KR102081230B1 - Pharmarceutical composition for preventiing or treating of bone related disorder - Google Patents
Pharmarceutical composition for preventiing or treating of bone related disorder Download PDFInfo
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- KR102081230B1 KR102081230B1 KR1020180055737A KR20180055737A KR102081230B1 KR 102081230 B1 KR102081230 B1 KR 102081230B1 KR 1020180055737 A KR1020180055737 A KR 1020180055737A KR 20180055737 A KR20180055737 A KR 20180055737A KR 102081230 B1 KR102081230 B1 KR 102081230B1
- Authority
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- South Korea
- Prior art keywords
- bone
- osteoporosis
- pharmaceutical composition
- osteoblasts
- differentiation
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- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A—HUMAN NECESSITIES
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Abstract
본 발명은 골 관련 질환의 예방 또는 치료를 위한 약학 조성물에 관한 것으로, 전조골세포의 조골세포로의 분화를 촉진하여 석회화 결절의 생성을 유도할 뿐만 아니라, 동시에 골수세포의 파골세포로의 분화를 억제하고, 파골세포의 기능을 억제함으로써 골 항상성을 효과적으로 조절하여 골 관련 질환의 예방 또는 치료에 매우 효과적이다.The present invention relates to a pharmaceutical composition for the prevention or treatment of bone-related diseases, and promotes the differentiation of progenitor osteoblasts into osteoblasts to induce the production of calcified nodules, as well as the differentiation of bone marrow cells into osteoclasts It is effective in preventing or treating bone-related diseases by effectively controlling bone homeostasis by inhibiting the function of osteoclasts.
Description
본 발명은 골 관련 질환의 예방 또는 치료를 위한 약학 조성물에 관한 것이다.The present invention relates to pharmaceutical compositions for the prevention or treatment of bone related diseases.
대표적인 골 관련 질환인 골다공증은, 뼈를 흡수하는 파골세포와 뼈를 형성하는 조골세포의 골 항상성 조절 불균형으로 인해 발생하는 질환으로, 골절 위험성이 증가될 수 있는 약해진 골강도를 특징으로 하는 골격 장애를 말한다(미국 국립보건원 정의 NIH, 2000).Osteoporosis, a typical bone-related disease, is a disorder caused by bone homeostasis control imbalance between osteoclasts that absorb bone and osteoblasts that form bone, and refers to skeletal disorders characterized by weakened bone strength that may increase the risk of fracture. (US National Institutes of Health NIH, 2000).
상기 골 항상성 조절의 불균형은 노화, 전신질환, 폐경 등의 원인으로 인하여 발생할 수 있으며, 골밀도가 감소하고 골조직의 미세구조가 퇴화해 골절위험증가를 보이는 전신 질환에 해당한다. 즉, 낡은 뼈의 소멸과 새로운 뼈의 생성이 균형있게 유지되면서 골밀도가 유지되는데 노화, 폐경 등으로 새로운 뼈의 대체가 원활히 이루어지지 않아 뼈가 엉성해지고 이런 과정이 반복되면서 뼈가 얇아지고 부러지거나 부서질 위험성이 커지게 되는 것이다. Imbalance in the regulation of bone homeostasis may occur due to aging, systemic diseases, menopause, etc., and it corresponds to a systemic disease in which bone density decreases and the microstructure of bone tissue degenerates, thereby increasing the risk of fracture. In other words, the bone density is maintained as the old bones disappear and the formation of new bones is balanced, and the replacement of new bones due to aging, menopause, etc. is not made smoothly, and the bones become thin and broken or broken as this process is repeated. The risk of quality increases.
골다공증은 정상적인 활동을 유지하는데 뼈의 칼슘량이 줄어드는 등 필요한 골량이 감소되어, 즉, 골밀도가 감소되어 가벼운 충격에도 쉽게 골절이 유발되는 질환이다. 상기 골다공증으로 진행되기 전 상태를 골감소증이라고 하며, 뼈의 두께 등이 계속 얇아지고 가벼워 지면서 구멍이 뚫리기 전까지의 상태를 의미한다. 또한, 골연화증은 비타민 D가 부족하거나 칼슘을 대량으로 배설하는 신장질환이 있는 경우 뼈에 칼슘이 섞이지 않아 물렁뼈가 생겨버리는 상태로 뼈가 구부러지는 증상을 의미한다. 또한, 골 위축은 뼈의 퇴행 축소, 즉, 이미 완성된 골 조직의 골량이 줄어드는 증상을 의미한다.Osteoporosis is a disease in which bone mass required for maintaining normal activity is reduced, such as a decrease in the amount of calcium in the bone, that is, bone density is reduced, and fracture is easily caused even by a light impact. The state before the progression to osteoporosis is called osteopenia, the thickness of the bone and the like until it continues to become thinner and lighter means a state before the opening. In addition, osteomalacia is a condition in which bone is bent in a state in which a bone is formed because calcium is not mixed in bone when there is a kidney disease in which vitamin D is deficient or a large amount of calcium is excreted. In addition, bone atrophy refers to a symptom of degeneration of bone, that is, a decrease in bone mass of bone tissue that has already been completed.
