KR20190118754A - A pharmaceutical composition for promoting osteogenesis comprising cisapride - Google Patents
A pharmaceutical composition for promoting osteogenesis comprising cisapride Download PDFInfo
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- KR20190118754A KR20190118754A KR1020180042023A KR20180042023A KR20190118754A KR 20190118754 A KR20190118754 A KR 20190118754A KR 1020180042023 A KR1020180042023 A KR 1020180042023A KR 20180042023 A KR20180042023 A KR 20180042023A KR 20190118754 A KR20190118754 A KR 20190118754A
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- Prior art keywords
- bone
- cisapride
- pharmaceutical composition
- acid
- promoting
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/306—Foods, ingredients or supplements having a functional effect on health having an effect on bone mass, e.g. osteoporosis prevention
Abstract
Description
본 발명은 시사프라이드를 함유하는 인체 안전성이 우수한 골형성 촉진용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for promoting bone formation excellent in human safety containing cisapride.
뼈는 일생동안 지속적으로 변화하는 활동적인 조직이다. 뼈는 육안으로 외부의 피질골(치밀골)과 내부의 소주골(해면골, 스폰지뼈)로 구분하는데, 피질골은 물리적인 강도가 강하여 신체를 보호하고 지지하는 역할을 하고, 소주골은 충격을 흡수하거나 칼슘의 변화를 일정하게 유지하는 역할을 주로 한다.Bones are active tissues that change continuously throughout life. Bone is visually divided into external cortical bone (dense bone) and internal small bone (sponge bone, sponge bone). Cortical bone has strong physical strength to protect and support the body, and soju bone absorbs shock or calcium Mainly to keep the change constant.
뼈의 성장이 중단된 후에도 오래된 뼈는 파괴되어 없어지고(골 흡수), 새로운 뼈가 없어진 곳을 메우는 고정(골형성)이 일생동안 반복되는, 이러한 현상을 뼈의 재형성(remodeling)이라 한다. This phenomenon is called bone remodeling, in which old bones are destroyed (bone absorption) after the growth of bones has stopped (bone absorption), and the fixation (bone formation) that fills in where new bones are lost is repeated throughout life.
조골세포와 파골세포 사이의 상호작용이 균형을 이루어 골 흡수와 골형성이 균형을 이루어야 뼈의 항상성이 유지되고 혈액 속의 칼슘 농도가 일정하게 유지되는데, 혈액에 칼슘이 부족하게 되면 이를 보충하기 위하여 골 흡수가 증가되어 뼈의 칼슘을 혈액으로 방출하게 되며, 골 흡수가 지속되면 뼈가 약해져 골다공증과 같은 질환이 발생한다.The balance between osteoblasts and osteoclasts is balanced so that bone resorption and bone formation must be balanced to maintain bone homeostasis and to maintain a constant calcium concentration in the blood. The absorption is increased to release the calcium of the bone into the blood, and if the bone absorption continues, the bone is weakened, a disease such as osteoporosis occurs.
특히, 골다공증은 폐경에 따른 급격한 호르몬의 변화에 의한 파골세포(osteoclast)의 활성화에 따른 골흡수 증가로 나타나는 폐경 후 골다공증과, 노화가 되면서 조골세포(osteoblast)의 기능이 감소하여 골형성이 감소하는 노인성 골다공증으로 분류할 수 있다. In particular, osteoporosis is characterized by postmenopausal osteoporosis, which appears as an increase in bone resorption due to the activation of osteoclasts due to rapid hormonal changes following menopause, and osteoblasts as aging decreases osteoblast formation. It can be classified as senile osteoporosis.
골다공증으로 인한 골절은 심각한 활동 제한에 이르게 되고, 고관절 골절의 경우 약 15-35%의 높은 사망률과 관련되어 있기 때문에, 골다공증성 골절이 발생하기 이전에 골다공증의 진단과 치료가 중요하다.Since osteoporosis fractures lead to severe activity limitations and are associated with a high mortality rate of about 15-35% in hip fractures, the diagnosis and treatment of osteoporosis is important before osteoporotic fractures occur.
세계보건기구(WHO)에 따르면 미국에서 폐경기 이후 여성의 약 30%가 골다공증에 걸려있으며, 약 50%가 골감소증의 현상을 보이고 있고, 약 2,600만 명이 골다공증에 의한 골절 위험성을 내재하고 있는 것으로 보고되고 있다. 또한, 미국에서 이들 골다공증 환자는 매년 약 2%씩 증가할 것으로 예상되고 급속한 노령화가 진행되는 국내에서도 골다공증 환자가 급증하고 있다.According to the World Health Organization (WHO), in the United States, about 30% of women after menopause have osteoporosis, about 50% have osteopenia, and about 26 million people are at risk of osteoporosis fractures. have. In addition, in the United States, these osteoporosis patients are expected to increase by about 2% annually, and osteoporosis patients are rapidly increasing in Korea, where rapid aging is progressing.
골다공증 치료제는 골 흡수 저해제(antiresorptive drug)와 골형성 촉진제로 분류된다. 골 흡수 저해제는 파골세포의 형성과 활성을 조절하는 치료제로서 비스포스포네이트, 선택적 에스트로겐 수용체 조절자(SERMs), 칼시토닌 등이 있으며, 골형성 촉진제로서는 부갑상선 호르몬제(PTH), 불소제 등이 있다. Osteoporosis therapeutics are classified into antiresorptive drugs and osteogenic promoters. Bone resorption inhibitors include bisphosphonates, selective estrogen receptor modulators (SERMs), calcitonin, and the like, which regulate the formation and activity of osteoclasts, and parathyroid hormones (PTH) and fluorides.
골다공증 치료제 시장에서 가장 큰 시장을 차지하고 있는 비스포스포네이트 치료제는 식전 공복에 복용해야 하고 복용시 식도염, 식도 천공 등의 부작용이 발생하며 체내 흡수율이 낮다는 단점이 있다. The bisphosphonate drug, which occupies the largest market in the osteoporosis drug market, has to be taken on an empty stomach before meals, and side effects such as esophagitis and esophageal perforation occur when taking the drug.
