KR20200126260A - Composition comprising lactobacillus for treating or preventing Clostridium difficile infection - Google Patents
Composition comprising lactobacillus for treating or preventing Clostridium difficile infection Download PDFInfo
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- 206010009657 Clostridium difficile colitis Diseases 0.000 title claims description 7
- 241000186660 Lactobacillus Species 0.000 title abstract description 28
- 229940039696 lactobacillus Drugs 0.000 title abstract description 27
- 208000037384 Clostridium Infections Diseases 0.000 title description 5
- 206010054236 Clostridium difficile infection Diseases 0.000 title description 5
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- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
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- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
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Abstract
Description
본 발명은 클로스트리듐 디피실 장염 예방 또는 치료용 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating Clostridium difficile enteritis.
클로스트리듐 디피실(Clostridium difficile)은 혐기성 그람양성 간균이며 포자(spore)를 형성하므로 자연계에 널리 분포한다. Clostridium difficile is an anaerobic Gram-positive bacillus and is widely distributed in nature because it forms spores.
클로스트리듐 디피실은 치료목적으로 항생제를 복용한 환자에서 설사를 동반하는 질환으로 병원획득 설사질환의 가장 흔한 원인균으로 알려져 있다. 2003년 이후 북미와 유럽에서 고병원성 클로스트리듐 디피실에 의한 대규모의 유행이 있었고, 이로 인해 서구에서는 클로스트리듐 디피실 감염역학에 관한 많은 연구가 있었다. 2008년에서 2010년 사이, 이 균주에 의한 감염이 아시아 태평양 지역 등에서 보고되어 국제적인 감시의 필요성이 대두된다. 클로스트리듐 디피실 감염은 세계적으로 급격하게 증가하였는데 캐나다 퀘벡지역의 보고에 의하면 인구 10만 명당 유병율이 1991년 35.6명에서 2003년 156.3명으로 4.4배 증가하였고, 미국의 보고에 의하면 10만 건의 퇴원 중 클로스트리듐 디피실 장염에 의한 퇴원이 1993년 261건에서 2003년 546건으로 2.1배 증가하였다. Clostridium difficile is a disease that accompanies diarrhea in patients taking antibiotics for therapeutic purposes, and is known as the most common cause of diarrhea disease acquired by hospitals. Since 2003, there has been a large-scale epidemiology of highly pathogenic Clostridium difficile in North America and Europe, and due to this, there have been many studies on the epidemiology of Clostridium difficile in the West. Between 2008 and 2010, infections caused by this strain were reported in Asia-Pacific, and the need for international surveillance has emerged. Clostridium difficile infection has increased rapidly worldwide. According to a report in Quebec, Canada, the prevalence per 100,000 population increased 4.4 times from 35.6 in 1991 to 156.3 in 2003, and according to the US report, 100,000 discharges. Among them, the number of discharges due to Clostridium difficile enteritis increased 2.1 times from 261 in 1993 to 546 in 2003.
병원성 클로스트리듐 디피실 균주는 enterotoxin (Clostridium difficile toxin A), cytotoxin (Clostridium difficile toxin B) 등 여러 독소를 생성하며 설사 및 염증을 생성할 수 있다. 설사는 수 일간의 체액 손실에서부터 생명을 위협하는 위막성 대장염에 이르기까지 다양하다. The pathogenic Clostridium difficile toxin A strain produces several toxins such as enterotoxin ( Clostridium difficile toxin A) and cytotoxin ( Clostridium difficile toxin B) and can produce diarrhea and inflammation. Diarrhea can range from days of fluid loss to life-threatening pseudomembranous colitis.
미국 CDC는 클로스트리듐 디피실을 보건의료관련 감염의 긴급한 위협요인으로 정의하였고, 최근 fluoroquinolone 등의 항생제 내성 클로스트리듐 디피실 발생 보고가 증가하였다. The US CDC defined Clostridium difficile as an urgent threat to health-related infections, and recent reports of antibiotic-resistant Clostridium difficile such as fluoroquinolone have increased.
