KR102422449B1 - A composition for preventing, alleviating or treating tuberculosis and infected disease by nontuberculous mycobacteria - Google Patents
A composition for preventing, alleviating or treating tuberculosis and infected disease by nontuberculous mycobacteria Download PDFInfo
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- KR102422449B1 KR102422449B1 KR1020190129816A KR20190129816A KR102422449B1 KR 102422449 B1 KR102422449 B1 KR 102422449B1 KR 1020190129816 A KR1020190129816 A KR 1020190129816A KR 20190129816 A KR20190129816 A KR 20190129816A KR 102422449 B1 KR102422449 B1 KR 102422449B1
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- South Korea
- Prior art keywords
- tuberculosis
- mycobacterium
- pharmaceutical composition
- tuberculous
- amitriptyline
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Abstract
본 발명은 결핵 및 비결핵항산균 감염 질환의 예방 또는 치료용 약학 조성물에 관한 것으로서, 본 발명에 따른 상기 조성물은 결핵균 및 비결핵항산균, 특히 숙주 세포인 큰포식세포에서 발현되는 IFN-β의 발현 수준이 증가되는 경우 그 성장 속도가 더욱 증가되는 상기 균주들의 증식 및 성장을 억제하는데 현저한 시너지 효과를 갖는다. 이와 같은 효과를 통하여, 숙주 세포 중에서, 특히 큰포식세포를 주된 숙주 세포로 하는 결핵 및 비결핵항산균 감염 질환을 매우 효과적으로 치료할 수 있다.The present invention relates to a pharmaceutical composition for the prophylaxis or treatment of tuberculosis and non-tuberculous mycobacterium-infectious diseases, wherein the composition according to the present invention contains IFN-β expressed in Mycobacterium tuberculosis and non-tuberculous mycobacterium, particularly macrophages, which are host cells When the expression level is increased, it has a remarkable synergistic effect in inhibiting the proliferation and growth of the strains whose growth rate is further increased. Through this effect, it is possible to very effectively treat tuberculosis and non-tuberculous mycobacterium-infected diseases in which host cells, particularly macrophages, are the main host cells.
Description
본 발명은 결핵 및 비결핵항산균 감염 질환의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, improving, or treating tuberculosis and non-tuberculous mycobacterium-infectious diseases.
마이코박테리움 속 균종은 병원성 정도에 따라 절대병원성균인 결핵균 및 나병균을 포함하는 결핵균군과, 이를 제외한 기회감염성 균종인 비결핵항산균(nontuberculous mycobacteria, NTM)의 두 그룹으로 구분된다.According to the degree of pathogenicity, Mycobacterium is divided into two groups: Mycobacterium tuberculosis, which includes mycobacterium tuberculosis and leprosy, which are absolutely pathogenic bacteria, and nontuberculous mycobacteria, NTM, which is an opportunistic bacterial species excluding them.
상기 결핵균은 감염 후 일정기간 동안 잠복기를 거친 후 발병되거나 또는 잠복기 없이 급성으로 발병하여 폐의 염증과 천식을 동반하는 합병증을 일으켜 감염자를 결국 사망에 이르게 한다. 특히 결핵균을 단순히 보유하고 있는 보균자의 경우에는 자각증상이 없기 때문에 타인에게 쉽게 결핵균이 전염될 수 있어 결핵의 예방에 어려움이 있다.The Mycobacterium tuberculosis develops after an incubation period for a certain period of time after infection, or develops acutely without an incubation period, causing complications accompanying lung inflammation and asthma, and ultimately leads to death of the infected person. In particular, in the case of carriers who simply possess Mycobacterium tuberculosis, it is difficult to prevent tuberculosis because the tuberculosis bacteria can be easily transmitted to others because there are no subjective symptoms.
상기 비결핵항산균은 자연계에 널리 분포하며 균종에 따라 질환을 일으키는 발병력이 달라, M. kansasii, M. avium, M. abscessus 등은 상대적으로 발병력이 크고, M. fortuitum은 상대적으로 발병력이 낮다. 비결핵항산균으로 인한 질환은 폐질환, 림프절염, 피부·연조직·골감염증, 파종성 질환 등 4가지 특징적인 임상 증후를 나타낸다.The non-tuberculous mycobacterium is widely distributed in nature and has a different disease-causing power depending on the species, M. kansasii, M. avium, M. abscessus, etc. have a relatively large virulence, and M. fortuitum has a relatively high virulence. this is low Diseases caused by non-tuberculous mycobacteria exhibit four characteristic clinical symptoms: lung disease, lymphadenitis, skin/soft tissue/bone infection, and disseminated disease.
상기 결핵(TB; Tuberculosis)은 세계보건기구 (WHO; World Health Organization)에서 지정한 인류 건강을 위협하는 3대 감염 질병 중 하나이다. 결핵을 발병시키는 주요 원인균으로는 마이코박테리움 투베르쿨로시스 (MTB; Mycobacterium tuberculosis)가 대표적이고, 전 세계 인구 중 3분의 1정도는 감염된 이력이 있다고 보고되고 있다(Global TB reports, WHO, 2017). 2017년 세계보건기구에서 작성한 Global TB report에서는 2016년 기준으로 전 세계에서 새롭게 결핵에 걸린 환자는 약 1,040만명으로 추산하고 있으며 기존의 결핵환자 중 140만명은 결핵으로 인한 사망, 그리고 추가적으로 40만명은 인간 면역결핍 바이러스(HIV; Human Immunodeficiency Virus)와의 동시감염으로 인한 사망이 발생하였다고 보고하고 있다. 그러나 최근 결핵 감염 수는 매년 감소 추세에 이르지만 다제내성(MDR; Multi-drug resistant) 및 광범위 내성 (XDR; Extensively-drug resistant)을 지닌 결핵균의 증가로 인하여 결핵 치료가 어려워지고 있다. 이로 인해 결핵의 치료 비용도 증가하였고, 치료 효율마저 낮아져 난치성 결핵으로 발전하는 모습을 보여주고 있다.Tuberculosis (TB) is one of the three major infectious diseases that threaten human health designated by the World Health Organization (WHO). The main causative agent of tuberculosis is Mycobacterium tuberculosis (MTB), and it is reported that about one-third of the world's population has a history of infection (Global TB reports, WHO, 2017). According to the Global TB report prepared by the World Health Organization in 2017, it is estimated that there were about 10.4 million new tuberculosis patients worldwide as of 2016, 1.4 million of the existing tuberculosis patients died from tuberculosis, and an additional 400,000 people It has been reported that death occurred due to co-infection with human immunodeficiency virus (HIV). However, in recent years, the number of tuberculosis infections has been decreasing every year, but tuberculosis treatment is becoming difficult due to the increase of MDR (Multi-drug resistant) and Extensively-drug resistant (XDR) Mycobacterium tuberculosis. As a result, the treatment cost of tuberculosis has also increased, and the treatment efficiency has also decreased, showing the development of intractable tuberculosis.
한편, 비결핵항산균에 의해 유발되는 폐질환에 대한 보고는 2000년 이후 증가하고 있으며, 국내에서 상기 폐질환의 원인균으로 가장 흔한 균은 M. Avium이며, 외국에서는 상대적으로 드물지만 국내에서는 두번째로 관찰되는 M. abscessus가 원인균으로 보고되고 있다. 상기 M. abscessus의 감염에 의해 유발되는 폐질환은 중년 이상의 비흡연자 여성에서 흔히 발생되며, 기침, 발열, 객혈 및 객담과 같은 증상이 나타난다.On the other hand, reports of lung diseases caused by non-tuberculous mycobacteria have increased since 2000, and M. Avium is the most common causative agent of the lung disease in Korea. M. abscessus has been reported as the causative organism. The lung disease caused by M. abscessus infection is common in middle-aged or older non-smokers, and symptoms such as cough, fever, hemoptysis and sputum appear.