선택적 에스트로겐 수용체 조절자로는 라록시펜, 드롤록시펜, 라소폭시펜 등이 있으나, 이들 치료제는 유방암 및 자궁암 유발 위험성을 증가시키는 부작용이 있다. Selective estrogen receptor modulators include raloxifene, droroxifene, and lasopoxifen, but these therapeutic agents have side effects that increase the risk of developing breast and uterine cancers.
또한, 칼시토닌 치료제는 고가이며 투여방법이 어렵고 칼슘 제제는 부작용은 적지만 골다공증 치료보다는 예방에 국한된다는 단점이 있다.In addition, calcitonin therapeutics are expensive and difficult to administer, and calcium preparations have fewer side effects, but are limited to prevention rather than osteoporosis treatment.
현재까지 개발된 골다공증 치료제들은 부갑상선 호르몬제를 제외하고는 골형성 작용이 미미하여 치료효과보다는 증상의 진행을 예방하는 효과에 그치고 있다. 또한, 골형성 효과를 갖는 부갑상선 호르몬제의 경우는 골형성을 촉진하여 치료효과를 얻을 수 있지만 장기 사용에 대한 안전성이 확립되지 않아 그 사용이 제한되고 있다. Except for parathyroid hormones, osteoporosis treatments developed to date have minimal bone formation and are only effective in preventing the progression of symptoms rather than therapeutic effects. In addition, in the case of parathyroid hormone having an osteogenic effect, it is possible to promote bone formation and obtain a therapeutic effect, but its use is limited because safety for long-term use is not established.
한편, 시사프라이드(Cisapride)는 위장관 계통의 운동성을 조절하여 그 기능을 정상화시키는데 널리 사용되는 약물로서 우수한 위장 운동 촉진작용을 가지며, 항도파민작용 활성이 없는 것으로 보고된 바 있다.Meanwhile, cisapride is a drug widely used to regulate the motility of the gastrointestinal tract and normalize its function, and has been reported to have excellent gastrointestinal motility and no antidopaminergic activity.
시사프라이드는 각종 위장 질환에서의 그 유용성은 이미 광범하게 보고된 바 있으나, 골 질환의 치료 용도나 관련된 활성은 알려진 바 없으며, 본 발명자들은 시사프라이드의 파골세포 특이적 활성을 규명함으로써 골 질환의 예방 및 치료 용도로서 활용하고자 하였다.Although cisapride has been widely reported in its usefulness in various gastrointestinal diseases, there is no known therapeutic use or related activity of bone diseases, and the present inventors have identified osteoclast-specific activity of cisapride to prevent bone diseases. And as therapeutic uses.
본 발명은 전술한 종래기술의 문제점을 해결하기 위하여 인체 안전성이 우수할 뿐만 아니라 파골세포의 분화를 선택적으로 억제하는 신규 화합물을 제공하는 것을 목적으로 한다.In order to solve the above-mentioned problems of the prior art, an object of the present invention is to provide a novel compound which not only has excellent human safety but also selectively inhibits the differentiation of osteoclasts.
또한, 본 발명은 상기 신규 화합물을 포함하는 골 질환 예방 및 치료용 조성물을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide a composition for preventing and treating bone diseases comprising the novel compound.
본 발명의 일 측면에 따르면, 하기 화학식 1의 화합물 또는 그의 약제학적으로 허용 가능한 염을 유효 성분으로 포함하는 골형성 촉진용 약학적 조성물이 제공된다.According to one aspect of the invention, there is provided a pharmaceutical composition for promoting bone formation comprising the compound of
[화학식 1][Formula 1]
일 실시예에 있어서, 상기 조성물은 RANKL(Receptor activator of NK-κκB ligand)에 의해 유도되는 파골세포 분화를 억제할 수 있다.In one embodiment, the composition may inhibit osteoclast differentiation induced by the receptor activator of NK-κκB ligand (RANKL).
일 실시예에 있어서, 상기 조성물은 조골세포 분화에 영향을 미치지 않을 수 있다.In one embodiment, the composition may not affect osteoblast differentiation.
일 실시예에 있어서, 상기 조성물은 골 질환 예방 또는 치료용일 수 있다.In one embodiment, the composition may be for the prevention or treatment of bone disease.
일 실시예에 있어서, 상기 골 질환은 골다공증, 골형성 부전증, 골연화증, 골량 감소증, 골절, 골 결손 및 고관절 감소증으로 이루어진 군으로부터 하나 이상 선택될 수 있다.In one embodiment, the bone disease may be selected from the group consisting of osteoporosis, osteopenia, osteomalacia, osteomalacia, bone loss, fractures, bone defects and hip reduction.
일 실시예에 있어서, 상기 조성물은 인공골, 인공관절, 골 고정재, 골 대체제, 골 수복재, 골 충진재 및 골 이식재로 이루어진 군으로부터 선택된 하나 이상의 물질에 사용될 수 있다.In one embodiment, the composition may be used in one or more materials selected from the group consisting of artificial bones, artificial joints, bone fixation, bone substitutes, bone restorations, bone fillers and bone grafts.
본 발명의 다른 측면에 따르면, 하기 화학식 1의 화합물 또는 그의 식품학적으로 허용 가능한 염을 유효 성분으로 포함하는 골 질환 예방 또는 개선용 건강기능식품이 제공된다.According to another aspect of the present invention, there is provided a health functional food for preventing or improving bone diseases, including the compound of
[화학식 1][Formula 1]
본 발명에 따르면, 상기 골형성 촉진용 조성물은 종래 위장 질환 치료에 활용되었는 바 인체 투여에 따른 위험성이 낮고, 파골세포의 분화를 선택적으로 억제하므로 골 질환 예방 및 치료에 유용하게 활용될 수 있다. According to the present invention, the composition for promoting bone formation is conventionally used in the treatment of gastrointestinal diseases, the risk of human administration is low, and since it selectively inhibits the differentiation of osteoclasts, it can be usefully used for preventing and treating bone diseases.
본 발명의 효과는 상기한 효과로 한정되는 것은 아니며, 본 발명의 상세한 설명 또는 특허청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.The effects of the present invention are not limited to the above-described effects, but should be understood to include all the effects deduced from the configuration of the invention described in the detailed description or claims of the present invention.