클로스트리듐 디피실 감염(C. difficile infection, CDI)은 항생제를 투여받은 환자의 장내 정상 세균총 구성이 변화되어 클로스트리듐 디피실이 집락하면서 발생하게 된다. CDI는 가장 흔한 병원 관련 감염의 원인 중 하나이며, 전 세계적으로 그 발생률과 사망률이 증가하고 있는 추세이다. 이는 고령의 환자와 요양시설에서 입원하고 있는 환자가 증가하고 있는 국내에서도 같은 경향을 보여주고 있다.Clostridium difficile infection (C. difficile infection, CDI) is the change in the intestinal normal flora configuration of the patients who received the antibiotic is generated while the Clostridium difficile colonization. CDI is one of the most common causes of hospital-related infections, and its incidence and mortality rates are increasing worldwide. This shows the same trend in Korea, where the number of elderly patients and patients hospitalized in nursing facilities is increasing.
통상적인 클로스트리듐 디피실 감염의 치료로는 metronidazole과 이에 반응이 없는 경우 vancomycin 경구 투여가 표준 치료이며, 초기 반응은 우수한 편이다. 하지만 35%의 환자에서 1-8주 이내에 재발하고, 그중 두 번째 이상의 재발을 경험하는 환자가 50-65%에 이르고 있다. 이는 합병증 및 합병증과 관련된 사망률의 증가와 함께 입원 기간의 연장에 따른 의료비용 상승 등의 사회적 문제로까지 연결된다.As a typical treatment for Clostridium difficile infection, oral administration of metronidazole and vancomycin in the case of no response is standard treatment, and the initial response is excellent. However, 35% of patients recur within 1-8 weeks, of which 50-65% of patients experience a second or more recurrence. This leads to social problems such as an increase in complications and complication-related mortality, as well as an increase in medical costs due to an extended hospital stay.
클로스트리듐 디피실 감염의 발병기전이 장내 세균총의 불균형(dysbiosis)에서 기인하는 것에 착안하여 정상적인 대변 이식을 통한 dysbiosis를 회복시키는 방법으로 대변 세균총 이식(fecal microbiota transplantation, FMT)이 고안되었다.Fecal microbiota transplantation (FMT) was devised as a method to recover dysbiosis through normal stool transplantation, focusing on the pathogenesis of Clostridium difficile infection due to dysbiosis of the intestinal flora.
이에, 본 발명자들은 상기 종래기술들의 문제점들을 극복하기 위하여 예의 연구노력한 결과, 발효식품으로부터 분리된 락토바실러스 복합물이 클로스트리듐 디피실 장염에 탁월한 효과가 있음을 확인하고, 본 발명을 완성하게 되었다. Accordingly, the present inventors have made intensive research efforts to overcome the problems of the prior art, as a result of confirming that the Lactobacillus complex separated from fermented food has an excellent effect on Clostridium difficile enteritis, and completed the present invention.
본 발명자들은 클로스트리듐 디피실리(Clostridium difficile)로 인한 장 질환을 예방 또는 치료할 수 있는 균을 발굴하기 위해 연구 노력하였다. 그 결과, 전통발효식품으로부터 분리된 락토바실러스 복합 균주가 클로스트리듐 디피실리에 의해 발생한 질환에 대하여 우수한 예방 및 치료 효과를 나타낸다는 것을 실험적으로 증명하여 본 발명을 완성하였다.The present inventors have made research efforts to discover bacteria capable of preventing or treating intestinal diseases caused by Clostridium difficile . As a result, the present invention was completed by experimentally demonstrating that the Lactobacillus complex strain isolated from the traditional fermented food exhibits excellent prophylactic and therapeutic effects against diseases caused by Clostridium difficile.
본 발명의 해결하고자 하는 과제는 Lactobacillus sakei PMC21, Lactobacillus curvatus PMC35, Lactobacillus paracasei PMC23, Lactobacillus acidophilus PMC65 및 Lactobacillus pentosus PMC122로 이루어진 군에서 선택되는 어느 하나 이상의 락토바실러스 균주(Strain) 또는 이의 배양물을 유효성분으로 포함하는 장 질환의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.The problem to be solved of the present invention is any one or more Lactobacillus selected from the group consisting of Lactobacillus sakei PMC21 , Lactobacillus curvatus PMC35 , Lactobacillus paracasei PMC23 , Lactobacillus acidophilus PMC65 and Lactobacillus pentosus PMC122 as an active ingredient or a culture thereof. It is to provide a pharmaceutical composition for preventing or treating intestinal diseases, including.