인체 내 뼈의 양은 조골세포와 파골세포의 균형에 의해 골 항상성 조절을 통해 유지되므로 이들 세포에서 중요한 역할을 하는 분자들을 표적으로 한 치료제 개발이 중요하다. 즉, 뼈를 형성하는 조골세포의 활성이 감소하고 뼈를 흡수하는 파골세포의 활성이 증가하게 되면, 뼈의 분해가 촉진, 뼈가 얇아지고 쉽게 부러지는 골다공증과 같은 질병이 일어나게 되므로, 조골세포 및 파골 세포의 활성을 조절할 수 있는 단백질들이 골 질환의 치료제로서 연구되고 있다(Gregory R. Mundy, Journal of Bone and Mineral Metabolism (1996) 14:59-64; Chad Deal, nature clinical practice RHEUMATOLOGY (2009) vol 5 no 1; Kalervo Vaananen, Advanced Drug Delivery Reviews 57 (2005) 959-971). 그러나 현재 시판되는 골다공증 치료 약물은 parathyroid hormone을 제외하고 대부분 파골세포 활성을 억제하는 약물이며, 이에 조골세포를 타겟으로 하는 약물 개발이 절실한 상황이다.Since the amount of bone in the human body is maintained through the regulation of bone homeostasis by the balance between osteoblasts and osteoclasts, it is important to develop therapeutics targeting molecules that play an important role in these cells. That is, when the activity of osteoblasts that form bone decreases and the activity of osteoclasts that absorb bone increases, diseases such as osteoporosis that promote bone breakdown, thinner and easily broken bones, and osteoblasts occur. Proteins that can regulate the activity of osteoclasts are being studied as therapeutic agents for bone disease (Gregory R. Mundy, Journal of Bone and Mineral Metabolism (1996) 14: 59-64; Chad Deal, nature clinical practice RHEUMATOLOGY (2009) vol 5
한편, 스테롤 황산염에 해당하는 콜레스테롤 황산염은 세포막을 이루는 구성 성분 중 하나로, 혈액 및 피부 등에 높은 농도로 존재하고 있으나, 현재까지 면역 기능과 피부 세포로의 분화와 관련된 기능의 일부만이 밝혀졌을 뿐, 생체 내 역할에 대해 명확히 보고된 바 없다.Meanwhile, cholesterol sulfate, which corresponds to sterol sulfate, is one of the constituents of cell membranes, and is present in high concentrations in blood and skin. However, only a part of functions related to immune function and differentiation into skin cells have been revealed. My role has not been clearly reported.
본 발명의 일 목적은 스테롤 황산염을 유효성분으로 포함하는 골 관련 질환의 예방 또는 치료용 약학 조성물을 제공하는 것이다.One object of the present invention to provide a pharmaceutical composition for the prevention or treatment of bone-related diseases comprising sterol sulfate as an active ingredient.
본 발명의 다른 목적은 스테롤 황산염을 유효성분으로 포함하는 골 관련 질환의 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention to provide a food composition for the prevention or improvement of bone-related diseases comprising sterol sulfate as an active ingredient.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task not mentioned will be clearly understood by those skilled in the art from the following description.
본 발명자들은 조골세포에 의한 골 형성을 증가시키고, 파골세포에 의한 골 흡수를 억제 시키는 효과를 동시에 발휘하는 약물은 보고된 바 없어, 상기와 같은 화합물에 대해 연구를 거듭한 결과, 스테롤 황산염, 특히 [(3S,8S,9S,10R,13R,14S,17R)-10,13-디메틸-17-[(2R)-6-메틸헵탄-2-일]-2,3,4,7,8,9,11,12,14,15,16,17-도데카하이드로-1H-사이클로펜타[[a]페난트렌-3-일] 하이드로젠 설페이트 ([(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] hydrogen sulfate)가 골 항상성을 조절하는 과정을 통해 골 관련 질환의 치료 및 예방에 현저한 효과가 존재하여 본 발명을 완성하게 되었다.The inventors of the present invention have not been reported to increase the bone formation caused by osteoblasts and to suppress the bone resorption by osteoclasts, and as a result of repeated studies on such compounds, sterol sulfates, in particular, [(3S, 8S, 9S, 10R, 13R, 14S, 17R) -10,13-dimethyl-17-[(2R) -6-methylheptan-2-yl] -2,3,4,7,8, 9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta [[a] phenanthren-3-yl] hydrogen sulfate ([(3S, 8S, 9S, 10R, 13R, 14S , 17R) -10,13-dimethyl-17-[(2R) -6-methylheptan-2-yl] -2,3,4,7,8,9,11,12,14,15,16,17- Through the process of dodecahydro-1H-cyclopenta [a] phenanthren-3-yl] hydrogen sulfate to regulate bone homeostasis, there is a remarkable effect in the treatment and prevention of bone-related diseases to complete the present invention.
본 발명의 일 구현 예는 스테롤(Sterol) 황산염을 유효성분으로 포함하는 골 관련 질환의 예방 또는 치료용 약학 조성물을 제공한다.One embodiment of the present invention provides a pharmaceutical composition for the prevention or treatment of bone-related diseases comprising a sterol sulfate as an active ingredient.
