the present invention means introducing a predetermined substance to humans or animals by any suitable method, and the route of administration of the therapeutic composition according to the present invention is through any general route as long as it can reach the target tissue. It can be administered orally or parenterally. In addition, the therapeutic composition according to the present invention can be administered by any device capable of moving the active ingredient to target cells.
본 발명에 따른 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. The preferred dosage of the pharmaceutical composition according to the present invention varies depending on the condition and weight of the patient, the degree of the disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art.
본 발명의 또 다른 측면은 리팍시민 및 니클로사마이드를 포함하는, 염증성 장 질환의 예방 또는 개선용 식품 조성물에 관한 것이다.Another aspect of the present invention relates to a food composition for preventing or improving inflammatory bowel disease, comprising rifaximin and niclosamide.
상기 식품의 종류에는 특별한 제한은 없다. 본 발명의 조성물을 첨가할 수 있는 식품은 소세지, 육류, 빵, 초콜릿류, 스넥류, 캔디류, 과자류, 라면, 피자, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등이 있다. 음료수로 제형화할 경우에 본 발명의 조성물 외에 첨가되는 액체 성분으로는 이에 한정되지는 않으나, 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 모노사카라이드(예, 포도당, 과당 등), 디사카라이드(예, 말토오스, 수크로오스 등) 및 폴리사카라이드(예, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당), 및 자일리톨, 소르비톨, 에리스리톨 등의 당 알코올일 수 있다.There is no particular limitation on the type of food. Foods to which the composition of the present invention can be added include sausage, meat, bread, chocolate, snacks, candies, confectionery, ramen, pizza, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, and drinks. , Alcoholic beverages and vitamin complexes. When formulated as a beverage, the liquid component added in addition to the composition of the present invention is not limited thereto, but may contain various flavoring agents or natural carbohydrates as an additional component, such as a conventional beverage. The natural carbohydrates described above are monosaccharides (e.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.) and polysaccharides (e.g., common sugars such as dextrin, cyclodextrin, etc.), and xylitol, sorbitol. And sugar alcohols such as erythritol.
상기 식품의 종류는 구체적으로 건강기능식품일 수 있다. 상기 건강기능 식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 증진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 유기산, 보호성 콜로이드 점증제, pH 조절제, 안정화제, 보존제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 또한, 본 발명의 건강기능 식품은 과일 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 단독으로 또는 조합으로 사용될 수 있으며, 이러한 첨가제의 비율은 조성물 전체 중량당 0.001 내지 50 중량부의 범위에서 선택되는 것이 일반적이다.The type of food may specifically be a health functional food. The health functional foods include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and enhancers (cheese, chocolate, etc.), pectic acid and its salts, organic acids, protective colloidal growth It may contain an agent, a pH adjuster, a stabilizer, a preservative, glycerin, alcohol, a carbonation agent used in carbonated beverages, and the like. In addition, the health functional food of the present invention may contain pulp for the manufacture of fruit and vegetable beverages. These components may be used alone or in combination, and the proportion of these additives is generally selected from 0.001 to 50 parts by weight per total weight of the composition.
상기 건강기능식품은 식품의 생체 조절 기능을 강조한 식품으로 물리적, 생화학적, 생물공학적인 방법을 이용하여 특정 목적에 작용 및 발현하도록 부가가치를 부여한 식품이다. 이러한 건강기능 식품의 성분은 생체 방어와 신체 리듬의 조절, 질환의 방지 및 회복에 관계하는 신체 조절 기능을 생체에 대하여 충분히 발휘하도록 설계하여 가공하게 되며, 식품으로 허용 가능한 식품 보조 첨가제, 감미료 또는 기능성 원료를 함유할 수 있다. The health functional food is a food that emphasizes the biological regulation function of food, and is a food that has added value to act and express it for a specific purpose by using physical, biochemical, and bioengineering methods. Ingredients of these health functional foods are designed and processed to fully exert the body's control functions related to body defense, regulation of body rhythm, prevention and recovery of diseases to the living body, and food additives, sweeteners, or functional foods acceptable as foods. It may contain raw materials.
본 발명의 조성물을 건강기능식품(또는 건강기능 음료 첨가물)으로 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용하고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 상기 조성물의 혼합량은 그의 사용 목적(예방, 건강 또는 개선, 치료적 처치)에 따라 적합하게 결정될 수 있다.When the composition of the present invention is used as a health functional food (or health functional beverage additive), the composition may be added as it is or used with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the composition may be appropriately determined according to the purpose of use (prevention, health or improvement, therapeutic treatment).