상기 결핵을 치료할 수 있는 항생제의 경우, 최초로 사용된지 최소 50년 이상된 것으로서, 현재 결핵과 항생제 내성을 갖는 결핵균에 대한 치료제에 대한 신규 약에 대한 연구는 미비한 실정이다. 뿐만 아니라, 상기 비결핵항산균에 의해 유발되는 폐질환은 폐결핵과는 달리 항생제 병합 치료를 실시함에도 불구하고 아직까지 그 치료 효과가 만족스럽지 못하며, 주로 질환이 발생되는 연령대가 중년 이상의 고령의 환자이기 때문에 각종 항생제 및 여러 치료 요법을 시도할 때 수반되는 부작용이 높은 실정이다.Antibiotics capable of treating tuberculosis have been used for at least 50 years since they were first used, and research on new drugs for treatment of tuberculosis and Mycobacterium tuberculosis with antibiotic resistance is insufficient. In addition, the pulmonary disease caused by the non-tuberculous mycobacterium, unlike pulmonary tuberculosis, despite the combined treatment with antibiotics, the treatment effect is still not satisfactory, and the age at which the disease occurs is mainly middle-aged or older patients. For this reason, the side effects associated with various antibiotics and various treatment regimens are high.
본 발명의 목적은 결핵의 예방, 개선 또는 치료용 조성물을 제공하는 것이다.It is an object of the present invention to provide a composition for preventing, improving or treating tuberculosis.
본 발명의 다른 목적은 비결핵항산균 감염질환의 예방, 개선 또는 치료용 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for preventing, improving, or treating non-tuberculous mycobacterium infectious diseases.
본 발명의 또 다른 목적은 결핵균 또는 비결핵항산균의 증식 또는 성장 억제용 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for inhibiting the proliferation or growth of Mycobacterium tuberculosis or non-tuberculous mycobacterium.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당 업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical task to be achieved by the present invention is not limited to the tasks mentioned above, and other tasks not mentioned will be clearly understood by those of ordinary skill in the art from the following description.
본 발명의 일 구현 예에서는 결핵의 예방, 개선 또는 치료용 조성물을 제공한다.One embodiment of the present invention provides a composition for preventing, improving or treating tuberculosis.
본 발명의 상기 조성물은 약학 조성물 또는 식품 조성물로 사용될 수 있다.The composition of the present invention may be used as a pharmaceutical composition or a food composition.
본 발명의 상기 결핵의 예방, 개선 또는 치료용 조성물은 아미트립틸린(amitriptyline) 및 데시프라민(despramine) 중 적어도 어느 하나를 유효성분으로 포함한다.The composition for preventing, improving or treating tuberculosis of the present invention includes at least one of amitriptyline and despramine as an active ingredient.
본 발명의 상기 "아미트립틸린"은 삼환계 항우울제의 한 종류로, 하기 화학식 1로 표시되는 화합물이며, 주요우울장애, 불안장애, 주의력결핍 과다행동장애 및 조울증 등의 치료에 효과가 있는 물질로 알려져 있다. 그러나, 본 발명의 목적상 상기 아미트립틸린은 단독 또는 기존의 항생제와 병용하여 사용됨으로써 숙주 세포인 큰포식세포에서 발현되는 IFN-β의 발현 수준이 증가되는 경우 그 성장 속도가 더욱 증가되는 결핵균의 증식 및 성장을 억제할 수 있다:The "amitriptyline" of the present invention is a kind of tricyclic antidepressant, a compound represented by the following formula (1), and is known to be effective in the treatment of major depressive disorder, anxiety disorder, attention deficit hyperactivity disorder and bipolar disorder. have. However, for the purpose of the present invention, when the expression level of IFN-β expressed in macrophages, which is a host cell, is increased by using the amitriptyline alone or in combination with an existing antibiotic, the growth rate of Mycobacterium tuberculosis is further increased. It can inhibit proliferation and growth:
[화학식 1][Formula 1]
본 발명의 상기 "데시프라민"은 삼환계 항우울제의 한 종류로, 하기 화학식 2로 표시되는 화합물이며, 세로토닌 재흡수 억제, 항콜린성 효과 등의 효과를 발휘하며 노르에피네프린 재흡수 억제제로서의 역할을 할 수 있다. 이와 같은 화합물은 우울증 및 주의력 결핍 과잉행동장애 등의 치료에 효과가 있는 물질로 알려져있다. 그러나, 본 발명의 목적상 상기 데시프라민은 단독 또는 기존의 항생제와 병용하여 사용됨으로써 숙주 세포인 큰포식세포에서 발현되는 IFN-β의 발현 수준이 증가되는 경우 그 성장 속도가 더욱 증가되는 결핵균의 증식 및 성장을 억제할 수 있다:The "desipramine" of the present invention is a kind of tricyclic antidepressant, is a compound represented by the following formula (2), exhibits effects such as serotonin reuptake inhibition and anticholinergic effects, and can serve as a norepinephrine reuptake inhibitor. have. Such compounds are known to be effective in the treatment of depression and attention deficit/hyperactivity disorder. However, for the purpose of the present invention, the desipramine is used alone or in combination with conventional antibiotics, so that when the expression level of IFN-β expressed in macrophages, which is a host cell, is increased, the growth rate of Mycobacterium tuberculosis is further increased. It can inhibit proliferation and growth:
[화학식 2][Formula 2]
본 발명의 상기 조성물은 리팜핀(rifampin), 아이소니아지드(isoniazid), 피라진아마이드(pyrazinamide), 에탐부톨(ethambutol), 스트렙토마이신(streptomycin), 플로퀴노론(fluoroquinolone), 카나마이신(kanamycin), 시클로세린 (Cycloserine), 프로치온 아미드(Prothionamide), 레보플록사신(Levofloxacin), 목시플록사신(Moxifloxacin), 오플록사신(Ofloxacin), 리파부틴(Rifabutin), 카프레오마이신(Capeomycin), 아미카신(amikacin), 시프로플록사신(ciprofloxacin), 프로티오나마이드(protionamide), 에티오나마이드(ethionamide), 사이클로세린(cycloserine), 티오아세타존(thioacetazone), 클로파지마인(clofazimine), 아목실린/클라불라네이트(amoxicillin/clavulanate), 다이아미노다이페닐설폰의 유도체(derivative of dianomidiphenylsulphone) 및 리네졸리드(Linezolid)로 이루어진 군으로부터 선택되는 적어도 하나를 더 포함하는 것일 수 있다.The composition of the present invention is rifampin, isoniazid, pyrazinamide, ethambutol, streptomycin, floquinolone, kanamycin, cycloserine ), Prothionamide, Levofloxacin, Moxifloxacin, Ofloxacin, Rifabutin, Capeomycin, Amikacin, Ciprofloxacin ciprofloxacin, protionamide, ethionamide, cycloserine, thioacetazone, clofazimine, amoxicillin/clavulanate ), derivatives of diaminodiphenyl sulfone (derivative of diaminodiphenylsulphone) and linezolid may further include at least one selected from the group consisting of.