본 발명에서 상기 스테롤(Sterol)은 스테로이드 알코올의 줄임말로, 스테로이드계 화합물의 유기분자를 의미한다. 대부분의 식물과 동물, 곰팡이류에서 발견될 수 있는 것으로 보고되어 있으며, 진핵 생명체에 중요한 생리적 기능, 예를 들면 동물 세포의 막을 구성하거나 유동성에 영향을 미치고, 2차 신호전달자 등으로 작용할 수 있다. 본 발명의 목적상 상기 스테롤은 식물성 스테롤인 캄페스테롤(Campesterol), 시토스테롤(Sitosterol), 및 스티그마스테롤(Stigmasterol)과, 동물성 스테롤인 콜레스테롤(Cholesterol)의 황산염일 수 있다. 바람직하게는 상기 스테롤 황산염은 콜레스테롤 황산염으로, 하기 화학식 1로 표시되는 화합물인[(3S,8S,9S,10R,13R,14S,17R)-10,13-디메틸-17-[(2R)-6-메틸헵탄-2-일]-2,3,4,7,8,9,11,12,14,15,16,17-도데카하이드로-1H-사이클로펜타[[a]페난트렌-3-일] 하이드로젠 설페이트 ([(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] hydrogen sulfate)일 수 있으나, 이에 제한되는 것은 아니다:In the present invention, the sterol (Sterol) is short for steroid alcohol, it means an organic molecule of the steroid compound. It is reported that it can be found in most plants, animals and fungi, and can play important physiological functions in eukaryotic organisms, such as the composition of membranes or the fluidity of animal cells, and secondary signaling. For the purposes of the present invention, the sterols may be sulfates of vegetable sterols, Campesterol, Sitosterol, and Stigmasterol, and animal sterols, Cholesterol. Preferably, the sterol sulfate is cholesterol sulfate, which is a compound represented by the following Formula 1 [(3S, 8S, 9S, 10R, 13R, 14S, 17R) -10,13-dimethyl-17-[(2R) -6 -Methylheptan-2-yl] -2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta [[a] phenanthrene-3- Japanese] hydrogen sulfate ([(3S, 8S, 9S, 10R, 13R, 14S, 17R) -10,13-dimethyl-17-[(2R) -6-methylheptan-2-yl] -2,3,4 , 7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-3-yl] hydrogen sulfate), but is not limited to:
[화학식 1][Formula 1]
본 발명의 다른 구체 예에서는 [(3S,8S,9S,10R,13R,14S,17R)-10,13-디메틸-17-[(2R)-6-메틸헵탄-2-일]-2,3,4,7,8,9,11,12,14,15,16,17-도데카하이드로-1H-사이클로펜타[[a]페난트렌-3-일] 하이드로젠 설페이트 ([(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] hydrogen sulfate)을 유효성분으로 포함하는 골 관련 질환의 예방 또는 치료용 약학 조성물을 제공한다.In another embodiment of the invention [(3S, 8S, 9S, 10R, 13R, 14S, 17R) -10,13-dimethyl-17-[(2R) -6-methylheptan-2-yl] -2,3 , 4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta [[a] phenanthren-3-yl] hydrogen sulfate ([(3S, 8S, 9S, 10R, 13R, 14S, 17R) -10,13-dimethyl-17-[(2R) -6-methylheptan-2-yl] -2,3,4,7,8,9,11,12,14 It provides a pharmaceutical composition for the prevention or treatment of bone-related diseases comprising, 15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-3-yl hydrogen sulfate) as an active ingredient.
단, 본 발명에서 상기 화학식 1로 표시되는 화합물은 인체 내에서 순환되는 스테로이드 황산염인 DHEAS(Dehydroepiandrosterone sulfate)과 동일한 농도로 존재하며, 세포막의 구성성분으로 삼투성 용해로부터 적혈구를 보호하고, 정자의 수용체를 조절하는 성분일 뿐만 아니라, 세포 신호 전달, 혈액응고, 섬유소 용해, 및 표피 세포 부착과 관련된 활성을 조절한다(J Lipid Res. 2003 Jul;44(7):1268-78).However, in the present invention, the compound represented by Chemical Formula 1 is present at the same concentration as DHEAS (Dehydroepiandrosterone sulfate), a steroid sulfate circulating in the human body, and protects red blood cells from osmotic lysis as a component of cell membrane, and the sperm receptor Not only is it a component that modulates but also modulates activities associated with cell signal transduction, coagulation, fibrin lysis, and epidermal cell adhesion (J Lipid Res. 2003 Jul; 44 (7): 1268-78).
본 발명에서 상기 골 관련 질환은 신체 내에서 뼈를 생성하는 역할을 하는 조골세포 (osteoblast)와 뼈를 파괴하는 역할을 하는 파골세포(osteoclast) 간의 활성에 조화가 깨어지게 되면서 초래될 수 있다.In the present invention, the bone-related disease may be caused while the harmony between the osteoblasts (osteoblast), which plays a role of producing bone, and the osteoclasts (osteoclast), which plays a role of destroying bone, in the body.