본 발명의 리팍시민 및 니클로사마이드를 포함하는 약학적 조성물은 염증성 장 질환에 대하여 스테로이드 제제 수준 이상의 우수한 치료 효과를 나타내면서도, 부작용 문제로 인해 관해 유지가 어려운 스테로이드와 달리 관해 유지를 위한 보다 장기적인 투여가 가능함으로써 우수한 치료 효과가 더 장기적으로 유지되도록 할 수 있다. The pharmaceutical composition comprising rifaximin and niclosamide of the present invention exhibits excellent therapeutic effects over inflammatory bowel disease levels, but is difficult to maintain remission due to side effects. It is possible to maintain excellent therapeutic effect for a longer period of time.
본 발명의 효과는 상기한 효과로 한정되는 것은 아니며, 본 발명의 상세한 설명 또는 청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.The effects of the present invention are not limited to the above effects, and should be understood to include all effects that can be deduced from the configuration of the invention described in the detailed description or claims of the present invention.
도 1은 염증성 장 질환 유발 모델에서의 Macroscopic score를 측정한 결과를 나타낸 것이다.1 shows the results of measuring Macroscopic score in an inflammatory bowel disease induction model.
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by examples. However, the following examples are only illustrative of the present invention, and the present invention is not limited by the following examples.
실험예 1. 리팍시민 및 니클로사마이드의 복합 구성 및 투여량Experimental Example 1. Complex composition and dosage of rifaximin and niclosamide
본 발명에서 사용된 리팍시민(Rifaximin) 및 니클로사마이드(niclosamide)의 복합 구성은 하기 표 1에 나타난 바와 같다. 리팍시민은 MSN Laboratories Private Limited, India로부터 구입하였으며, 니클로사마이드는 Sigma-aldrich, USA로부터 구입하여 사용하였다.The composite composition of rifaximin and niclosamide used in the present invention is shown in Table 1 below. Rifaximin was purchased from MSN Laboratories Private Limited, India, and niclosamide was purchased from Sigma-aldrich, USA and used.
0.5 w/v% 메틸셀룰로오스(Methylcellulose) 및 0.01 v/v% Tween 80을 담체(vehicle)로 하여 시험액을 조제하였다.A test solution was prepared using 0.5 w/v% methylcellulose and 0.01 v/v% Tween 80 as carriers.
실험예 2. 염증성 장 질환(inflammatory bowel diseases, IBD) 마우스 모델 제작Experimental Example 2. Inflammatory bowel diseases (IBD) mouse model production
C57BL/6NHsd 수컷, 6주령 마우스를 온도 23±3 ℃, 상대습도 55±15 %, 환기횟수 10∼20 회/hr, 조명시간 12 시간(오전 8 시 점등∼오후 8 시 소등) 및 조도 150∼300 Lux로 유지되는 환경에서 사육하였다. 이후, 순화기간 중 건강한 것으로 판정된 동물들의 체중을 측정하고 순위화한 체중에 따라 각 군의 평균 체중이 최대한 균일하게 분포하도록 무작위법으로 분배하고, 염증성 장 질환을 유발하였다.C57BL/6NHsd male and 6-week-old mice were subjected to temperature 23±3 ℃, relative humidity 55±15%, ventilation frequency 10-20 times/hr, lighting time 12 hours (8 am to 8 pm off) and illumination 150 to It was raised in an environment maintained at 300 Lux. Thereafter, the weights of animals determined to be healthy during the acclimatization period were measured and distributed in a random manner so that the average weight of each group was distributed as uniformly as possible according to the ranked weight, and inflammatory bowel disease was induced.
구체적으로, 염증성 장 질환 유발일에 해당 동물을 조레틸50(Zoletil 50, VIRBAC, France, 5 mg/kg) 및 자일라진(xylazine, Rompun®, Bayer AG, Germany)을 이용하여 마취를 실시한 후, 50 % 에탄올로 희석한 1.5 % TNBS(trinitrobenzene sulphonic acid) 용액 0.1 mL을 항문을 통해 직장 내로 투여하였다. 투여한 TNBS 용액이 항문으로 새어나오지 않도록 투여 후 1분간 수직 자세를 유지하도록 하였다.Specifically, on the day of induction of inflammatory bowel disease, the animal was anesthetized using zoretil 50 (Zoletil 50, VIRBAC, France, 5 mg/kg) and xylazine (xylazine, Rompun ® , Bayer AG, Germany), 0.1 mL of a 1.5% trinitrobenzene sulphonic acid (TNBS) solution diluted with 50% ethanol was administered into the rectum through the anus. The administered TNBS solution was maintained in a vertical position for 1 minute after administration to prevent leakage into the anus.
실험예 3. 시험군의 구성 및 시험물질의 투여Experimental Example 3. Composition of test group and administration of test substance
비교예 1 및 실시예 1 내지 3의 시험물질을 상기 제조한 염증성 장 질환 모델 동물에 투여하였다. 시험군 구성은 하기 표 2에 나타난 바와 같다. The test substances of Comparative Examples 1 and 1 to 3 were administered to the inflammatory bowel disease model animals prepared above. The test group configuration is as shown in Table 2 below.