본 발명의 상기 유효성분은 단독으로 사용된 경우와 비교하여, 기존의 항생제와 병용하여 사용되었을 때에 결핵균, 특히 숙주 세포인 큰포식세포에서 발현되는 IFN-β의 발현 수준이 증가되는 경우 그 성장 속도가 더욱 증가되는 결핵균의 증식 및 성장을 억제하는데 현저한 시너지 효과를 갖는다.When the active ingredient of the present invention is used in combination with an existing antibiotic, compared to when used alone, the growth rate of Mycobacterium tuberculosis, especially when the expression level of IFN-β expressed in macrophages, which is a host cell, is increased. has a remarkable synergistic effect in inhibiting the further increased proliferation and growth of Mycobacterium tuberculosis.
본 발명의 상기 유효성분은 기존의 항생제와 병용하여 사용되었을 때, 상기 결핵을 유발하는 결핵균에 대하여 항생제에 대한 감수성 또는 민감성을 증진시킴으로써, 단독으로 사용된 경우와 비교하여 결핵균의 증식 및 성장을 더욱 효과적으로 억제할 수 있다.When the active ingredient of the present invention is used in combination with an existing antibiotic, by enhancing the sensitivity or sensitivity to the antibiotic for Mycobacterium tuberculosis causing the tuberculosis, the proliferation and growth of Mycobacterium tuberculosis is further increased compared to when used alone can be effectively suppressed.
본 발명의 상기 결핵은 당 분야에 알려진 결핵균에 의해 발병되는 결핵을 모두 포함하며, 예를 들면, 마이코박테리움 투베르쿨로시스(M. tuberculosis), 마이코박테리움 보비스(M. bovis), 마이코박테리움 보비스(M. bovis) BCG, 마이코박테리움 아프리카눔(M. africanum), 마이코박테리움 카네티(M. canetti), 마이코박테리움 카프라에(M. caprae), 마이코박테리움 마이크로티(M. microti) 및 K 균주(Mycobacterium tuberculosis K strain)로 이루어진 군으로부터 선택되는 적어도 하나의 감염에 의해 유발되는 것일 수 있다. 본 발명의 실시예에서는 마이코박테리움 투베르쿨로시스가 큰포식세포에 감염되었을 때, 본 발명의 상기 유효성분을 단독으로 사용한 경우뿐만 아니라, 상기 기존의 항생제와 병용하여 사용된 경우 상기 마이코박테리움 투베르쿨로시스의 성장 억제에 시너지 효과가 있는 것을 확인하였다(도 2 및 도 3 참조).The tuberculosis of the present invention includes all tuberculosis caused by Mycobacterium tuberculosis known in the art, for example, Mycobacterium tuberculosis (M. tuberculosis), Mycobacterium bovis (M. bovis), Mycobacterium bovis (M. bovis) BCG, Mycobacterium africanum (M. africanum), Mycobacterium canetti (M. canetti), Mycobacterium caprae (M. caprae), Mycobacterium It may be caused by at least one infection selected from the group consisting of M. microti and Mycobacterium tuberculosis K strain. In an embodiment of the present invention, when Mycobacterium tuberculosis is infected with macrophages, when the active ingredient of the present invention is used alone as well as when used in combination with the existing antibiotic, the Mycobacterium tuberculosis It was confirmed that there is a synergistic effect on the growth inhibition of Therium tuberculosis (see FIGS. 2 and 3).
상기 "K 균주"란, 한국형 고변원성 결핵균으로, 베이징 패밀리(Beijing family)에 속하는 균주, 즉 표준 균주인 마이코박테리움 투베르쿨로시스에 비하여 병원성이 높고 치료 후, 재발율이 높은 것을 특징으로 한다. 한국의 결핵 환자로부터 분리되는 결핵 균주의 77%는 베이징 패밀리에 속하는 것으로 알려져 있고 중고등학교에서 집단으로 발생하는 결핵균들의 제한효소 절편 다형(restriction fragment length polymorphism; RFLP) 프로파일을 조사한 결과, 약 18.4%에서 독특한 균주 집단이 발견되어 이를 K 균주로 명명하고, 이와 같은 유사한 특징을 갖는 균주들을 K 패밀리로 명명하였다 (Kim SJ, et al. Int. J. Tuberc. Lung Dis.5:824-830, 2001).The "K strain" is a Korean-type highly mutagenic Mycobacterium tuberculosis, and it is characterized by high pathogenicity and a high recurrence rate after treatment compared to a strain belonging to the Beijing family, that is, the standard strain Mycobacterium tuberculosis. . It is known that 77% of tuberculosis strains isolated from tuberculosis patients in Korea belong to the Beijing family. A unique strain group was discovered and named K strains, and strains with these similar characteristics were named K family (Kim SJ, et al. Int. J. Tuberc. Lung Dis. 5:824-830, 2001). .
본 발명의 목적상 상기 결핵균은 숙주 세포에 감염되는 경우, 특히 큰포식세포의 변화를 유도하여 세포 내 지질이 증가되는 포말 세포를 형성하도록 한 뒤, 이와 같은 포말 세포를 에너지원으로 사용하는 것일 수 있다.For the purpose of the present invention, when Mycobacterium tuberculosis is infected with a host cell, in particular, it induces changes in macrophages to form foam cells in which intracellular lipids are increased, and then uses such foam cells as an energy source. have.
본 발명의 상기 결핵은 안결핵, 피부 결핵, 부신 결핵, 신장 결핵, 부고환 결핵, 림프선 결핵, 후두 결핵, 중이 결핵, 장결핵, 다제내성 결핵, 폐결핵, 담결핵, 골결핵, 인후결핵, 임파선 결핵, 폐허증, 유방 결핵 및 척추 결핵으로 이루어진 군으로부터 선택되는 적어도 하나인 것일 수 있으나, 이에 제한되는 것은 아니다.The tuberculosis of the present invention is ocular tuberculosis, skin tuberculosis, adrenal tuberculosis, renal tuberculosis, epididymal tuberculosis, lymph gland tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tuberculosis, pulmonary tuberculosis, biliary tuberculosis, bone tuberculosis, throat tuberculosis, lymph node tuberculosis, It may be at least one selected from the group consisting of pulmonary tuberculosis, breast tuberculosis, and spinal tuberculosis, but is not limited thereto.
본 발명의 상기 "예방"은 본 발명의 상기 조성물을 이용하여 결핵으로 인해 발생한 증상을 차단하거나, 그 증상을 억제 또는 지연시키는 모든 행위라면 제한없이 모두 포함될 수 있다.The "prevention" of the present invention may be included without limitation as long as it blocks symptoms caused by tuberculosis using the composition of the present invention, or suppresses or delays the symptoms.
본 발명의 상기 "개선" 및 "치료"는 본 발명의 상기 조성물을 이용하여 결핵으로 인해 발생한 증상이 호전되거나 이롭게 되는 행위라면 제한없이 모두 포함될 수 있다.The "improvement" and "treatment" of the present invention may be included without limitation as long as the symptoms caused by tuberculosis are improved or beneficial by using the composition of the present invention.
본 발명의 상기 약학 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. The pharmaceutical composition of the present invention may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be characterized in that it is targeted to humans.