본 발명에서 상기 파골 세포(osteoclast)는 뼈가 성장하는 과정에서 불필요하게 된 뼈조직을 파괴 또는 흡수하는 대형의 다핵 세포이며, 성숙된 파골세포는 다핵 세포이며 조혈모세포를 기원으로 분화되어 형성된다. 또한, 중간엽 간세포에서 분화된 조골세포는 약 34개월간 생존하여 활성화된 파골세포가 낡은 뼈를 분해 시킨 자리에서 새로운 뼈를 형성하고, 수많은 조골세포가 골기질을 만들어 기질이 무기질화되는 과정을 통하여 골 형성이 완성된다. 이와 같은 골 형성이 완성된 후 조골세포의 약 70% 이상은 사멸되고 일부는 골세포 (osteocyte) 및 골 표면 세포 (bone lining cell)로 분화되어 생존하는데, 이와 같은 항상성이 지속적으로 불균형을 이루는 경우에 골 관련 질환이 발생할 수 있다. In the present invention, the osteoclast (osteoclast) is a large multinucleated cell that destroys or absorbs bone tissue that is unnecessary in the process of bone growth, and mature osteoclasts are multinucleated cells and are formed by differentiating hematopoietic stem cells. In addition, osteoblasts differentiated from mesenchymal stem cells survive for about 34 months to form new bones where activated osteoclasts break down old bones, and numerous osteoblasts form bone matrix to mineralize the matrix. This is done. After this bone formation is completed, more than about 70% of osteoblasts are killed and some are differentiated into osteoblasts and bone lining cells to survive. Bone related diseases may occur.
따라서, 본 발명의 목적상 상기 스테롤 황산염을 유효성분으로 포함하는 약학 조성물은 기존에 보고된 골 관련 질환의 약학 조성물과 달리 조골세포의 분화를 촉진하고, 파골세포의 분화 및 기능을 억제하는 역할을 동시에 수행할 수 있고, 이로써, 골 관련 질환의 치료에 더욱 효과적이다.Therefore, the pharmaceutical composition comprising the sterol sulfate as an active ingredient for the purposes of the present invention, unlike previously reported pharmaceutical composition of bone-related diseases, promotes the differentiation of osteoblasts, and serves to inhibit the differentiation and function of osteoclasts. Can be performed simultaneously, thereby making it more effective in the treatment of bone related diseases.
구체적으로, 본 발명에서 상기 골 관련 질환은 골다공증(osteoporosis), 골연화증(osteomalacia), 골감소증(osteopenia), 골위축(bone atrophy), 섬유성골이형성증(fibrous dysplasia), 페이젯병(Paget's disease), 고칼슘혈증(hypercalcemia), 뼈의 종양성 파괴(neoplastic destruction), 암(cancer) 관련 골재흡수 질병, 골절(fracture), 골용해(osteolysis), 골관절염(osteoarthritis), 및 류머티스 관절염(rheumatoid arthritis)으로부터 구성된 군으로부터 선택되는 1종 이상인 것일 수 있다.Specifically, the bone-related diseases in the present invention, osteoporosis (osteoporosis), osteomalacia (osteomalacia), osteopenia (osteopenia), bone atrophy (bone atrophy), fibrous dysplasia (Pageb's disease), hypercalcemia from hypercalcemia, neoplastic destruction of bone, cancer-related bone resorption diseases, fractures, osteolysis, osteoarthritis, and rheumatoid arthritis It may be one or more selected.
단, 본 발명에서 상기 골다공증은 노화에 의한 원발성 골다공증, 폐경에 의한 원발성 골다공증, 및 난소 적출술에 의한 원발성 골다공증으로 구성된 군으로부터 선택되는 1종 이상일 수 있다. 또한, 글루코코르티코이드 유발성 골다공증, 갑상선 기능 항진성 골다공증, 고정 유발성 골다공증, 헤파린 유발성 골다공증, 면역 억제 유발성 골다공증, 신부전에 따른 골다공증, 염증성 골다공증, 쿠싱 증후군에 따른 골다공증, 류마티스성 골다공증, 및 에스트로젠 합성 억제제에 의한 골다공증으로 구성된 군으로부터 선택되는 1종 이상일 수 있다.However, in the present invention, the osteoporosis may be at least one selected from the group consisting of primary osteoporosis by aging, primary osteoporosis by menopause, and primary osteoporosis by ovarian extraction. In addition, glucocorticoid-induced osteoporosis, hyperthyroidism, fixed-induced osteoporosis, fixed-induced osteoporosis, heparin-induced osteoporosis, immunosuppressive osteoporosis, osteoporosis following renal failure, inflammatory osteoporosis, osteoporosis following Cushing's syndrome, rheumatoid osteoporosis, and estrogen At least one member selected from the group consisting of osteoporosis by a synthetic inhibitor.
한편, 본 발명에서, "예방"은 본 발명의 약학 조성물을 이용하여 골 관련 질환으로 인해 발생한 증상을 차단하거나, 그 증상을 억제 또는 지연시키는 모든 행위라면 제한없이 포함할 수 있다. On the other hand, in the present invention, "prevention" may be used without limitation any blocking action, or inhibiting or delaying the symptoms caused by a bone-related disease using the pharmaceutical composition of the present invention.
또한, 본 발명에서, "치료"는 본 발명의 약학 조성물을 이용하여 골 관련 질환으로 인해 발생한 증상이 호전되거나 이롭게 되는 모든 행위라면 제한없이 포함할 수 있다.In addition, in the present invention, "treatment" may be used without limitation as long as the symptoms caused by bone-related diseases improve or benefit by using the pharmaceutical composition of the present invention.
본 발명에서 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. In the present invention, the pharmaceutical composition may be characterized in that the capsule, tablets, granules, injections, ointments, powder or beverage form, the pharmaceutical composition may be characterized in that it is intended for humans.