도 1은 시사프라이드의 파골세포에 대한 세포독성을 분석한 것이다. (A) 시사프라이드의 화학적 구조를 나타낸 것이다. (B) 1, 5 및 10 μμM의 시사프라이드를 24시간 동안 처리한 것이다. (C, D) 100 ng/mL의 RANKL의 존재 하에 시사프라이드를 처리하고 1일, 3일 및 5일 동안 배양한 것이다.
도 2는 시사프라이드의 RANKL 매개 TRAP-양성 MNC에 대한 효과를 분석한 것이다. (A, B) 1 및 5μμM의 시사프라이드를 처리하고 5일 동안 30 ng/mL의 MCSF 및 100 ng/mL의 RANKL와 함께 BMM을 배양한 후 TRAP 스테이닝한 결과이다.
도 3은 시사프라이드의 RANKL 매개 F-actin ring formation에 대한 효과를 분석한 것이다. (A, B) F-actin 링 형성(적색)은 FITC-phalloidin(녹색) 및 DAPI(청색)으로 스테이닝한 후 형광 현미경으로 관찰하였다.
도 4는 시사프라이드의 RANKL 매개 파골세포 유전자 발현에 대한 효과를 분석한 것이다. (A - D) 10 및 30μμM의 시사프라이드를 처리하고 3일 동안 30 ng/mL의 MCSF 및 100 ng/mL의 RANKL와 함께 BMM을 배양한 후 qRT-PCR을 통해 c-Fos, NF-ATc1, TRAP, 및 CTK 마커 유전자를 분석하였다.
도 5는 RANKL 매개 파골세포형성 과정에서 시사프라이드가 세포자멸에 미치는 영향을 분석한 것이다. (A, B) 세포자멸은 TUNEL(적색) 및 DAPI(청색)으로 스테이닝한 후 형광 현미경으로 관찰하였다.
도 6은 마우스 초대 두개관 전-조골세포에서 시사프라이드의 조골세포 분화에 대한 효과를 분석한 것이다. (A, B) ALP 활성을 측정한 것이다. (C) ARS(Alizarin red S) 스테이닝 결과이다.Figure 1 shows the cytotoxicity of cysapride on osteoclasts. (A) shows the chemical structure of cisapride. (B) 1, 5 and 10 μM cisapride were treated for 24 hours. (C, D) Cysapride was treated in the presence of 100 ng / mL RANKL and incubated for 1, 3 and 5 days.
FIG. 2 analyzes the effect of cisapride on RANKL mediated TRAP-positive MNCs. (A, B) TRAP staining after treatment of 1 and 5 μM cisapride and incubation of BMM with 30 ng / mL MCSF and 100 ng / mL RANKL for 5 days.
Figure 3 is an analysis of the effect of sisapride on RANKL-mediated F-actin ring formation. (A, B) F-actin ring formation (red) was observed by fluorescence microscopy after staining with FITC-phalloidin (green) and DAPI (blue).
Figure 4 analyzes the effect of cisapride on RANKL mediated osteoclast gene expression. (A-D) BMMs were treated with 10 and 30 μM cisapride and incubated with 30 ng / mL of MCSF and 100 ng / mL of RANKL for 3 days, then c-Fos, NF-ATc1, TRAP, and CTK marker genes were analyzed.
Figure 5 analyzes the effect of cisapride on apoptosis in the process of RANKL-mediated osteoclast formation. (A, B) Apoptosis was stained with TUNEL (red) and DAPI (blue) and observed by fluorescence microscopy.
Figure 6 analyzes the effect on the osteoblast differentiation of cisapride in the primary cranial pre-osteoblasts. (A, B) ALP activity was measured. (C) ARS (Alizarin red S) staining results.
이하에서는 첨부한 도면을 참조하여 본 발명을 설명하기로 한다. 그러나 본 발명은 여러 가지 상이한 형태로 구현될 수 있으며, 따라서 여기에서 설명하는 실시예로 한정되는 것은 아니다. 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 구비할 수 있다는 것을 의미한다.Hereinafter, with reference to the accompanying drawings will be described the present invention. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention. When a part is said to "include" a certain component, this means that it may further include other components, without excluding other components, unless specifically stated otherwise.
달리 정의되지 않는 한, 분자 생물학, 미생물학, 단백질 정제, 단백질 공학, 및 DNA 서열 분석 및 당업자의 능력 범위 안에서 재조합 DNA 분야에서 흔히 사용되는 통상적인 기술에 의해 수행될 수 있다. 상기 기술들은 당업자에게 알려져 있고, 많은 표준화된 교재 및 참고저서에 기술되어 있다.Unless defined otherwise, molecular biology, microbiology, protein purification, protein engineering, and DNA sequencing can be performed by conventional techniques commonly used in the field of recombinant DNA within the capabilities of those skilled in the art. These techniques are known to those skilled in the art and are described in many standardized textbooks and reference books.
본 명세서에 포함되는 용어를 포함하는 다양한 과학적 사전이 잘 알려져 있고, 당업계에서 이용가능하다. 본 명세서에 설명된 것과 유사 또는 등가인 임의의 방법 및 물질이 본원의 실행 또는 시험에 사용되는 것으로 발견되나, 몇몇 방법 및 물질이 설명되어 있다. 당업자가 사용하는 맥락에 따라, 다양하게 사용될 수 있기 때문에, 특정 방법학, 프로토콜 및 시약으로 본 발명이 제한되는 것은 아니다. Various scientific dictionaries that include the terms included herein are well known and available in the art. While any methods and materials similar or equivalent to those described herein are found to be used in the practice or testing herein, some methods and materials have been described. Depending on the context used by those skilled in the art, the present invention is not limited to specific methodologies, protocols, and reagents, because it can be used in a variety of ways.
본 명세서에서 사용되는 바와 같이, 단수형은 문맥이 명확하게 달리 지시하지 않으면 복수의 대상을 포함한다. 또한, 달리 지시된 바가 없으면, 핵산은 각각 왼쪽에서 오른쪽, 5'에서 3' 방향으로 씌여지고, 아미노산 서열은 왼쪽에서 오른쪽, 아미노에서 카르복실 방향으로 씌여진다. 이하 본 발명을 더욱 상세히 설명한다. As used herein, the singular encompasses the plural objects unless the context clearly dictates otherwise. Also, unless otherwise indicated, nucleic acids are written from left to right, 5 'to 3', respectively, and amino acid sequences are written from left to right, amino to carboxyl directions. Hereinafter, the present invention will be described in more detail.