본 발명의 상기 약학 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사 용액의 형태로 제형화되어 사용될 수 있다. 본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등이 사용될 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등이 혼합되어 사용될 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등이 사용될 수 있다. 본 발명의 약학 조성물의 제형은 상술한 바와 같은 약학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수 회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화할 수 있다.The pharmaceutical composition of the present invention is not limited thereto, but each is formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods to be used. can The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, fragrances, etc., for oral administration, and in the case of injections, buffers, preservatives, and pain relief Agents, solubilizers, isotonic agents, stabilizers, etc. may be mixed and used, and in the case of topical administration, bases, excipients, lubricants, preservatives, etc. may be used. The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, in the case of oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. have. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Meanwhile, examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used. In addition, it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.
본 발명의 상기 약학 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. The route of administration of the pharmaceutical composition of the present invention is, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal. Oral or parenteral administration is preferred.
본 발명의 상기 "비경구"란, 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다.The "parenteral" of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
본 발명의 상기 약학 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여 시간, 투여 경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약무 형태, 투여 경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50 mg/kg 또는 0.001 내지 50 mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형화될 수 있다.The pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. The dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg/day per day kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
본 발명의 상기 식품 조성물은 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다. The food composition of the present invention may be prepared in the form of various foods, for example, beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, bread, and the like.
본 발명의 상기 조성물의 유효성분이 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 50%의 비율로 첨가할 수 있으나, 이에 제한되는 것은 아니다.When the active ingredient of the composition of the present invention is included in the food composition, the amount may be added in a proportion of 0.1 to 50% of the total weight, but is not limited thereto.
본 발명의 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 포함하는 것 외에 특별한 제한점은 없으며, 통상의 음료와 같이 다양한 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 구체적으로, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등) 등일 수 있다. When the food composition of the present invention is prepared in the form of a beverage, there is no particular limitation other than including the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients, like a conventional beverage. . Specifically, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, and polysaccharides such as sucrose, conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol are used as natural carbohydrates. may include The flavoring agent may be a natural flavoring agent (taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agent (saccharin, aspartame, etc.).
본 발명의 상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등이 더 포함될 수 있다.The food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, A pH adjuster, a stabilizer, a preservative, glycerin, alcohol, a carbonation agent used in carbonated beverages, and the like may be further included.
본 발명의 상기 식품 조성물에 포함되는 성분들은 독립적으로 또는 조합하여 사용될 수 있다. 상기 첨가제의 비율은 본 발명의 핵심적인 요소에 해당하지 아니하지만, 본 발명의 식품 조성물 100 중량부 당 0.1 내지 약 50 중량부의 범위에서 선택될 수 있으나, 이에 제한되는 것은 아니다.The ingredients included in the food composition of the present invention may be used independently or in combination. The proportion of the additive is not a key element of the present invention, but may be selected from 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.
본 발명의 다른 구현 예에서는 비결핵항산균 감염질환의 예방, 개선 또는 치료용 조성물을 제공한다.In another embodiment of the present invention, there is provided a composition for preventing, improving, or treating non-tuberculous mycobacterium infectious diseases.
본 발명의 상기 조성물은 약학 조성물 및 식품 조성물로 사용될 수 있다.The composition of the present invention can be used as a pharmaceutical composition and a food composition.
본 발명의 상기 포함하는 비결핵항산균 감염질환의 예방, 개선 또는 치료용 조성물은 아미트립틸린 및 데시프라민 중 적어도 어느 하나를 유효성분으로 포함한다.The composition for preventing, ameliorating or treating non-tuberculous mycobacterium infectious diseases including the above of the present invention includes at least one of amitriptyline and desipramine as an active ingredient.
본 발명의 상기 유효성분은 단독으로 사용된 경우뿐만 아니라, 기존의 항생제와 병용하여 사용되었을 때에 결핵균, 특히 숙주 세포인 큰포식세포에서 발현되는 IFN-β의 발현 수준이 증가되는 경우 그 성장 속도가 더욱 증가되는 결핵균의 증식 및 성장을 억제하는데 현저한 시너지 효과를 갖는다.The growth rate of the active ingredient of the present invention is increased when the expression level of IFN-β expressed in Mycobacterium tuberculosis, particularly, macrophages, which are host cells, is increased when used alone as well as when used in combination with conventional antibiotics. It has a remarkable synergistic effect in inhibiting the proliferation and growth of Mycobacterium tuberculosis, which is further increased.
본 발명의 상기 비결핵항산균 감염질환의 예방, 개선 또는 치료용 조성물에서, 유효성분, 기존 항생제, 예방, 개선, 치료, 약학 조성물 및 식품 조성물과 관련된 내용은 앞서 기재한 바와 동일하여 명세서의 과도한 복잡성을 피하기 위해 생략한다.In the composition for preventing, improving or treating non-tuberculous mycobacterium infectious disease of the present invention, the content related to the active ingredient, existing antibiotic, prevention, improvement, treatment, pharmaceutical composition and food composition is the same as described above, omitted to avoid complexity.
본 발명의 상기 "비결핵항산균"이란, 결핵균종(mycobacterium complex)과 나병균(M. leprae)를 제외한 다른 모든 마이코박테리아를 지칭하는 것으로서, 예를 들면, 마이코박테리움 아비늄(Mycobacterium avium), 마이코박테리움 인트라셀룰레어(Mycobacterium intracellulare), 마이코박테리움 칸사시(Mycobacterium kansasii), 마이코박테리움 포푸이툼(Mycobacterium fortuitum) 및 마이코박테리움 압세수스(Mycobacterium abscessus)로 이루어진 군으로부터 선택되는 적어도 하나인 것일 수 있으나, 이에 제한되는 것은 아니다.The "non-tuberculous mycobacteria" of the present invention refers to all other mycobacteria except mycobacterium complex and M. leprae, for example, Mycobacterium avium. , Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium fortuitum and Mycobacterium abscessus It may be at least one selected from, but is not limited thereto.
본 발명의 목적상 상기 비결핵항산균은 숙주 세포에 감염되는 경우, 그 균주의 종류에 따라 큰포식세포의 변화를 유도하여 세포 내 지질이 증가되는 포말 세포를 형성하도록 한 뒤, 이와 같은 포말 세포를 에너지원으로 사용하는 것일 수 있다.For the purpose of the present invention, when the non-tuberculous mycobacterium is infected with a host cell, it induces changes in macrophages depending on the type of the strain to form foam cells in which intracellular lipids are increased, and then, such foam cells may be used as an energy source.
본 발명의 상기 비결핵항산균 감염 질환은 폐질환, 림프절염, 피부·연조직·골감염증 및 파종성 질환(disseminated disease)으로 이루어진 군으로부터 선택되는 적어도 하나인 것일 수 있으나, 이에 제한되는 것은 아니다.The non-tuberculous mycobacterium infection disease of the present invention may be at least one selected from the group consisting of lung disease, lymphadenitis, skin, soft tissue, bone infection, and disseminated disease, but is not limited thereto.
본 발명의 또 다른 구현 예에서는 결핵균 또는 비결핵항산균의 증식 또는 성장 억제용 조성물을 제공한다.Another embodiment of the present invention provides a composition for inhibiting the proliferation or growth of Mycobacterium tuberculosis or non-tuberculous mycobacterium.
본 발명의 상기 증식 또는 성장 억제용 조성물은 아미트립틸린 및 데시프라민 중 적어도 어느 하나를 포함한다.The composition for growth or growth inhibition of the present invention includes at least one of amitriptyline and desipramine.