본 발명에서 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 제형화하여 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 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약학 조성물의 제형은 상술한 바와 같은 약제학적으로 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 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화할 수 있다.In the present invention, the pharmaceutical composition is not limited thereto, but is formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injectable solutions, respectively, according to a conventional method. Can be used. The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, suspending agents, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, flavors, and the like in the case of oral administration, and in the case of injections, buffers, preservatives, analgesic Topical agents, solubilizers, isotonic agents, stabilizers and the like can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives and the like can be used. The formulation 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, oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, in the case of injections, in unit dosage ampoules or multiple dosage forms. have. And other solutions, suspensions, tablets, capsules, sustained release preparations 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, 항 응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Examples of suitable carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate , Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may further be included.
본 발명에 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 in the present invention is not limited thereto, but is oral, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Sublingual or rectal. Oral or parenteral release is preferred.
본 발명에서 상기 "비경구"란, 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내, 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intramuscular, intrasternal, intradural, intralesional, and intracranial injection or infusion techniques. The pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration.
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 10g/kg 또는 0.001 내지 10g/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 제형될 수 있다.The pharmaceutical composition of the present invention may be subjected to a number of factors including the activity, age, weight, general health, sex, formulation, time of administration, route of administration, rate of release, drug combination, and severity of the particular disease to be prevented or treated, of the specific compound employed. The dosage amount of the pharmaceutical composition varies depending on the patient's condition, weight, degree of disease, drug form, route of administration, and duration, and may be appropriately selected by those skilled in the art, and 0.0001 to 10 g per day. It may be administered at / kg or 0.001 to 10g / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.
본 발명의 다른 구현 예는 스테롤(Sterol) 황산염을 유효성분으로 포함하는 골 관련 질환의 예방 또는 개선용 식품 조성물을 제공한다.Another embodiment of the present invention provides a food composition for preventing or ameliorating a bone-related disease comprising a sterol sulfate as an active ingredient.
본 발명의 다른 구체 예에서는 상기 화학식 1로 표시되는 화합물을 유효성분으로 포함하는 골 관련 질환의 예방 또는 개선용 식품 조성물을 제공한다.Another embodiment of the present invention provides a food composition for preventing or improving a bone-related disease comprising the compound represented by
본 발명의 식품 조성물에서 상기 스테롤 황산염, 골 관련 질환, 화학식 1, 골다공증, 및 예방에 대한 내용은 약학 조성물에서 기재한 바와 중복되어, 이하 구체적인 기재를 생략한다.In the food composition of the present invention, the contents of the sterol sulfate, bone-related diseases, formula (1), osteoporosis, and prevention are overlapped with those described in the pharmaceutical composition, and detailed descriptions thereof will be omitted below.
한편, 본 발명에서, “개선”은 본 발명의 식품 조성물을 이용하여 골 관련 질환으로 인해 발생한 증상이 호전 또는 이롭게 변경되는 모든 행위라면 제한없이 포함할 수 있다.On the other hand, in the present invention, "improvement" may be included without limitation, any action that improves or beneficially changed symptoms caused by bone-related diseases using the food composition of the present invention.
본 발명의 상기 화합물을 유효성분으로 포함하는 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 comprising the compound of the present invention as an active ingredient may be prepared in the form of various foods, for example, beverages, gums, teas, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, and bread. have.
본 발명에서 상기 화합물이 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 50%의 비율로 첨가할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, when the compound is included in the food composition, the amount may be added at a ratio of 0.1 to 50% of the total weight, but is not limited thereto.
본 발명에서 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 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. In the present invention, when the food composition is prepared in the form of a beverage, there is no particular limitation other than including the food composition in the ratio indicated, and may include various flavors or natural carbohydrates, etc. as additional ingredients, as in general beverages. . Specifically, monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, conventional sugars such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol are mentioned as natural carbohydrates. It may include. The flavourant may be a natural flavourant (tautin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.), synthetic flavors (saccharin, aspartame, etc.).
본 발명에서, 그 외 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 등을 포함할 수 있다.In the present invention, the above food composition of the present invention is a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids , Protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
본 발명에서 상기 성분은 독립적 또는 조합하여 사용할 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.In the present invention, the above components may be used independently or in combination. The ratio 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 발명에 따른 스테롤 황산염을 유효성분으로 포함하는 약학 조성물 및 식품 조성물은 전조골세포의 조골세포로의 분화를 촉진하여 석회화 결절의 생성을 유도할 뿐만 아니라, 동시에 골수세포의 파골세포로의 분화를 억제하고, 파골세포의 기능을 억제함으로써 골 항상성을 효과적으로 조절하여 골 관련 질환의 예방 또는 치료에 매우 효과적이다.The pharmaceutical composition and the food composition comprising the sterol sulfate according to the present invention as an active ingredient promote the differentiation of progenitor osteoblasts into osteoblasts to induce the production of calcified nodules, and at the same time to differentiate the bone marrow cells into osteoclasts. It is effective in preventing or treating bone-related diseases by effectively controlling bone homeostasis by inhibiting the function of osteoclasts.
도 1은 본 발명의 일 실시예에 따른 화학식 1, 타우로우로소데옥시콜리산, 데옥시콜산, 또는 타우로콜산 첨가로 인한 조골세포 석회화 결절(Mineralized nodule) 생성 정도를 확인한 결과를 나타낸 것이다.
도 2는 본 발명의 일 실시예에 따른 화학식 1 첨가로 인한 조골세포의 석회화 결절(Mineralized nodule)의 생성 정도를 확인한 결과를 나타낸 것이다.