본 발명의 일 측면에 따르면, 하기 화학식 1의 화합물 또는 그의 약제학적으로 허용 가능한 염을 유효 성분으로 포함하는 골형성 촉진용 약학적 조성물이 제공된다.According to one aspect of the invention, there is provided a pharmaceutical composition for promoting bone formation comprising the compound of
[화학식 1][Formula 1]
상기 화합물의 정식 화학명은 시스-4-아미노-5-클로로-N-[1-[3-(4-플루오로페녹시)프로필]-3-메톡시-4-피페리디닐]-2-메톡시벤즈아미드이며, 상기 시사프라이드는 두 거울상이성체의 라세미 혼합물이다.The official chemical name of the compound is cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-meth Oxybenzamide, the cisapride is a racemic mixture of the two enantiomers.
상기 시사프라이드의 각종 위장 질환에 대한 치료 효과가 보고된 바 있으나, 골형성 촉진 활성 또는 파골세포 분화에 대한 억제 활성은 아직 보고된 바 없다.Although the therapeutic effect of the cisapride on various gastrointestinal diseases has been reported, osteogenic activity or inhibitory activity against osteoclast differentiation has not been reported yet.
상기 화합물은 약제학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 상기 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용할 수 있다. The compound may be used in the form of a pharmaceutically acceptable salt, and as the salt, acid addition salts formed by pharmaceutically acceptable free acid may be useful.
상기 화합물은 당해 기술 분야에서 통상적인 방법에 따라 약제학적으로 허용되는 산 부가염을 형성할 수 있다. The compounds may form pharmaceutically acceptable acid addition salts according to methods conventional in the art.
유리산은 유기산 및 무기산이 사용될 수 있으며, 예컨대, 상기 무기산은 염산, 브롬산, 황산, 또는 인산 일 수 있으며, 상기 유기산은 구연산(Citric acid), 초산, 젖산, 주석산(Tartaric acid), 말레인산, 푸마르산(Fumaric acid), 포름산, 프로피온산(Propionic acid), 옥살산, 트리플루오로아세트산, 벤조산, 글루콘산, 메탄설폰산, 글리콜산, 숙신산(Succinic acid), 4-톨루엔설폰산, 벤젠설폰산, 살리실산, 니코틴산, 이소니코틴산, 피콜린산, 글루탐산 또는 아스파르트산일 수 있으나, 이에 제한되는 것은 아니다.The free acid may be an organic acid and an inorganic acid. For example, the inorganic acid may be hydrochloric acid, bromic acid, sulfuric acid, or phosphoric acid. The organic acid may be citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid. (Fumaric acid), formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, benzenesulfonic acid, salicylic acid, It may be, but is not limited to, nicotinic acid, isnicotinic acid, picolinic acid, glutamic acid, or aspartic acid.
상기 조성물은 RANKL(Receptor activator of NK-κκB ligand)에 의해 유도되는 파골세포 분화를 억제할 수 있고, 조골세포 분화에는 영향을 미치지 않을 수 있다.The composition may inhibit osteoclast differentiation induced by RANKL (Receptor activator of NK-κκB ligand) and may not affect osteoblast differentiation.
상기 RANKL은 파골세포 전구체 상에 발현되는 RANK 수용체에 결합하여, MAPK 경로를 포함한 다양한 신호 경로를 활성화하고, c-Fos 및 NFATc1와 같은 전사인자를 조절할 수 있다. The RANKL binds to RANK receptors expressed on osteoclast precursors, activates various signal pathways including the MAPK pathway, and regulates transcription factors such as c-Fos and NFATc1.
상기 시사프라이드는 RANKL에 의해 자극된 BMM 파골전구세포에서 파골세포 발생과 관련된 전사인자, NF-ATc1, TRAP, 및 CTK(cathepsin K)의 발현 수준을 선택적으로 감소시킬 수 있음에도 불구하고, 조골세포의 분화에는 영향을 미치지 아니할 수 있다.Although the cisapride may selectively reduce the expression levels of transcription factors, NF-ATc1, TRAP, and cathepsin K (CTK) associated with osteoclast development in RANKL-stimulated BMM osteoclast precursor cells, It may not affect differentiation.
즉, 통상적으로 골 형성을 촉진하는 물질의 경우 파골세포의 분화를 억제함과 동시에, 조골세포의 분화를 촉진시킴으로써 골 형성을 촉진할 수 있었으나, 상기 시사프라이드는 파골세포의 분화만을 선택적으로 억제하므로 질병의 증상이나 환자의 특성에 따라 유용하게 활용 가능하다.That is, in the case of a substance that promotes bone formation, in general, osteoclasts may be inhibited and at the same time, osteoblasts may be promoted by promoting differentiation of osteoblasts, but the cisapride selectively inhibits the differentiation of osteoclasts. It can be usefully used depending on the symptoms of the disease or the characteristics of the patient.
상기 화학식 1의 화합물은 반 댈레 쥐(Van Daele G.) 등에 의한 문헌[Drug Dev. Res., 8(1-4), 225-232(1986)], ES-2,019,047호 및 ES-0,076,530호에 개시된 바와 같이 시스-4-아미노-3-메톡시-1-피페리딘카복실산 에틸 에스테르를 출발물질로 하여 제조될 수 있으나, 합성 방법은 특별히 제한되지 않는다.The compound of
상기 조성물은 골 질환 예방 또는 치료용일 수 있고, 상기 골 질환은 대사성 골 질환 또는 정형외과적 골 질환일 수 있다.The composition may be for preventing or treating bone diseases, and the bone diseases may be metabolic bone diseases or orthopedic bone diseases.
상기 ““대사성 골 질환””은 파골세포의 과다한 생성 또는 활성으로 인해 나타나는 상태 또는 질병을 의미하는 것으로, 골량 저하 질환을 포함할 수 있다. 상기 골량 저하 질환이란 골밀도의 저하, 골조직의 연화 등의 증상을 수반하는 골량의 저하가 나타나는 상태 또는 질환을 의미한다.The "metabolic bone disease" refers to a condition or a disease that occurs due to excessive production or activity of osteoclasts, and may include a bone mass lowering disease. The bone loss-related disease refers to a condition or disease in which a decrease in bone mass accompanied by symptoms such as a decrease in bone density and softening of bone tissues occurs.