본 발명의 상기 아미트립틸린 및 데시프라민은 단독으로 사용된 경우뿐만 아니라, 기존의 항생제와 병용하여 사용되었을 때에 결핵균 및 비결핵항산균, 특히 숙주 세포인 큰포식세포에서 발현되는 IFN-β의 발현 수준이 증가되는 경우 그 성장 속도가 더욱 증가되는 상기 균주들의 증식 및 성장을 억제하는데 현저한 시너지 효과를 갖는다.The amitriptyline and desipramine of the present invention are not only used alone, but also when used in combination with conventional antibiotics, IFN-β expressed in Mycobacterium tuberculosis and non-tuberculous mycobacteria, particularly macrophages, which are host cells. When the expression level is increased, it has a remarkable synergistic effect in inhibiting the proliferation and growth of the strains whose growth rate is further increased.
본 발명의 상기 증식 또는 성장 억제용 약학 조성물에서, 유효성분, 기존 항생제, 결핵균, 비결핵항산균, 예방, 개선, 치료 및 조성물과 관련된 내용은 앞서 기재한 바와 동일하여 명세서의 과도한 복잡성을 피하기 위해 생략한다.In the pharmaceutical composition for growth or growth inhibition of the present invention, the active ingredient, existing antibiotics, Mycobacterium tuberculosis, non-tuberculous mycobacterium, prevention, improvement, treatment, and content related to the composition are the same as those described above, in order to avoid excessive complexity of the specification. omit
본 발명에 따른 조성물은 결핵균 및 비결핵항산균, 특히 숙주 세포인 큰포식세포에서 발현되는 IFN-β의 발현 수준이 증가되는 경우 그 성장 속도가 더욱 증가되는 상기 균주들의 증식 및 성장을 억제하는데 현저한 시너지 효과를 갖는다. 이와 같은 효과를 통해, 숙주 세포 중에서, 특히 큰포식세포를 주된 숙주 세포로 하는 결핵 및 비결핵항산균 감염 질환을 매우 효과적으로 치료할 수 있다.The composition according to the present invention is remarkable in inhibiting the proliferation and growth of Mycobacterium tuberculosis and Mycobacterium tuberculosis, especially the strains whose growth rate is further increased when the expression level of IFN-β expressed in macrophages, which is a host cell, is increased. have a synergistic effect. Through such an effect, it is possible to very effectively treat tuberculosis and non-tuberculous mycobacterium-infected diseases in which host cells, particularly macrophages, are the main host cells.
도 1의 A 및 B는 본 발명의 일 실시예에 따른 IFN-β에 의한 결핵균의 성장 증가와 세라마이드(ceramide) 방출량을 측정한 결과를 나타낸 것이다.
도 2의 A 및 B는 본 발명의 일 실시예에 따른 큰포식세포에서 아미트립틸린 및 데시프라민 처리에 의한 결핵균의 성장 억제 효과를 확인한 결과를 나타낸 것이다.
도 3은 본 발명의 일 실시예에 따른 큰포식세포에서 아미트립틸린 또는 데시프라민과 결핵치료제의 병용처리에 의한 결핵균의 성장 억제 효과를 확인한 결과를 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른 큰포식세포에서 아미트립틸린 및 데시프라민 처리에 의한 비결핵항산균의 성장 억제 효과를 확인한 결과를 나타낸 것이다.1A and B show the results of measuring the growth increase of Mycobacterium tuberculosis and the amount of ceramide released by IFN-β according to an embodiment of the present invention.
2A and 2B show the results of confirming the growth inhibitory effect of Mycobacterium tuberculosis by treatment with amitriptyline and desipramine in macrophages according to an embodiment of the present invention.
3 shows the results of confirming the growth inhibitory effect of Mycobacterium tuberculosis by the combined treatment of amitriptyline or desipramine and a tuberculosis therapeutic agent in macrophages according to an embodiment of the present invention.
Figure 4 shows the results of confirming the growth inhibitory effect of non-tuberculous mycobacteria by treatment with amitriptyline and desipramine in macrophages according to an embodiment of the present invention.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example
[제조예 1 내지 6] [Preparation Examples 1 to 6] 실시예에서 사용된 배지 제조Preparation of the medium used in the examples
[제조예 1 및 2] cDMEM 배지 및 감염 배지의 제조 [Preparation Examples 1 and 2] Preparation of cDMEM medium and infection medium
450 ml의 DMEM 배지에, 50 ml의 열에 의해 불활성화된 우태아혈청(FBS)와 5 ml의 100 X 항생제를 넣고 충분히 섞는 과정을 통해 500 ml의 cDMEM 배지를 제조하였다(제조예 1). 여기서, 감염 배지는 제조예 1과 동일한 조건으로 제조하면서, 5 ml의 항생제는 제외하였다(제조예 2).In 450 ml of DMEM medium, 50 ml of heat-inactivated fetal bovine serum (FBS) and 5 ml of 100 X antibiotic were added and thoroughly mixed to prepare 500 ml of cDMEM medium (Preparation Example 1). Here, the infection medium was prepared under the same conditions as in Preparation Example 1, except for 5 ml of antibiotics (Preparation Example 2).
[제조예 3] L929 세포주 배양액(conditioned media) 제조 [Preparation Example 3] Preparation of L929 cell line culture medium (conditioned media)
상기 제조예 1의 cDMEM 배지에 L929 세포주를 1 × 105 세포/ml의 농도로 현탁한 뒤, T 175 플라스크에 상기 세포 현탁액을 50 ml의 양으로 분주하고, 5% CO2 및 37 ℃의 조건에서 7일 동안 배양하였다. 그런 다음, 상기 7일 동안 배양된 배양액을 수득(1차 cDMEM 배양액)하고, 50 ml의 새로운 상기 cDMEM 배지를 상기 7일 배양된 세포주에 넣고 7일 동안(최초 분주일로부터 14일) 추가로 배양하였다. 이후, 최초 분주일로부터 14일이 되는 날, 배양액을 수득하였다(2차 cDMEM 배양액).After suspending the L929 cell line in the cDMEM medium of Preparation Example 1 at a concentration of 1 × 10 5 cells/ml, the cell suspension was dispensed in an amount of 50 ml in a T 175 flask, 5% CO 2 and conditions of 37 ° C. incubated for 7 days. Then, a culture medium cultured for 7 days was obtained (primary cDMEM culture medium), 50 ml of new cDMEM medium was added to the cell line cultured for 7 days, and further cultured for 7 days (14 days from the first seeding week) did. Then, on the 14th day from the first dispensing week, a culture solution was obtained (second cDMEM culture solution).
[제조예 4] L929-cDMEM 배지의 제조 [Preparation Example 4] Preparation of L929-cDMEM medium
상기 제조예 1의 cDMEM 배지 90 ml에, 상기 제조예 2의 1차 cDMEM 배양액 및 2차 cDMEM 배양액을 각각 5 ml씩 넣고 잘 섞어, L929-cDMEM 배지를 제조하였다.In 90 ml of the cDMEM medium of Preparation Example 1, 5 ml of each of the primary cDMEM culture medium and the secondary cDMEM culture medium of Preparation Example 2 were added and mixed well to prepare L929-cDMEM medium.
[제조예 5] L929-감염 배지의 제조 [Preparation Example 5] Preparation of L929-infection medium
90 ml의 상기 제조예 1의 감염 배지에 상기 제조예 3의 1차 cDMEM 배양액 및 2차 cDMEM 배양액을 각각 5 ml씩 넣고 잘 섞어 L929-감염 배지를 제조하였다.In 90 ml of the infection medium of Preparation Example 1, 5 ml each of the primary cDMEM culture medium and the secondary cDMEM culture medium of Preparation Example 3 were added and mixed well to prepare an L929-infection medium.