도 3은 본 발명의 일 실시예에 따른 타우로우로소데옥시콜리산, 데옥시콜산, 또는 타우로콜산 첨가로 인한 조골세포의 석회화 결절(Mineralized nodule)의 생성 정도를 확인한 결과를 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른 조골세포의 분화 마커 유전자의 발현을 확인한 결과를 나타낸 것이다.
도 5는 본 발명의 일 실시예에 따른 골수 세포의 파골세포로의 분화 정도를 확인한 결과를 나타낸 것이다.
도 6은 본 발명의 일 실시예에 따른 파골세포의 기능 평가 결과를 나타낸 것이다.Figure 1 shows the results confirming the degree of osteoblast calcification (Mineralized nodule) generation due to the addition of the
Figure 2 shows the results confirming the degree of generation of calcified nodule (Mineralized nodule) of osteoblasts due to the addition of
Figure 3 shows the results confirming the degree of generation of calcified nodule (Mineralized nodule) of osteoblasts due to addition of tauurosodeoxycholic acid, deoxycholic acid, or taurocholic acid according to an embodiment of the present invention.
Figure 4 shows the results of confirming the expression of the differentiation marker gene of osteoblasts according to an embodiment of the present invention.
Figure 5 shows the results of confirming the degree of differentiation of bone marrow cells into osteoclasts according to an embodiment of the present invention.
Figure 6 shows the results of the functional evaluation of the osteoclasts according to an embodiment of the present invention.
이하, 본 발명을 하기의 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.
실시예Example
[준비예 1] 전조골세포(Preosteoblast cell) 및 골수 세포 분리Preparation Example 1 Isolation of Preosteoblast Cells and Bone Marrow Cells
본 발명에 따른 화합물의 골 항상성 조절 효과를 확인하기 위하여 전조골세포(preosteoblast cell) 및 골수 세포(Bone marrow cell)를 쥐에서 분리하였다.In order to confirm the bone homeostasis control effect of the compound according to the present invention, the preosteoblast cells and bone marrow cells (Bone marrow cells) were isolated from the mice.
전조골세포를 분리하기 위하여, 1 ~ 3일령의 쥐의 두개관(calvaria)을 채취한 뒤, 1mg/ml 콜라게나제(collagenase) 및 2mg/ml 디스파제(Dispase)를 처리하는 과정을 통하여 전조골세포를 수득하였다.In order to separate progenitor bone cells, calvaria from 1 to 3 days old rats were collected, followed by 1 mg / ml collagenase and 2 mg / ml dispase. Osteocytes were obtained.
또한, 골수 세포를 분리하기 위하여 4 ~ 6주령 수컷 쥐의 정강뼈(tibia) 및 넙다리뼈(femur)를 분리한 뒤, 뼈의 양 끝을 절단하고 가운데 부분에서 세포를 추출하는 과정을 통하여 골수 세포를 수득하였다.In addition, to separate the bone marrow cells, the tibia and femur of 4 to 6 week old male rats are separated, and then the bone marrow is cut through both ends of the bone and the cells are extracted from the middle part. Cells were obtained.
[실시예 1] 조골세포의 석회화 결절(Mineralized nodule) 측정Example 1 Measurement of Calcified Nodule of Osteoblasts
본 발명에 따른 화합물에 의하여 조골세포의 석회화 결절(Mineralized nodule)을 현저하게 촉진하는지 확인하였다.It was confirmed whether the compound according to the present invention markedly promotes calcified nodule (Mineralized nodule) of osteoblasts.
상기 준비예 1에서 얻은 전조골세포를 12-웰 세포 배양 플레이트에 0.5 X 105 cells/well의 수만큼 분주하고, 배지 볼륨의 10%에 해당하는 우태아혈청(FBS)와, 배지 볼륨의 1%에 해당하는 항생제(penicillin-streptomycin), 50㎍/ml의 L-아스코르빅산(L-ascorbic acid), 및 10mM β-글리세로포스페이트(β-glycerophosphate)이 포함되어 있는 α-MEM 배지에 본 발명의 화합물인 화학식 1, 또는 본 발명의 화합물과 동일하게 담즙산으로부터 유도되는 화합물로서 타우로우로소데옥시콜리산, 데옥시콜산, 또는 타우로콜산을 0 ~ 50μM의 농도로 각각 첨가하여 조골세포의 분화를 유도하였다. 단, 상기 분화를 유도하는 배지는 2 ~ 3일의 간격으로 신선한 배지로 교체하였으며, 총 21일간의 시간으로 분화를 유도하였다. 상기 분화된 조골세포의 분화를 확인하기 위하여 알리자린 레드(alizarin red) 염색을 수행하였다. 분화 유도가 완료된 세포를 10%의 중성 포르말린(neutral formalin)으로 4℃에서 20분간 배양하여 고정한 뒤, 1.36%, pH4.1 ~ 4.3의 알리자린 레드 용액으로 40분간 배양하여 염색하였다. 상기 결과를 도 1에 나타내었다. 실험 결과, 본 발명의 화합물인 화학식 1을 첨가한 전조골세포는 상기 화합물을 처리하지 않은 음성 대조군(0μM)에 비하여, 15μM에서 35μM로 처리 농도가 증가할수록 결절에 착색된 색소의 양이 증가되었다. 그러나 화학식 1과 동일하게 담즙산으로부터 유도되는 화합물로 분류되는 타우로우로소데옥시콜리산, 데옥시콜산, 또는 타우로콜산을 첨가한 전조골세포들은 실험에 적용된 모든 농도에서 전조골세포의 분화 효과가 전혀 없는 것으로 나타났다. 