상기 골 질환은 골다공증, 골형성 부전증, 골연화증, 골량 감소증, 골절, 골 결손 및 고관절 감소증으로 이루어진 군으로부터 하나 이상 선택될 수 있으나, 이에 한정되는 것은 아니다.The bone disease may be selected from one or more selected from the group consisting of osteoporosis, osteopenia, osteomalacia, osteopenia, bone loss, fracture, bone defect, and hip reduction, but is not limited thereto.
상기 조성물은 인공골, 인공관절, 골 고정재, 골 대체제, 골 수복재, 골 충진재 및 골 이식재로 이루어진 군으로부터 선택된 하나 이상의 물질에 사용될 수 있다.The composition may be used in one or more materials selected from the group consisting of artificial bones, artificial joints, bone fixation, bone substitutes, bone restorations, bone fillers and bone grafts.
상기 골형성 촉진용 조성물은 골 질환 또는 치주질환의 예방 및 치료용으로 사용될 수 있으며, 인공골, 골 고정재, 골 대체제, 골 수복재, 골 충진재 또는 골 이식재에 적용되기 용이한 형태로 제조될 수 있다.The composition for promoting bone formation may be used for the prevention and treatment of bone disease or periodontal disease, and may be prepared in a form that is easy to be applied to artificial bone, bone fixation, bone substitute, bone restoration, bone filler or bone graft. .
예컨대, 상기 골 이식재나 골 대체체는 협의로는 골 조직 내의 공간을 충진하기 위하여 사용될 수도 있고, 광의로는 뼈나 치아의 일부를 대체하는데 사용될 수 있으므로, 상기 골형성 촉진용 조성물은 압착, 압축, 가압접촉, 패킹, 압박, 굳힘 등의 방법을 사용하여 퍼티, 페이스트, 주형 가능한 스트립, 블록, 칩 등의 형태로 사용될 수 있고, 화학적 첨가물을 이용하여, 겔, 과립, 페이스트, 정제, 펠렛 등의 형태로 제형화하여 사용될 수 있으며, 분말 형태로도 사용될 수 있다.For example, the bone graft material or bone substitute may be used to fill a space in bone tissue in consultation, and broadly used to replace a portion of bone or tooth, so that the bone formation composition may be compressed, compressed, It can be used in the form of putty, paste, moldable strip, block, chip, etc. by using pressure contact, packing, pressing, hardening, etc., and by using chemical additives, gels, granules, pastes, tablets, pellets, etc. It may be used in the form of a formulation, and may also be used in powder form.
상기 조성물은 경구적 전달, 비경구적 전달의 형태로 투여될 수 있다. 상기 조성물은 전신 또는 국소 투여될 수 있으며, 상기 투여는 경구 투여 및 비경구 투여를 포함할 수 있다. 상기 조성물은 적절한 투여 형태를 제공하도록 적합한 양의 약학적으로 허용되는 비히클 또는 담체와 함께 제형화될 수 있다.The composition may be administered in the form of oral delivery, parenteral delivery. The composition can be administered systemically or topically, and the administration can include oral and parenteral administration. The composition may be formulated with a suitable amount of pharmaceutically acceptable vehicle or carrier to provide a suitable dosage form.
상기 화합물을 포함하는 조성물은 약학 조성물의 제조에 사용되는 담체, 부형제 및 희석제를 더 포함할 수 있다.The composition comprising the compound may further comprise a carrier, excipient and diluent used in the preparation of the pharmaceutical composition.
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 또는 광물유를 들 수 있으나, 이에 한정되는 것은 아니다.The carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil, but are not limited thereto.
또한, 상기 조성물은 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제제화 하여 사용할 수 있다.In addition, the composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, suppositories, and sterile injectable solutions.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물에 적어도 하나 이상의 부형제, 예컨대, 전분, 칼슘카보네이트, 수크로스, 락토오스, 또는 젤라틴 등을 혼합하여 조제할 수 있다. 또한, 상기 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제가 사용될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, or gelatin in the compound. It can mix and prepare. In addition to the above excipients, lubricants such as magnesium styrate and talc may be used.
경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 사용될 수 있으며, 단순희석제인 물, 리퀴드 파라핀 외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Liquid preparations for oral administration may include suspensions, solutions, emulsions, syrups, and the like, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to simple diluents such as water and liquid paraffin. .
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 사용될 수 있다. 상기 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르가 사용될 수 있다. 상기 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴이 사용될 수 있다.Sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories can be used in the preparations for parenteral administration. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate may be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, and glycerogelatin may be used.
본 발명의 다른 측면에 따르면, 하기 화학식 1의 화합물 또는 그의 식품학적으로 허용 가능한 염을 유효 성분으로 포함하는 골 질환 예방 또는 개선용 건강기능식품이 제공된다.According to another aspect of the present invention, there is provided a health functional food for preventing or improving bone diseases, including the compound of
[화학식 1][Formula 1]
상기 건강기능식품은 건강기능식품에 관한 법률에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미할 수 있으며, 상기 기능성은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미할 수 있으나, 건강의 개선을 위한 목적으로 섭취하는 식품이라면 그 종류가 특별히 제한되는 것은 아니다.The health functional food may mean a food manufactured and processed using raw materials or ingredients having useful functions for the human body according to the law on health functional foods, and the functionalities may be used to adjust nutrients to the structure and function of the human body, It may mean ingestion for the purpose of obtaining a useful effect for health use, such as physiological action, but if the food is ingested for the purpose of improving the health is not particularly limited.
상기 건강기능식품은 정제, 과립, 분말, 캅셀, 액상의 용액 및 환으로 이루어진 군에서 선택된 어느 하나의 제형으로 제조될 수 있다.The health functional food may be prepared in any one formulation selected from the group consisting of tablets, granules, powders, capsules, liquid solutions, and pills.