본 발명의 다른 목적은 Lactobacillus sakei PMC21, Lactobacillus curvatus PMC35, Lactobacillus paracasei PMC23, Lactobacillus acidophilus PMC65 및 Lactobacillus pentosus PMC122로 이루어진 군에서 선택되는 어느 하나 이상의 락토바실러스 균주(Strain) 또는 이의 배양물을 유효성분으로 포함하는 장 질환의 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is any one or more Lactobacillus strains selected from the group consisting of Lactobacillus sakei PMC21 , Lactobacillus curvatus PMC35 , Lactobacillus paracasei PMC23 , Lactobacillus acidophilus PMC65 and Lactobacillus pentosus PMC122, or a culture thereof comprising an active ingredient or a culture thereof It is to provide a food composition for preventing or improving intestinal diseases.
본 발명의 또 다른 목적은 Lactobacillus sakei, Lactobacillus curvatus, Lactobacillus paracasei, Lactobacillus acidophilus, Lactobacillus pentosus로 이루어진 군에서 선택되는 어느 1종(species) 이상의 미생물 균주 또는 이의 배양물을 유효성분으로 포함하는 장 질환의 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is the prevention of intestinal diseases comprising one or more microbial strains or cultures thereof selected from the group consisting of Lactobacillus sakei, Lactobacillus curvatus, Lactobacillus paracasei, Lactobacillus acidophilus, and Lactobacillus pentosus as an active ingredient. Or to provide an improvement food composition.
상기의 과제를 해결하기 위해 본 발명자들은 클로스트리듐 디피실(Clostridium difficile)로 인한 장 질환을 예방 또는 치료할 수 있는 균을 발굴하기 위해 연구 노력하였다. 그 결과, 전통발효식품으로부터 분리된 락토바실러스 복합 균주가 클로스트리듐 디피실에 의해 발생한 질환에 대하여 우수한 예방 및 치료 효과를 나타냄을 확인하고 본 발명을 완성하였다.In order to solve the above problems, the present inventors have made efforts to discover bacteria that can prevent or treat intestinal diseases caused by Clostridium difficile . As a result, it was confirmed that the Lactobacillus complex strain isolated from the traditional fermented food exhibited excellent preventive and therapeutic effects against diseases caused by Clostridium difficile, and the present invention was completed.
본 발명은 상기 과제를 해결하고자 하나의 양태로 Lactobacillus sakei PMC21, Lactobacillus curvatus PMC35, Lactobacillus paracasei PMC23, Lactobacillus acidophilus PMC65 및 Lactobacillus pentosus PMC122로 이루어진 군에서 선택되는 어느 하나 이상의 락토바실러스 균주(Strain) 또는 이의 배양물을 유효성분으로 포함하는 장 질환의 예방 또는 치료용 약제학적 조성물을 제공한다.The present invention is one aspect to solve the above problems, Lactobacillus sakei PMC21 , Lactobacillus curvatus PMC35 , Lactobacillus paracasei PMC23 , Lactobacillus acidophilus PMC65 and Lactobacillus pentosus PMC122 Any one or more Lactobacillus strains selected from the group consisting of PMC122 or a culture of It provides a pharmaceutical composition for preventing or treating intestinal diseases comprising as an active ingredient.
본 발명의 다른 양태로 Lactobacillus sakei PMC21, Lactobacillus curvatus PMC35, Lactobacillus paracasei PMC23, Lactobacillus acidophilus PMC65 및 Lactobacillus pentosus PMC122로 이루어진 군에서 선택되는 어느 하나 이상의 락토바실러스 균주(Strain) 또는 이의 배양물을 유효성분으로 포함하는 장 질환의 예방 또는 개선용 식품 조성물을 제공한다.In another aspect of the present invention, Lactobacillus sakei PMC21 , Lactobacillus curvatus PMC35 , Lactobacillus paracasei PMC23 , Lactobacillus acidophilus PMC65 and Lactobacillus pentosus PMC122 are selected from the group consisting of any one or more Lactobacillus strains or cultures thereof comprising an active ingredient or a culture thereof. It provides a food composition for preventing or improving intestinal diseases.