상기 구성에 따라, 2회/일, 7일 동안 경구투여 하였으며, 2 종의 시험물질을 투여하는 실시예 2의 경우, 각각의 시험물질을 1일 투여량의 절반씩 2회 투여하였다. 투여량은 최근 체중 측정일에 측정한 체중을 기준으로 10 mL/kg/day로 산출하여 투여하였으며, 마우스를 경배부 피부 고정법으로 고정하고, 경구투여용 존데를 이용하여 위 내에 직접 투여하였다. 체중은 시험물질 투여 전, 이후에는 1회/일, 7일 동안 측정하였다.According to the above configuration, it was orally administered twice/day for 7 days, and in the case of Example 2 in which two test substances were administered, each test substance was administered twice, half of the daily dose. The dose was calculated and administered as 10 mL/kg/day based on the body weight measured on the latest body weight measurement day, and the mouse was fixed by the cervical skin fixation method, and administered directly into the stomach using a sonde for oral administration. Body weight was measured before administration of the test substance, once/day thereafter, for 7 days.
실험예 4. 염증성 장 질환 치료효과 확인Experimental Example 4. Inflammatory Bowel Disease Treatment Effect Confirmation
투여 및 관찰기간 동안 사망을 포함한 일반 증상의 종류, 발현일 및 증상의 정도를 1 일 1 회 관찰하고 개체 별로 기록하며, 하기 표 3에 나타난 기준(disease activity index, DAI)에 따라 스코어링(scoring)을 실시하였다. During the administration and observation period, the type of general symptoms including death, the date of onset, and the degree of symptoms are observed once a day and recorded for each individual, and scoring according to the criteria (disease activity index, DAI) shown in Table 3 below. Was carried out.
Stool typeStool form
Stool type
Bleedingbleeding
Bleeding
그 결과, 도 1에 나타난 바와 같이 종래 염증성 장 질환 치료제로 알려진 바 있는 리팍시민(실시예 3)에 비해 리팍시민 및 니클로사마이드를 함께 투여한 경우(실시예 2) 현저히 우수한 치료 효과를 나타냄을 확인하였다. 특히, 이는 스테로이드제인 프레드니솔론(실시예 1)과 유사 수준의 이상의 효과를 나타내었으며, 일부 구간(6일 이후)에서는 프레드니솔론 보다 더욱 우수한 효과를 나타내었다.As a result, as shown in FIG. 1, when rifaximin and niclosamide were administered together (Example 2) compared to rifaximin (Example 3), which has been known as a conventional inflammatory bowel disease treatment agent (Example 2), a significantly superior therapeutic effect was shown. Confirmed. In particular, it exhibited an effect similar to that of the steroid prednisolone (Example 1), and exhibited more excellent effects than prednisolone in some sections (after 6 days).
실험예 5. 통계분석Experimental Example 5. Statistical Analysis
본 시험의 결과에 대하여 모수적인 다중비교(parametric multiple comparison procedures) 혹은 비모수적인 다중비교(non-parametric multiple comparison procedures)를 사용하였다. 모수적인 다중비교의 경우, 자료의 정규성을 가정하고, 모수적 일원분산분석(One-way ANOVA)으로 검정하며, 그 결과가 유의할 경우, Dunnett's multiple comparison test를 이용하여 사후검정을 실시하여 시험군간 유의한 차이를 분석하였다.Parametric multiple comparison procedures or non-parametric multiple comparison procedures were used for the results of this test. In the case of a parametric multiple comparison, the normality of the data is assumed, and the test is performed with a parametric one-way ANOVA.If the result is significant, a post-test is performed using Dunnett's multiple comparison test to be significant between the test groups. One difference was analyzed.
비모수적인 다중비교의 경우, Kruskal-Wallis'H-test로 검정하여, 그 결과가 유의할 경우 사후분석인 Dunn's multiple comparison test를 이용하여 시험군 간 유의한 차이를 분석하였다.In the case of nonparametric multiple comparison, the test was performed with the Kruskal-Wallis'H-test, and if the result was significant, the significant difference between the test groups was analyzed using the post-mortem Dunn's multiple comparison test.
통계학적 분석은 Prism 7.04(GraphPad Software Inc., San Diego, CA, USA)을 이용하여 실시하며, p값이 0.05 미만일 경우, 통계학적으로 유의한 것으로 판정하였다.Statistical analysis was performed using Prism 7.04 (GraphPad Software Inc., San Diego, CA, USA), and a p value of less than 0.05 was determined to be statistically significant.