[제조예 6] 7H10 배지 제조 [Preparation Example 6] Preparation of 7H10 medium
450 ml의 증류수에 9.5 g의 7H10 가루를 넣고, 충분히 섞어준 뒤 121 ℃에서 15분 동안 열을 가하는 멸균 과정을 수행하고, 상기 멸균된 배지를 60 ℃까지 식힌 뒤에 50 ml의 OADC(Oleic Acid + Albumin + Dextrose + Catalase)를 넣었다. 이후, 상기 OADC가 포함된 배지를 100 파이 배양 접시에 22 ml 정도 붓고, 상온에서 하루 동안 방치하여 충분히 굳힌 뒤 추후 실험에 사용될 때까지 냉장보관 하였다.Add 9.5 g of 7H10 powder to 450 ml of distilled water, mix thoroughly, and perform a sterilization process by applying heat at 121 °C for 15 minutes, and after cooling the sterilized medium to 60 °C, 50 ml of OADC (Oleic Acid + Albumin + Dextrose + Catalase) was added. Then, about 22 ml of the medium containing the OADC was poured into a 100 pie culture dish, and left at room temperature for one day to harden sufficiently and then refrigerated until used for further experiments.
[실시예 1] [Example 1] 마우스 골수 유래 큰포식세포 분화Differentiation of mouse bone marrow-derived macrophages
7~9 주령의 C57BL/6J 암컷 마우스 또는 7~9 주령의 A/J 암컷 마우스의 대퇴골과 경골에 DMEM을 주사기로 흘려 넣어 골수 세포를 분리하였다. 상기 분리된 골수 세포를 상기 제조예 4에서 제조된 80 ml의 L929-cDMEM을 사용하여 충분히 현탁시켰다. 이후, 상기 골수 세포 현탁액을 100 파이 배양 접시 8개에 10 ml씩 분주하고, 5% CO2 37 ℃ 조건에서 배양하였다. 이렇게 배양한 지 3일 후에 L929-cDMEM을 상기 각각의 배양 접시에 10 ml씩 추가로 넣고, 배양 시작일로부터 7일째에 골수로부터 유래된 큰포식세포를 배양 접시에서 T/E를 이용하여 분리시킨 뒤 세포 개수를 세었다. 이후, 상기 분리된 큰포식세포를 48 웰 플레이트에 1.5× 105 세포수/0.5 ml의 양만큼 분주하고, 5% CO2, 37℃ 조건에서 밤새도록 배양하여 상기 큰포식세포가 바닥에 충분히 붙을 수 있도록 하였다.Bone marrow cells were isolated by injecting DMEM into the femur and tibia of 7-9 week-old C57BL/6J female mice or 7-9 week-old female A/J mice. The isolated bone marrow cells were sufficiently suspended using 80 ml of L929-cDMEM prepared in Preparation Example 4. Thereafter, 10 ml of the bone marrow cell suspension was dispensed into 8 100 pie culture dishes, and cultured at 5% CO 2 37 ° C. condition. After 3 days of culturing in this way, 10 ml of L929-cDMEM was additionally added to each culture dish, and macrophages derived from bone marrow were separated from the culture dish on the 7th day from the start of the culture using T/E. The number of cells was counted. Thereafter, the isolated macrophages are aliquoted in an amount of 1.5×10 5 cells/0.5 ml in a 48-well plate, and cultured overnight at 5% CO 2 , 37° C. to ensure that the macrophages are sufficiently attached to the bottom. made it possible
[실시예 2] [Example 2] 결핵균 또는 비결핵항산균에 의한 감염 방법Method of infection by Mycobacterium tuberculosis or Mycobacterium tuberculosis
결핵균의 경우 큰포식세포 1개당 2개의 비율, 및 비결핵항산균의 경우 큰포식세포 1개당 3개의 비율에 해당하는 균주가 감염될 수 있도록 계산하여, 계산된 수만큼의 균주를 상기 제조예 1의 감염 배지에 현탁시켰다. 그런 다음, 상기 실시예 1에서 큰포식세포가 분주된 48웰 플레이트를 PBS(phosphate buffered saline)를 이용하여 2차례 씻어준 뒤, 상기 플레이트에 상기 결핵균 또는 비결핵항산균이 현탁된 감염 배지를 0.5ml 넣고, 5% CO2, 37 ℃ 조건에서 4시간동안 배양하였다. 이후, PBS를 이용하여 상기 플레이트를 씻어준 뒤에 상기 제조예 5의 L929-감염 배지 0.5 ml를 넣었다.In the case of Mycobacterium tuberculosis, two ratios per macrophage, and in the case of non-tuberculous mycobacteria, three ratios per macrophage were calculated to be infected, and the calculated number of strains was prepared in Preparation Example 1 was suspended in the infection medium of Then, the 48-well plate in which macrophages were seeded in Example 1 was washed twice using PBS (phosphate buffered saline), and then the plate was mixed with an infection medium in which Mycobacterium tuberculosis or non-tuberculous mycobacterium was suspended in the plate. ml, and incubated at 5% CO 2 , 37 °C for 4 hours. After washing the plate using PBS, 0.5 ml of the L929-infection medium of Preparation Example 5 was added.
[실시예 3] [Example 3] 단백질 및 약물 처리 방법Protein and drug processing methods
상기 실시예 2에서 상기 결핵균 또는 비결핵항산균을 넣고 1일 동안 추가로 배양한 뒤, 상기 L929-감염 배지를 제거하고, 단백질 및 약물이 포함된 감염 배지를 0.5 ml씩 플레이트의 각 웰에 넣었다. 이때, 세포에 처리되는 약물 농도는 IFN-β의 경우 20 ng/ml로, 아미트립틸린(amitriptyline)의 경우 25 μM로, 그리고 데시프라민(Desipramine)의 경우 50μM의 농도로, 리팜핀(Rifampin)의 경우 10 ㎍/ml의 농도로 처리하였다.In Example 2, the Mycobacterium tuberculosis or mycobacterium tuberculosis was further cultured for 1 day, the L929-infection medium was removed, and 0.5 ml of the infection medium containing proteins and drugs was placed in each well of the plate. . At this time, the concentration of the drug treated to the cells is 20 ng/ml for IFN-β, 25 μM for amitriptyline, and 50 μM for desipramine, Rifampin. was treated at a concentration of 10 μg/ml.
[실시예 4] [Example 4] 큰포식세포에서 균주의 성장 확인 방법Method for confirming the growth of strains in macrophages
상기 실시예 3의 세포를 PBS를 이용하여 2회 씻어준 뒤, 플레이트의 각 웰에 0.2 ml의 0.05% 트립톤-×100을 넣고 배양하였다. 이후, 결핵균(Micobacterium tuberculosis; ATCC)으로 감염시킨 큰포식세포의 경우 0.05% 트립톤-×100 용액을 PBS를 1/10으로 2회 희석하여 최종적으로 1/100의 농도로 희석하였다. 또한, 비결핵항산균으로 감염시킨 큰포식세포의 경우 0.05% 트립톤-×100 용액을 PBS를 1/10으로 3회 희석하여 최종적으로 1/1000의 농도로 희석하였다. 이후, 이렇게 얻어진 상기 희석액 0.05 ml를 상기 제조예 6의 7H10 배지가 포함된 배양접시에 각각 접종한 뒤, 37 ℃에서 10 ~ 14일 동안 배양하였다. 배양이 완료되면 배양 접시에 발생된 콜로니의 개수를 측정하였다.After washing the cells of Example 3 twice with PBS, 0.2 ml of 0.05% tryptone-×100 was added to each well of the plate and incubated. Then, in the case of macrophages infected with Mycobacterium tuberculosis (ATCC), a 0.05% tryptone-×100 solution was diluted twice with 1/10 of PBS and finally diluted to a concentration of 1/100. In addition, in the case of macrophages infected with non-tuberculous mycobacteria, a 0.05% tryptone-x100 solution was diluted 3 times with 1/10 PBS and finally diluted to a concentration of 1/1000. Then, 0.05 ml of the diluted solution thus obtained was inoculated into a culture dish containing the 7H10 medium of Preparation Example 6, respectively, and then cultured at 37° C. for 10 to 14 days. When the culture was completed, the number of colonies generated in the culture dish was measured.