본 발명의 또 다른 양태로 Lactobacillus sakei, Lactobacillus curvatus, Lactobacillus paracasei, Lactobacillus acidophilus, Lactobacillus pentosus로 이루어진 군에서 선택되는 어느 1종(species) 이상의 미생물 균주 또는 이의 배양물을 유효성분으로 포함하는 장 질환의 예방 또는 개선용 식품 조성물을 제공한다.In another aspect of the present invention, Lactobacillus sakei, Lactobacillus curvatus, Lactobacillus paracasei, Lactobacillus acidophilus, Lactobacillus acidophilus, Lactobacillus pentosus prevention of intestinal diseases comprising one or more microbial strains or cultures thereof as an active ingredient selected from the group consisting of Or it provides a food composition for improvement.
본 발명은 락토바실러스 복합물 또는 상기 균주 배양물을 유효성분으로 포함하는 장 질환의 예방 또는 치료용 약제학적 조성물 및 식품조성물을 제공한다.The present invention provides a pharmaceutical composition and food composition for the prevention or treatment of intestinal diseases comprising a lactobacillus complex or the strain culture as an active ingredient.
본 발명의 락토바실러스 복합물은 클로스트리듐 디피실에 의해 유발되는 장 질환의 예방, 개선 또는 치료를 위해 생균용 조성물, 사료첨가제, 식품첨가제 및 기타 발효제품 등에 다양하게 이용될 수 있다.The Lactobacillus complex of the present invention may be variously used in compositions for probiotics, feed additives, food additives, and other fermented products for the prevention, improvement or treatment of intestinal diseases caused by Clostridium difficile.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for describing the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예 1: 락토바실러스 복합물의 분리 및 배양 Example 1: Isolation and culture of Lactobacillus complex
발효식품(총각김치, 전복성게젓갈, 묵은지김치, 전통요구르트, 깻잎김치)의 희석액을 MRS 아가플레이트에 도말하여 발효식품 속의 락토바실러스를 배양하였다. A diluted solution of fermented foods (Chonggak kimchi, salted abalone sea urchin, kimchi, traditional yogurt, and sesame leaf kimchi) was spread on MRS agar plate to incubate Lactobacillus in fermented food.
MRS 아가플레이트에서 단일 콜로니를 따서 MRS 액체배지 상에서 배양하였으며, 분리된 균주는 16s sequencing을 통해 동정하였다. 락토바실러스 균주를 MRS 배지에서 3회 계대 배양하여 활력을 높인 후 최종 MRS 배지에서 24시간 배양하였다. 락토바실러스 균주를 14,000 × g로 30분간 원심분리한 후 PBS 완충액에 3회 세척하였다. A single colony was picked from the MRS agar plate and cultured on MRS liquid medium, and the isolated strain was identified through 16s sequencing. The Lactobacillus strain was subcultured three times in MRS medium to increase vitality, and then cultured in the final MRS medium for 24 hours. The Lactobacillus strain was centrifuged at 14,000 × g for 30 minutes and washed 3 times in PBS buffer.
분리된 락토바실러스는 표 1과 같다.The separated lactobacilli are shown in Table 1.