상기 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 상기 식품 첨가물은 다른 규정이 없는 한 식품의약품 안정청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 적합성 여부를 판단할 수 있다. 상기 식품 첨가물 공전에 기재된 품목은 예컨대 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성물, 감색소, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류를 들 수 있다.The health functional food may include a conventional food additive, and the food additive may be in accordance with the standards and standards for the corresponding item in accordance with the General Regulations and General Test Law of the Food Additives Authorized by the Korea Food and Drug Administration unless otherwise specified. Compliance can be determined. The items described in the food additive orbital are, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid and cinnamon acid, natural additives such as dark blue pigment, crystalline cellulose, high pigment, guar gum, sodium L-glutamate preparations, noodle additives, Mixed preparations, such as a preservative preparation and a tar pigment preparation, are mentioned.
상기 건강기능식품은 골다공증을 포함하는 골 질환 예방 또는 개선을 위한 식품 및 음료 등에 다양하게 이용될 수 있으며, 예컨대, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강기능성 보조 식품, 식품 첨가제 등에 사용될 수 있다.The health functional food may be used in a variety of foods and drinks for preventing or improving bone diseases including osteoporosis, for example, various foods, beverages, gum, tea, vitamin complexes, health functional supplements, food additives, etc. Can be.
상기 건강기능식품은 골 질환의 예방 또는 개선을 목적으로, 전체 중량 대비 1.0 내지 10.0 중량%의 시사프라이드를 포함할 수 있다. 상기 시사프라이드의 함량이 1.0 중량% 미만이면 골 질환의 개선 효과가 충분히 구현되지 않을 수 있고 10.0 중량% 초과이면 제품 본연의 품질이 구현되지 않거나 비용 효율이 저하되고 예측되지 아니한 부작용을 유발할 수 있다.The health functional food may include 1.0 to 10.0% by weight of cisapride relative to the total weight for the purpose of preventing or improving bone disease. If the content of the cisapride is less than 1.0% by weight, the effect of improving bone disease may not be sufficiently realized. If the content of the cisapride is greater than 10.0% by weight, the inherent quality of the product may not be realized or the cost efficiency may be lowered and an unexpected side effect may be caused.
또한, 상기 건강기능식품은 골 질환의 예방 또는 개선을 목적으로 정제, 과립, 분말, 캅셀, 액상의 용액 및 환으로 이루어진 군에서 선택된 어느 하나의 제형으로 제조 및 가공될 수 있다. In addition, the health functional food may be prepared and processed in any one formulation selected from the group consisting of tablets, granules, powders, capsules, liquid solutions and pills for the purpose of preventing or improving bone diseases.
구체적으로 상기 정제 형태의 건강기능식품은 상기 화합물, 부형제, 결합제, 붕해제 및 다른 첨가제와의 혼합물을 통상의 방법으로 과립화한 후, 활택제 등을 넣어 압축 성형하거나, 상기 혼합물을 직접 압축 성형하여 제조할 수 있다. 또한, 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수 있으며, 필요에 따라 적당한 제피제로 제피할 수도 있다.Specifically, the health functional food in the form of tablets is a mixture of the compound, excipients, binders, disintegrants and other additives by granulation in a conventional manner, and then compression-molded with a lubricant, or directly compression-molded the mixture Can be prepared. In addition, the health functional food in the form of tablets may contain a mating agent and the like, if necessary, may be coated with a suitable coating agent.
상기 캅셀 형태의 건강기능식품 중 경질캅셀제는 통상의 경질캅셀에 상기 화합물 및 부형제 등의 첨가제와의 혼합물 또는 그의 입상물 또는 제피한 입상물을 충진하여 제조할 수 있으며, 연질캅셀제는 상기 화합물 및 부형제 등의 첨가제와의 혼합물을 젤라틴 등 캅셀기제에 충진하여 제조할 수 있다. 상기 연질캅셀제는 필요에 따라 글리세린 또는 솔비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.The hard capsules of the health functional food in the form of capsules may be prepared by filling a conventional hard capsule with a mixture of additives such as the compound and excipients or granules or peeled granules thereof, and the soft capsules may contain the compounds and excipients. The mixture with additives, such as these, can be prepared by filling in capsule bases, such as gelatin. The soft capsule agent may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, as necessary.
상기 환 형태의 건강기능식품은 상기 화합물, 부형제, 결합제, 붕해제 등의 혼합물을 적당한 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 적당한 제피제로 제피를, 또는 전분, 탈크 또는 적당한 물질로 환의를 입힐 수도 있다.The dietary supplement in the form of a cyclic form may be prepared by molding a mixture of the compound, excipient, binder, disintegrating agent, etc. in a suitable manner, and may be coated with sucrose or other suitable coating agent, or starch, talc, or a suitable substance. You can also give a favor.
상기 과립형태의 건강기능식품은 상기 화합물, 부형제, 결합제, 붕해제 등의 혼합물을 적당한 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다. The granular health functional food may be prepared by granulating a mixture of the compound, excipient, binder, disintegrating agent and the like in an appropriate manner, and may contain a flavoring agent, a copper, and the like as necessary.
또한, 상기 부형제, 결합제, 붕해제, 활택제, 교미제, 착향제 등에 대한 용어 정의는 당업계에 공지된 문헌에 기재된 것으로 그 기능 등이 동일 내지 유사한 것들을 포함할 수 있다. In addition, the definitions of the excipients, binders, disintegrants, glidants, copulation agents, flavoring agents and the like are described in documents known in the art and may include those having the same or similar functions.
이하 실시예를 통해, 본 발명을 더욱 상술하나 하기 실시예에 의해 본 발명이 제한되지 아니함은 자명하다.Through the following examples, the present invention will be described in more detail, but the present invention is not limited by the following examples.
실험예 1 : 시사프라이드의 파골세포에 대한 독성 평가Experimental Example 1 Evaluation of Toxicity of Cysapride to Osteoclasts
파골세포 분화에 있어서 시사프라이드의 잠재적 영향을 평가하고자 마우스 골수 세포 유래의 BMM(bone marrow macrophage)에서 시사프라이드의 파골세포 분화에 대한 세포독성 분석법(cytotoxicity assay)을 수행하였다(도 1A).To assess the potential effect of cisapride on osteoclast differentiation, a cytotoxicity assay for osteoclast differentiation of cisapride in mouse bone marrow cell-derived bone marrow macrophage (BMM) was performed (FIG. 1A).