[[ 실시예Example 5] 5] 큰포식세포에서in macrophages IFNIFN -β에 의한 균주의 성장 증가 확인Confirmation of growth increase of strain by -β
상기 실시예 3 및 4에 기재된 방법에 따라, C57BL/6J 암컷 마우스 로부터 유래된 큰포식세포에 결핵균을 감염시키고, 20 ng/ml의 IFN-β 또는 PBS를 처리한지 5일째에 균주의 콜로니 개수를 확인하고, 상기 INF-β 또는 PBS를 처리한지 3일째에 질량분석법을 통해 큰포식세포내 존재하는 세라마이드의 양을 측정하여, 도 1의 A 및 B에 나타내었다.According to the method described in Examples 3 and 4 above, macrophages derived from C57BL/6J female mice were infected with Mycobacterium tuberculosis, and the number of colonies of the strain was counted on
도 1의 A에서 보는 바와 같이, PBS를 처리한 경우(Mtb)와 비교하여, IFN-β가 처리되었을 때(Mtb+IFN-β)에 큰포식세포에 감염된 결핵균에서 확인되는 콜로니의 개수가 2배 이상 증가되었다.As shown in FIG. 1A, compared to the case of PBS treatment (Mtb), when IFN-β was treated (Mtb+IFN-β), the number of colonies confirmed in Mycobacterium tuberculosis infected with macrophages was 2 more than doubled.
도 1의 B에서 보는 바와 같이, 결핵균이 감염되지 않은 큰포식세포에 PBS(Ctrl) 및 IFN-β(IFN-β)가 처리된 경우와, 결핵균이 감염된 큰포식세포(Mtb)에서는 세라마이드의 방출량이 100000 정도인 반면, 결핵균이 감연된 큰포식세포에 IFN-β가 처리되었을 때(Mtb+IFN-β)에는 세라마이드의 방출량이 300000로, 3배 증가 되었다.As shown in FIG. 1B, the amount of ceramide released in the case of treatment with Mycobacterium tuberculosis macrophages uninfected with PBS (Ctrl) and IFN-β (IFN-β), and macrophages infected with Mycobacterium tuberculosis (Mtb). On the other hand, when Mycobacterium tuberculosis-infected macrophages were treated with IFN-β (Mtb+IFN-β), the amount of ceramide released was 3 times increased to 300,000.
상기 결과를 통해, 큰포식세포에 감염된 결핵균은 IFN-β에 의해 증가되며, 세라마이드의 방출량을 현저히 증가시키는 것을 알 수 있다.Through the above results, it can be seen that Mycobacterium tuberculosis infected with macrophages is increased by IFN-β, and the amount of ceramide released is significantly increased.
[실시예 6] [Example 6] 큰포식세포에서 균주의 성장 억제 효과 확인Confirmation of the growth inhibitory effect of the strain in macrophages
상기 실시예 3에 기재된 방법에 따라, C57BL/6J 암컷 마우스 또는 A/J 암컷 마우스로부터 유래된 큰포식세포에 결핵균을 감염시키고, 20 ng/ml의 IFN-β 또는 PBS를 처리한 뒤에 25 μM의 아미트립틸린 또는 50μM의 데시프라민을 각각 처리한지 5일째에 상기 실시예 4에 기재된 방법을 통해 균주의 콜로니 개수를 확인하여 그 결과를 도 2의 A 및 B에 나타내었다.According to the method described in Example 3 above, macrophages derived from C57BL/6J female mice or A/J female mice were infected with Mycobacterium tuberculosis, treated with 20 ng/ml IFN-β or PBS, and then treated with 25 μM On the 5th day after each treatment with amitriptyline or 50 μM desipramine, the number of colonies of the strain was confirmed by the method described in Example 4, and the results are shown in FIGS. 2A and 2B.
도 2의 A 및 B에서 보는 바와 같이, C57BL/6J 암컷 마우스 또는 A/J 암컷 마우스로부터 유래된 큰포식세포에 감염된 결핵균에서 IFN-β에 의해 그 콜로니 개수가 증가되었다(Mtb+IFN-β). 반면, 이와 같이 IFN-β에 의해 콜로니 개수가 증가되는 현상은 아미트립틸린(Mtb+IFN-β+Ami) 및 데시프라민(Mtb+IFN-β+Desi)를 처리하였을 때 사라져, 결핵균의 콜로니 개수가 감소되었다(A). 나아가, IFN-β 신호가 많이 유발된다고 알려져 있는 A/J 암컷 마우스로부터 유래된 큰포식세포에서도 아미트립틸린(A/J+Mtb+ Ami) 및 데시프라민(A/J+Mtb+Desi)를 처리하였을 때 결핵균의 콜로니 개수가 감소되었다(B).As shown in A and B of Figure 2, the number of colonies was increased by IFN-β in Mycobacterium tuberculosis infected with macrophages derived from C57BL/6J female mice or A/J female mice (Mtb+IFN-β) . On the other hand, this phenomenon of increasing the number of colonies by IFN-β disappears when treated with amitriptyline (Mtb+IFN-β+Ami) and desipramine (Mtb+IFN-β+Desi), and colonies of Mycobacterium tuberculosis The number was reduced (A). Furthermore, macrophages derived from female A/J mice, which are known to induce a lot of IFN-β signaling, were also treated with amitriptyline (A/J+Mtb+Ami) and desipramine (A/J+Mtb+Desi). The number of colonies of Mycobacterium tuberculosis was reduced (B).
상기 결과를 통해 본 발명에 따른 삼환계 항우울제들은 IFN-β에 의해 성장이 증가되는 결핵균의 성장을 매우 효과적으로 억제하는 것을 알 수 있다.From the above results, it can be seen that the tricyclic antidepressants according to the present invention very effectively inhibit the growth of Mycobacterium tuberculosis, whose growth is increased by IFN-β.
[실시예 7] [Example 7] 큰포식세포에서 병용투여에 따른 균주의 성장 억제 효과 확인(1)Confirmation of the growth inhibitory effect of the strain according to the co-administration in macrophages (1)
상기 실시예 3에 기재된 방법에 따라, C57BL/6J 암컷 마우스로부터 유래된 큰포식세포에 결핵균을 감염시키고, 25 μM 또는 50 μM의 아미트립틸린이나, 데시프라민을 처리하면서, 병용투여 효과 확인을 위해 10 ㎍/ml의 리팜핀을 함께 처리한지 3일째에 상기 실시예 4에 기재된 방법을 통해 균주의 콜로니 개수를 확인하여 그 결과를 도 3에 나타내었다.According to the method described in Example 3 above, macrophage cells derived from C57BL/6J female mice were infected with Mycobacterium tuberculosis and treated with 25 μM or 50 μM of amitriptyline or desipramine, to confirm the effect of co-administration. To confirm the number of colonies of the strain through the method described in Example 4 on the third day after treatment with 10 μg/ml of rifampin for the purpose, the results are shown in FIG. 3 .