실시예 2: 클로스트리듐 디피실의 분양 및 배양, 클로스트리듐 디피실 포자 생성 및 분리과정Example 2: Distribution and culture of Clostridium difficile, Clostridium difficile spores generation and separation process
항생제 내성균주은행으로부터 클로스트리듐 디피실을 분양받아 브루셀라 고체배지에 계대배양하고 포자 형성을 위해 1주일간 배양하였다. 1주일 후에 브루셀라 고체배지에서 자란 균을 긁어모아 차가운 1ml의 dH2O에 희석하였다. 4℃에서 2분간 13000rpm으로 원심 분리한 후 총 3회 차가운 1ml의 dH2O로 세척하였다. 모세포를 용해시키고 내포자를 용출시키기 위하여 48시간동안 -20°C에서 보관하였다. 이후, 4℃에서 2분간 13000rpm으로 원심 분리하고, 상층액을 버리고 포자를 1ml의 멸균된 차가운 dH2O로 희석하였다. 최종 세척 후 3ml의 멸균 dH2O로 희석하여 주었고, 4°C에서 2분 동안 4000 x g에서 회전하는 버킷 로터에서 원심분리하여 상층액을 버렸다. 이 과정을 5회 반복한 후 최종적으로 1ml의 1% BSA 가 함유된 1X PBS로 희석하였다. Clostridium difficile was pre-divided from the antibiotic-resistant strain bank, subcultured in Brucella solid medium, and cultured for 1 week to form spores. After one week, the bacteria grown in the Brucella solid medium were scraped and diluted in 1 ml of cold dH2O. After centrifugation at 13000 rpm for 2 minutes at 4° C., it was washed with cold 1 ml of dH 2 O three times. The hair cells were stored at -20 °C for 48 hours to lyse and elute inclusion spores. Thereafter, centrifugation was performed at 4° C. for 2 minutes at 13000 rpm, the supernatant was discarded, and the spores were diluted with 1 ml of sterilized cold dH2O. After the final washing, it was diluted with 3 ml of sterile dH2O, and the supernatant was discarded by centrifugation in a bucket rotor rotating at 4000 x g at 4°C for 2 minutes. After repeating this process 5 times, it was finally diluted with 1 ml of 1% BSA-containing 1X PBS.
실시예 3: 햄스터에 락토바실러스 복합물 투여 및 클린다마이신을 이용한 햄스터 장내 정상세균총 제거, 클로스트리듐 디피실 포자 장내 감염Example 3: Administration of a Lactobacillus complex to a hamster and removal of normal bacteria in the hamster using clindamycin, Clostridium difficile spore intestinal infection
물병을 통해 109/ml의 락토바실러스 복합물을 열흘간 투여하였고, 30mg/kg 농도로 클린다마이신을 투여하였다. 48시간 이후 클로스트리듐 디피실의 포자를 1×104 개 구강을 통해 존데를 사용하여 투여하였고, 햄스터 사망시까지 109/ml의 락토바실러스 복합물(actobacillus sakei PMC21, Lactobacillus curvatus PMC35, Lactobacillus paracasei PMC23, Lactobacillus acidophilus PMC65 및 Lactobacillus pentosus PMC122)을 물병을 통해 투여하였다. 대조군은 오직 클린다마이신과 클로스트리듐 디피실의 포자만이 투여하였다.10 9 /ml of the Lactobacillus complex was administered through a water bottle for 10 days, and clindamycin was administered at a concentration of 30 mg/kg. After 48 hours, 1×10 4 spores of Clostridium difficile were administered through the oral cavity using Sonde, and until the death of the hamster, 10 9 /ml of Lactobacillus complex ( actobacillus sakei PMC21 , Lactobacillus curvatus PMC35 , Lactobacillus paracasei PMC23 , Lactobacillus acidophilus PMC65 and Lactobacillus pentosus PMC122) were administered through a water bottle. As a control group, only clindamycin and clostridium difficile spores were administered.
표 2에서 락토바실로스 복합물을 처리한 군에서 클로스트리듐 디피실의 장내 감염에 의한 사망이 지연되는 것을 확인하였는바, Lactobacillus sakei PMC21, Lactobacillus curvatus PMC35, Lactobacillus paracasei PMC23, Lactobacillus acidophilus PMC65 및 Lactobacillus pentosus PMC122의 락토바실러스 복합물이 클로스트리듐 디피실 장내감염 보호 효과를 가짐을 확인하였다.In Table 2, it was confirmed that death due to intestinal infection of Clostridium difficile was delayed in the group treated with the lactobacillus complex, Lactobacillus sakei PMC21 , Lactobacillus curvatus PMC35 , Lactobacillus paracasei PMC23 , Lactobacillus acidophilus PMC65 and Lactobacillus PMC65 and Lactobacillus PMC122 It was confirmed that the Lactobacillus complex has a protective effect of Clostridium difficile intestinal infection.
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