MTT assay 결과 시사프라이드는 BMM에서 10 μμM의 농도까지 세포독성을 나타내지 않았으며(도 1B), 1 및 μμM 농도의 시사프라이드는 100 ng/mL의 RANKL을 처리한 파골세포 분화 상태에서도 세포독성을 나타내지 않았다(도 1C).In the MTT assay, cisapride did not show cytotoxicity to a concentration of 10 μM in BMM (FIG. 1B), and cisapride at 1 and μM concentrations showed no cytotoxicity even in osteoclast differentiation with 100 ng / mL of RANKL. (FIG. 1C).
실험예 2 : 시사프라이드의 파골세포 분화 억제 효과 평가Experimental Example 2 Evaluation of Inhibitory Effect of Cisapride on Osteoclast Differentiation
시사프라이드가 파골세포 분화에 미치는 영향을 분석하였다. 시사프라이드의 처리 유무 및 농도(1 내지 5 μμM)를 달리하고 BMM을 100 ng/mL의 RANKL에 의해 5일간 분화시켰다.The effect of cisapride on osteoclast differentiation was analyzed. BMMs were differentiated by 100 ng / mL RANKL for 5 days, with and without the treatment of cisapride and concentrations (1-5 μM).
5일간 RANKL(100ng/mL)에 의한 세포 분화시 TRAP(tartrate-resistant acid phosphatase) assay를 통해 파골세포 형성 정도를 분석하였다.Osteoblast formation was analyzed by TRAP (tartrate-resistant acid phosphatase) assay during cell differentiation by RANKL (100ng / mL) for 5 days.
도 2A 및 2B을 참조하면, 시사프라이드는 TRAP-양성 스테이닝(TRAP-positive staining)을 억제하였으며, 핵(nuclei) 대비 TRAP-양성 다핵 파골세포(MNCs)의 수를 감소시켰다.2A and 2B, cisapride inhibited TRAP-positive staining and reduced the number of TRAP-positive multinuclear osteoclasts (MNCs) relative to the nuclei.
또한, 파골세포의 골 흡수 기능에 있어서 세포골격 구조의 변화는 필수적이므로, RANKL에 의해 유도된 파골세포 분화 과정에서 F-actin ring formation assay를 수행하였다.In addition, since the change in the cytoskeletal structure is essential for the osteoclast uptake of osteoclasts, F-actin ring formation assay was performed during osteoclast differentiation induced by RANKL.
기능적 파골세포 활성을 평가하고자, FITC-phalloidin 및 DAPI로 파골세포를 스테이닝하였다. 현미경을 이용한 면역형광 분석법에 있어서, 시사프라이드는 RANKL에 의한 F-actin의 링 형성을 현저히 억제하였다(도 3A 및 3B). To assess functional osteoclast activity, osteoclasts were stained with FITC-phalloidin and DAPI. In the immunofluorescence assay using a microscope, cisapride significantly inhibited ring formation of F-actin by RANKL (FIGS. 3A and 3B).
파골세포 분화에 있어서 시사프라이드가 mRNA 발현에 미치는 영향을 분석하였다.The effect of cisapride on mRNA expression in osteoclast differentiation was analyzed.
BMM은 시사프라이드의 처리 유무 및 농도(1 및 5 μμM)를 달리하고 100 ng/mL의 RANKL에 의해 3일간 분화시켰다.BMM was differentiated by 100 ng / mL of RANKL for 3 days with and without the treatment of cisapride and the concentration (1 and 5 μM).
도 4를 참조하면, 시사프라이드는 RANKL에 의해 유도된 NF-ATc1, TRAP, 및 CTK(cathepsin K) 유전자의 발현을 하향 조절하였으나, c-Fos는 하향 조절하지 않았다.Referring to FIG. 4, cisapride down-regulated the expression of the NF-ATc1, TRAP, and CTK (cathepsin K) genes induced by RANKL, but did not down-regulate c-Fos.
또한, 시사프라이드 매개의 파골세포 분화 억제 활성이 세포자멸(apoptosis)과 관련되는지 확인하였다.In addition, it was confirmed whether the inhibitory activity of cysapride-mediated osteoclast differentiation was associated with apoptosis.
BMM에 시사프라이드를 처리하고, TUNEL assay를 통해 DNA 분절화(DNA fragmentation) 현상을 관찰하였다.Cysapride was treated with BMM, and DNA fragmentation was observed through TUNEL assay.
농도-의존적으로 TUNEL-양성 세포가 형광현미경법에 의해 관찰되었으며(도 5A), RANKL을 처리한 세포 대비 시사프라이드를 처리한 세포에서 사멸세포(apoptotic cell) 비율이 증가하였다.Concentration-dependent TUNEL-positive cells were observed by fluorescence microscopy (FIG. 5A), and the ratio of apoptotic cells was increased in cells treated with cisapride compared to cells treated with RANKL.
상기 결과는 시사프라이드가 초기 배양된 마우스 BMM에서 RANKL에 의해 유도된 파골세포 분화를 효과적으로 억제할 수 있으며, 이는 세포 자멸에 의해 유도됨을 시사한다.The results suggest that cisapride can effectively inhibit osteoclast differentiation induced by RANKL in early cultured mouse BMM, which is induced by apoptosis.
실험예 3 : 시사프라이드의 조골세포에 대한 독성 평가Experimental Example 3 Evaluation of Toxicity of Cysapride on Osteoblasts
조골세포 분화에 있어서 시사프라이드의 잠재적 영향을 평가하고자 마우스 두개관 전-조골세포(calvarial pre-osteoblast)에서 세포독성 분석법(cytotoxicity assay)을 수행하였다.To assess the potential effect of cisapride on osteoblast differentiation, a cytotoxicity assay was performed on calvarial pre-osteoblasts.
MTT assay 결과 시사프라이드는 두개관 전-조골세포에 세포 독성을 나타내지 않았으며(도 4A), 5일 동안 골 형성 보충 배지(50 μμg/mL의 L- 아스코르빈산 및 10 mM의 베타-글리세롤포스페이트 함유)의 조골세포 분화 상태에서도 세포독성을 나타내지 않았다.The cisapride showed no cytotoxicity to the cranial pre-osteoblasts from the MTT assay (FIG. 4A), and bone formation supplementation medium (50 μg / mL of L-ascorbic acid and 10 mM beta-glycerolphosphate for 5 days). ) Did not show cytotoxicity even in osteoblast differentiation.