스테로이드는 관해 유도에는 효과적이나, 관해 유지에는 효과적이지 않은 것으로 알려져 있으며, 부작용이 유발됨에 따라 단기간 내에 중단을 해야 하는 문제가 있다. 본 발명에서는 리팍시민 및 니클로사마이드를 복합제로 활용하거나, 병용투여 방법을 통해 적용함으로써 스테로이드에 의한 부작용을 최소화하면서도 염증성 장 질환에 대한 치료효과를 현저히 높일 수 있도록 하였다.Steroids are known to be effective in inducing remission, but not effective in maintaining remission, and as side effects are induced, there is a problem that it must be stopped within a short period of time. In the present invention, by using rifaximin and niclosamide as a combination or through a combination administration method, side effects caused by steroids are minimized and the therapeutic effect for inflammatory bowel disease can be remarkably increased.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. 예를 들어, 단일형으로 설명되어 있는 각 구성 요소는 분산되어 실시될 수도 있으며, 마찬가지로 분산된 것으로 설명되어 있는 구성 요소들도 결합된 형태로 실시될 수 있다. The above description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains will be able to understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not limiting. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as being distributed may also be implemented in a combined form.
본 발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is indicated by the claims to be described later, and all changes or modified forms derived from the meaning and scope of the claims and the concept of equivalents thereof should be construed as being included in the scope of the present invention.
Claims (10)
상기 리팍시민은 전체 조성물 기준 1 내지 99 중량%; 및
상기 니클로사마이드는 전체 조성물 기준 1 내지 99중량% 포함되는 것인, 약학적 조성물.The method of claim 1,
Rifaximin is 1 to 99% by weight based on the total composition; And
The niclosamide is contained in 1 to 99% by weight based on the total composition, the pharmaceutical composition.
상기 염증성 장 질환은 궤양성 대장염(ulcerative colitis), 크론병(crohn's disease), 장형 베체트(intestinal behcet's disease), 불확정 대장염(indeterminate colitis), 세균성 장염, 바이러스성 장염, 아메바성 장염, 게실염(diverticulitis) 및 결핵성 장염으로 이루어진 군에서 선택되는 하나 이상인 것인, 약학적 조성물.The method of claim 1,
The inflammatory bowel disease is ulcerative colitis, Crohn's disease, intestinal behcet's disease, indeterminate colitis, bacterial enteritis, viral enteritis, amoebic enteritis, diverticulitis. And one or more selected from the group consisting of tuberculous enteritis, the pharmaceutical composition.
상기 조성물은 리팍시민 및 니클로사마이드가 동시, 순차적 또는 역순으로 병용 투여되는 것을 특징으로 하는, 약학적 조성물.The method of claim 1,
The composition is characterized in that rifaximin and niclosamide are administered simultaneously, sequentially or in reverse order.
상기 조성물은 리팍시민 및 니클로사마이드의 복합제 형태인 것인, 약학적 조성물.The method of claim 1,
The composition is in the form of a combination of rifaximin and niclosamide, the pharmaceutical composition.
상기 투여하는 단계는 리팍시민 및 니클로사마이드를 동시, 순차적 또는 역순으로 병용 투여하는 것을 특징으로 하는, 치료방법.The method of claim 7,
The administering step is characterized in that the combined administration of rifaximin and niclosamide in simultaneous, sequential or reverse order.
상기 염증성 장 질환은 궤양성 대장염(ulcerative colitis), 크론병(crohn's disease), 장형 베체트(intestinal behcet's disease), 불확정 대장염(indeterminate colitis), 세균성 장염, 바이러스성 장염, 아메바성 장염, 게실염(diverticulitis) 및 결핵성 장염으로 이루어진 군에서 선택되는 하나 이상인 것인, 식품 조성물.The method of claim 9,
The inflammatory bowel disease is ulcerative colitis, Crohn's disease, intestinal behcet's disease, indeterminate colitis, bacterial enteritis, viral enteritis, amoebic enteritis, diverticulitis. And one or more selected from the group consisting of tuberculosis enteritis, food composition.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR101398648B1 (en) | 2006-03-09 | 2014-06-27 | 샐릭스 파마슈티컬스 인코포레이티드 | Rifaximin anti-rectal dysfunction preparation |
| KR101928543B1 (en) | 2017-01-09 | 2018-12-13 | 사단법인 분자설계연구소 | Pharmaceutical Composition for Treating or Preventing Disease Concerining Axin-GSK3 Binding Containing Niclosamide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101398648B1 (en) | 2006-03-09 | 2014-06-27 | 샐릭스 파마슈티컬스 인코포레이티드 | Rifaximin anti-rectal dysfunction preparation |
| KR101928543B1 (en) | 2017-01-09 | 2018-12-13 | 사단법인 분자설계연구소 | Pharmaceutical Composition for Treating or Preventing Disease Concerining Axin-GSK3 Binding Containing Niclosamide |
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