도 3에서 보는 바와 같이, 아미트립틸린 및 데시프라민을 단독으로 처리한 경우와 비교하여, 결핵 치료제인 리팜핀을 함께 처리하였을 때(+Rifampin) 균주의 콜로니 개수가 더욱 현저하게 감소되었다.As shown in FIG. 3 , compared with the case of treatment with amitriptyline and desipramine alone, the number of colonies of the strain was more remarkably reduced when rifampin, a tuberculosis treatment, was treated together (+Rifampin).
상기 결과를 통해, 본 발명에 따른 아미트립틸린 및 데시프라민은 기존에 사용되고 있는 결핵 치료제와 병용하여 사용되었을 때 결핵균의 성장을 더욱 현저하게 억제함으로써 단독으로 사용된 경우와 비교하여 결핵 치료에 시너지 효과가 발휘되도록 할 수 있음을 알 수 있다.Through the above results, amitriptyline and desipramine according to the present invention more significantly inhibit the growth of Mycobacterium tuberculosis when used in combination with an existing tuberculosis treatment agent, thereby synergistically treating tuberculosis compared to when used alone. It can be seen that it can be made effective.
[실시예 8] [Example 8] 큰포식세포에서 비결핵항산균의 성장 억제 효과 확인Confirmation of growth inhibitory effect of non-tuberculous mycobacteria in macrophages
상기 실시예 3에 기재된 방법에 따라, C57BL/6J 암컷 마우스로부터 유래된 큰포식세포에 비결핵항산균(Mycobacterium avium)을 감염시키고, 25 μM의 아미트립틸린 또는 50μM의 데시프라민을 각각 처리한지 5일째에 상기 실시예 4에 기재된 방법을 통해 비결핵항산균의 콜로니 개수를 확인하여 그 결과를 도 4에 나타내었다.According to the method described in Example 3, macrophages derived from C57BL/6J female mice were infected with Mycobacterium avium and treated with 25 μM of amitriptyline or 50 μM of desipramine, respectively. On the 5th day, the number of colonies of non-tuberculous mycobacterium was confirmed by the method described in Example 4, and the results are shown in FIG. 4 .
도 4에서 보는 바와 같이, 삼환계 항우울제를 처리하지 않은 경우에는 비결핵항산균의 콜로니 개수가 10 × 105 CFU/ml인 반면, 아미트립틸린 및 데시프라민을 처리한 경우(NTM+Ami; NTM+Desi)에는 콜로니 개수가 5 × 105 CFU/ml로 현저하게 감소되었다.As shown in FIG. 4 , when tricyclic antidepressants were not treated, the number of colonies of non-tuberculous mycobacteria was 10 × 10 5 CFU/ml, whereas amitriptyline and desipramine were treated (NTM+Ami; NTM). +Desi), the number of colonies was significantly reduced to 5 × 10 5 CFU/ml.
상기 결과를 통해 본 발명에 따른 삼환계 항우울제는 결핵균뿐만 아니라, 비결핵항산균에서도 그 자체로서 성장 억제에 현저한 효과를 갖는 것을 알 수 있다. 나아가, 기존의 결핵 치료제와 함께 병용하여 사용되었을 때에 결핵균 및 비결핵항산균 모두에서 그 성장 억제에 현저한 시너지 효과가 발휘될 수 있는 것을 예상할 수 있다.From the above results, it can be seen that the tricyclic antidepressant according to the present invention has a remarkable effect on growth inhibition by itself not only in Mycobacterium tuberculosis, but also in non-tuberculous Mycobacterium. Furthermore, it can be expected that a remarkable synergistic effect can be exerted on the growth inhibition of both Mycobacterium tuberculosis and Mycobacterium tuberculosis when used in combination with existing anti-tuberculosis therapeutics.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (14)
상기 결핵은 마이코박테리움 투베르쿨로시스(M. tuberculosis), 마이코박테리움 보비스(M. bovis), 마이코박테리움 보비스(M. bovis) BCG, 마이코박테리움 아프리카눔(M. africanum), 마이코박테리움 카네티(M. canetti), 마이코박테리움 카프라에(M. caprae), 마이코박테리움 마이크로티(M. microti) 및 K 균주(Mycobacterium tuberculosis K strain)로 이루어진 군으로부터 선택되는 적어도 하나의 감염에 의해 유발되는 것인, 결핵의 예방 또는 치료용 약학 조성물.The method of claim 1,
The tuberculosis is Mycobacterium tuberculosis (M. tuberculosis), Mycobacterium bovis (M. bovis), Mycobacterium bovis (M. bovis) BCG, Mycobacterium africanum (M. africanum) ), from the group consisting of Mycobacterium canetti (M. canetti), Mycobacterium caprae (M. caprae), Mycobacterium microti (M. microti) and K strain (Mycobacterium tuberculosis K strain) A pharmaceutical composition for the prevention or treatment of tuberculosis, which is caused by at least one infection selected.
상기 결핵은 안결핵, 피부 결핵, 부신 결핵, 신장 결핵, 부고환 결핵, 림프선 결핵, 후두 결핵, 중이 결핵, 장결핵, 다제내성 결핵, 폐결핵, 담결핵, 골결핵, 인후결핵, 임파선 결핵, 폐허증, 유방 결핵 및 척추 결핵으로 이루어진 군으로부터 선택되는 적어도 하나인 것인, 결핵의 예방 또는 치료용 약학 조성물.The method of claim 1,
The tuberculosis is ocular tuberculosis, skin tuberculosis, adrenal tuberculosis, renal tuberculosis, epididymal tuberculosis, lymph gland tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tuberculosis, pulmonary tuberculosis, biliary tuberculosis, bone tuberculosis, throat tuberculosis, lymph node tuberculosis, pulmonary tuberculosis, A pharmaceutical composition for preventing or treating tuberculosis, which is at least one selected from the group consisting of breast tuberculosis and spinal tuberculosis.
상기 비결핵항산균은 마이코박테리움 아비늄(Mycobacterium avium), 마이코박테리움 인트라셀룰레어(Mycobacterium intracellulare), 마이코박테리움 칸사시(Mycobacterium kansasii), 마이코박테리움 포푸이툼(Mycobacterium fortuitum) 및 마이코박테리움 압세수스(Mycobacterium abscessus)로 이루어진 군으로부터 선택되는 적어도 하나인 것인, 비결핵항산균 감염질환의 예방 또는 치료용 약학 조성물.6. The method of claim 5,
The non-tuberculous mycobacteria are Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium fortuitum ) and Mycobacterium abscessus (Mycobacterium abscessus) will be at least one selected from the group consisting of, a pharmaceutical composition for the prevention or treatment of non-tuberculous mycobacterium infectious diseases.
상기 비결핵항산균 감염질환은 폐질환, 림프절염, 피부·연조직·골감염증 및 파종성 질환(disseminated disease)으로 이루어진 군으로부터 선택되는 적어도 하나인 것인, 비결핵항산균 감염질환의 예방 또는 치료용 약학 조성물.6. The method of claim 5,
The non-tuberculous mycobacterium infectious disease is at least one selected from the group consisting of lung disease, lymphadenitis, skin, soft tissue, bone infection, and disseminated disease. pharmaceutical composition.
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