이는 담즙산으로부터 유도된 화합물 중에서 본 발명의 화학식 1만 특이적으로 조골 분화 효과가 있다는 것을 의미한다.The progenitor bone cells obtained in Preparation Example 1 were dispensed in a 12-well cell culture plate by the number of 0.5 X 10 5 cells / well, fetal calf serum (FBS) corresponding to 10% of the medium volume, and 1 of the medium volume. % Of penicillin-streptomycin, 50 μg / ml L-ascorbic acid, and 10 mM β-glycerophosphate As a compound derived from bile acid in the same manner as the compound of the formula (1) or the compound of the present invention, tauurosodeoxycholic acid, deoxycholic acid, or taurocholic acid are added at a concentration of 0 to 50 μM, respectively, Differentiation was induced. However, the differentiation-inducing medium was replaced with fresh medium at intervals of 2 to 3 days, and differentiation was induced at a total of 21 days. Alizarin red staining was performed to confirm the differentiation of the differentiated osteoblasts. Differentiation-induced cells were fixed by incubating for 20 minutes at 4 ° C. with 10% neutral formalin and then stained by incubating for 40 minutes with 1.36%, alizarin red solution of pH4.1-4.3. The results are shown in FIG. As a result, the precursor bone cells to which the compound of the present invention is added, the amount of pigment pigmented in the nodules increased as the treatment concentration increased from 15 μM to 35 μM, compared to the negative control group (0 μM). . However, precursor bone cells added with tauurosodeoxycholic acid, deoxycholic acid, or taurocholic acid, which are classified as compounds derived from bile acids in the same manner as in
화학식 1을 첨가한 전조골세포의 분화 정도를 정량적으로 평가하기 위하여 10%의 세틸피리디늄 클로라이드(Cetylpyridinium chloride)로 결절에 착색된 색소를 추출한 뒤, 570nm에서 흡광도를 측정하여 그 결과를 도 2에 나타내었다. 실험 결과, OD 값이 10μM에서 약 0.5인 반면, 35μM에서는 2, 40μM에서는 약 3으로 측정되어, 10 내지 45 μM의 범위에서 농도 의존적으로 조골 분화 효과가 증가함을 알 수 있었다.In order to quantitatively evaluate the differentiation of progenitor bone cells added with
타우로우로소데옥시콜리산, 데옥시콜산, 또는 타우로콜산을 정량한 결과를 도 3에 나타내었다. 도 1의 이미지와 일치하게, 정량적으로도 음성 대조군(0μM)과 비교하여 유의미한 차이가 없는 것으로 나타났다.The results of quantifying taurosodeoxycholic acid, deoxycholic acid, or taurocholic acid are shown in FIG. 3. Consistent with the image of FIG. 1, there was no significant difference quantitatively compared to the negative control (0 μM).
[실시예 2] 조골세포의 분화 측정Example 2 Measurement of Differentiation of Osteoblasts
본 발명에 따른 화합물에 의하여 전조골세포가 조골세포로의 분화를 촉진하는지 확인하기 위하여, 조골세포의 분화 마커 유전자의 발현을 확인하였다.In order to confirm whether the osteoblasts promote differentiation into osteoblasts by the compound according to the present invention, the expression of osteoblast differentiation marker gene was confirmed.
상기 실시예 1에서 25μM의 [(3S,8S,9S,10R,13R,14S,17R)-10,13-디메틸-17-[(2R)-6-메틸헵탄-2-일]-2,3,4,7,8,9,11,12,14,15,16,17-도데카하이드로-1H-사이클로펜타[[a]페난트렌-3-일] 하이드로젠 설페이트 ([(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] hydrogen sulfate)를 처리하고, 15일간 배양하여 분화가 유도된 전조골세포에서 RNeasy Mini (QIAGEN)키트를 이용하여 상기 키트에서 제시된 프로토콜에 의해 각각의 RNA 전체(total RNA)를 추출하였다. 각각의 RNA 전체(total RNA)를 추출하였다. 상기 추출된 RNA 2 ㎍을 리벌트에이드 리벌트 역전사효소(RevertAid Revert Transcriptase)(Thermo Scientific, USA)와 42에서 1시간 동안 반응시켜 cDNA를 얻은 후 SensiFASTTMSYBR Hi-ROX 키트(Bioline)를 이용하여 실시간 중합효소 연쇄반응(real-time PCR)을 수행하였다. 구체적인 반응 조건은 95에서 3분간 변성시킨 후, 95에서 5초, 60에서 10초, 72에서 15초씩 40 사이클을 반응시켜 얻은 정량적인 결과를 도 4에 나타내었다.In Example 1, 25 μM of [(3S, 8S, 9S, 10R, 13R, 14S, 17R) -10,13-dimethyl-17-[(2R) -6-methylheptan-2-yl] -2,3 , 4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta [[a] phenanthren-3-yl] hydrogen sulfate ([(3S, 8S, 9S, 10R, 13R, 14S, 17R) -10,13-dimethyl-17-[(2R) -6-methylheptan-2-yl] -2,3,4,7,8,9,11,12,14 , 15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-3-yl] hydrogen sulfate), and cultured for 15 days using RNeasy Mini (QIAGEN) kit in differentiated progenitor bone cells Each total RNA was extracted by the protocol presented in the kit. Each total RNA was extracted. 2 μg of the extracted RNA was reacted with RevertAid Revert Transcriptase (Thermo Scientific, USA) for 1 hour at 42 to obtain cDNA using SensiFAST ™ SYBR Hi-ROX kit (Bioline). Real-time PCR was performed. Specific reaction conditions are shown in FIG. 4 after quantifying at 95 minutes for 3 minutes, and then reacting 40 cycles of 95 seconds at 5 seconds, 60 seconds at 10 seconds, and 72 seconds at 15 seconds.