실험예 4 : 시사프라이드의 조골세포 분화 촉진 효과 평가Experimental Example 4: Evaluation of the effect of cisapride to promote osteoblast differentiation
시사프라이드의 처리 유무 및 농도를 달리하여 시사프라이드가 조골세포 분화에 미치는 영향을 분석하였다.The effect of cisapride on osteoblast differentiation was analyzed by varying the presence and the concentration of cisapride.
조골세포 분화에 대한 시사프라이드의 영향을 분석하고자 초기 조골세포 분화 마커로서 알칼리 포스파타아제 효소 활성(ALP enzymatic activity)을 측정하였다.To analyze the effect of cisapride on osteoblast differentiation, alkaline phosphatase enzyme activity (ALP enzymatic activity) was measured as an early osteoblast differentiation marker.
도 5를 참조하면, 시사프라이드는 알칼리 포스파타아제 활성에 영향을 미치지 않았다(도 5A).Referring to FIG. 5, cisapride did not affect alkaline phosphatase activity (FIG. 5A).
또한, 후기 조골세포 분화 마커로서 14일 경과 후 ARS 스테이닝을 측정함으로써 석회화 결절 형성(mineralized nodule formation) 정도를 평가하였다.In addition, the degree of mineralized nodule formation was evaluated by measuring ARS staining after 14 days as a late osteoblast differentiation marker.
알칼리 포스파타아제 효소 활성 평과 결과와 마찬가지로, 시사프라이드는 석회화 결절 형성에 영향을 미치지 않았다(도 6C).Like the results of the alkaline phosphatase enzyme activity assessment, cisapride did not affect the formation of calcified nodules (FIG. 6C).
석회화 결절 형성에 대한 정량은 통계적으로 시사프라이드의 조골세포 분화에 대한 효과를 뒷받침하며, 상기 결과는 시사프라이드가 조골세포의 분화에 영향을 미치지 아니함을 시사한다.Quantification of calcified nodule formation statistically supports the effect of cisapride on osteoblast differentiation, and the results suggest that cisapride does not affect osteoblast differentiation.
본 발명자들은 시사프라이드가 초대 배양된 BMM에서 RANKL에 의해 유도된 파골세포 분화를 저해시키는 반면, 두개관 전-조골세포에서 조골세포의 분화에는 영향을 미치지 아니함을 확인하였다.The inventors confirmed that cisapride inhibited osteoclast differentiation induced by RANKL in primary cultured BMM, but did not affect osteoblast differentiation in cranial pre-osteoblasts.
즉, 시사프라이드는 파골세포발생과 관련된 전사인자 c NF-ATc1, TRAP, 및 CTK(cathepsin K)의 하향 조절을 통해 선택적으로 RANKL에 의해 유도된 파골세포 분화를 저해시켰으나 조골세포의 분화에는 영향을 미치지 아니하였으므로 질병의 증상이나 환자의 특성에 따라 골 질환의 치료의 용도로서 유용하게 활용 가능할 것이다.That is, cisapride inhibited osteoclast differentiation induced by RANKL selectively through down-regulation of transcription factors c NF-ATc1, TRAP, and CTK (cathepsin K) related to osteoclastogenesis, but did not affect osteoblast differentiation. Since it is not insane, it may be usefully used as a treatment for bone disease according to the symptoms of the disease and the characteristics of the patient.
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 foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in 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 exemplary in all respects and not restrictive. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.
본 발명의 범위는 후술하는 특허청구범위에 의하여 나타내어지며, 특허청구범위의 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 represented by the following claims, and it should be construed that all changes or modifications derived from the meaning and scope of the claims and their equivalents are included in the scope of the present invention.
Claims (7)
[화학식 1]
[Formula 1]
RANKL(Receptor activator of NK-κκB ligand)에 의해 유도되는 파골세포 분화를 억제하는 골형성 촉진용 약학적 조성물.The method of claim 1,
Pharmaceutical composition for promoting bone formation that inhibits osteoclast differentiation induced by RANKL (Receptor activator of NK-κκB ligand).
조골세포 분화에 영향을 미치지 않는 골형성 촉진용 약학적 조성물.The method of claim 1,
A pharmaceutical composition for promoting bone formation that does not affect osteoblast differentiation.
골 질환 예방 또는 치료용인 골형성 촉진용 약학적 조성물.The method of claim 1,
A pharmaceutical composition for promoting bone formation for preventing or treating bone diseases.
상기 골 질환은 골다공증, 골형성 부전증, 골연화증, 골량 감소증, 골절, 골 결손 및 고관절 감소증으로 이루어진 군으로부터 하나 이상 선택된 골형성 촉진용 약학적 조성물.The method of claim 4, wherein
The bone disease is at least one selected from the group consisting of osteoporosis, osteopenia, osteomalacia, osteopenia, bone loss, fracture, bone defect and hip joint reduction pharmaceutical composition for promoting bone formation.
인공골, 인공관절, 골 고정재, 골 대체제, 골 수복재, 골 충진재 및 골 이식재로 이루어진 군으로부터 선택된 하나 이상의 물질에 사용되는 골형성 촉진용 약학적 조성물.The method of claim 1,
A pharmaceutical composition for promoting bone formation used in at least one material selected from the group consisting of artificial bones, artificial joints, bone fixation, bone substitutes, bone restorations, bone fillers and bone grafts.
[화학식 1]
[Formula 1]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020180042023A KR20190118754A (en) | 2018-04-11 | 2018-04-11 | A pharmaceutical composition for promoting osteogenesis comprising cisapride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020180042023A KR20190118754A (en) | 2018-04-11 | 2018-04-11 | A pharmaceutical composition for promoting osteogenesis comprising cisapride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20190118754A true KR20190118754A (en) | 2019-10-21 |
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ID=68460552
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020180042023A KR20190118754A (en) | 2018-04-11 | 2018-04-11 | A pharmaceutical composition for promoting osteogenesis comprising cisapride |
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| Country | Link |
|---|---|
| KR (1) | KR20190118754A (en) |
-
2018
- 2018-04-11 KR KR1020180042023A patent/KR20190118754A/en not_active Application Discontinuation
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