도 4에서 보는 바와 같이, 조골세포의 분화 마커에 해당하는 유전자인 Sp7, Bgiap 및 Ibsp의 유전자 발현이 대조군(OS)에 비하여 2배 이상의 현저한 발현 차이를 보였다.As shown in FIG. 4, gene expression of Sp7, Bgiap, and Ibsp, which are genes corresponding to differentiation markers of osteoblasts, showed a significant difference of two times or more compared to the control (OS).
상기 결과를 통해, 본 발명에 따른 상기 화합물은 조골세포에서 발생하는 석회화 결절의 양을 현저하게 증가시키는 것뿐만 아니라, 전조골세포의 조골세포로의 분화를 촉진하는 것을 알 수 있다.Through the above results, it can be seen that the compound according to the present invention not only significantly increases the amount of calcified nodules occurring in osteoblasts, but also promotes differentiation of progenitor osteoblasts into osteoblasts.
[실시예 3] 파골세포의 분화 측정Example 3 Measurement of Differentiation of Osteoclasts
본 발명에 따른 화합물에 의하여 파골세포의 분화를 현저하게 억제하는지 확인하였다.It was confirmed whether the compound according to the present invention significantly inhibited the differentiation of osteoclasts.
상기 준비예 1에서 얻은 골수 세포를 96-웰 세포 배양 플레이트에 5 X 104 cells/well의 수만큼 분주하고, 배지 볼륨의 10%에 해당하는 우태아혈청(FBS)와, 배지 볼륨의 1%에 해당하는 항생제(penicillin-streptomycin), 30ng/ml의 M-CSF 및 50ng/ml의 RANKL이 포함되어 있는 α-MEM 배지에 [(3S,8S,9S,10R,13R,14S,17R)-10,13-디메틸-17-[(2R)-6-메틸헵탄-2-일]-2,3,4,7,8,9,11,12,14,15,16,17-도데카하이드로-1H-사이클로펜타[[a]페난트렌-3-일] 하이드로젠 설페이트 ([(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] hydrogen sulfate)를 0 ~ 25μM의 농도를 각각 첨가하여 파골세포의 분화를 유도하였다. 단, 상기 분화를 유도하는 배지는 2 일의 간격으로 신선한 배지로 교체하였으며, 총 4 ~ 5일간의 시간으로 분화를 유도하였다.Dispensing the bone marrow cells obtained in Preparation Example 1 in a number of 5 X 10 4 cells / well in a 96-well cell culture plate, fetal calf serum (FBS) corresponding to 10% of the medium volume, and 1% of the medium volume [(3S, 8S, 9S, 10R, 13R, 14S, 17R) -10 in α-MEM medium containing penicillin-streptomycin, 30ng / ml M-CSF and 50ng / ml RANKL , 13-dimethyl-17-[(2R) -6-methylheptan-2-yl] -2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro- 1H-cyclopenta [[a] phenanthren-3-yl] hydrogen sulfate ([(3S, 8S, 9S, 10R, 13R, 14S, 17R) -10,13-dimethyl-17-[(2R) -6 -methylheptan-2-yl] -2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-3-yl] hydrogen sulfate Differentiation of osteoclasts was induced by adding concentrations of 0-25 μM, respectively. However, the differentiation-inducing medium was replaced with fresh medium at intervals of two days, and differentiation was induced in a total of 4-5 days.
상기 분화가 완료된 골수 세포의 분화 정도를 확인하기 위하여 TRAP 염색 키트(Sigma Aldrich, USA)를 이용하여 제조사에서 제시된 프로토콜에 의해 염색을 실시하여 현미경으로 측정한 결과를 도 5에 나타내었고, TRAP 효소 활성을 측정한 결과를 도 6에 나타내었다.In order to confirm the degree of differentiation of the differentiated bone marrow cells, staining was carried out by a protocol provided by the manufacturer using a TRAP staining kit (Sigma Aldrich, USA), and the results of measurement under a microscope are shown in FIG. The measurement results are shown in FIG. 6.
도 5, 및 도 6에서 보는 바와 같이, 골수 세포가 파골세포로의 분화를 억제하고, 본 발명에 따른 화합물의 농도가 6.25μM, 및 12.5μM에서는 음성 대조군에 비하여 약 0.2 정도 기능이 억제되었고, 25μM에서는 약 0.3 정도 기능이 억제되었다.As shown in Figures 5 and 6, bone marrow cells inhibit the differentiation into osteoclasts, the concentration of the compound according to the invention at 6.25μM, and 12.5μM was inhibited by about 0.2 compared to the negative control, The function was suppressed by about 0.3 at 25 μM.
상기 결과를 통하여 본 발명에 따른 [(3S,8S,9S,10R,13R,14S,17R)-10,13-디메틸-17-[(2R)-6-메틸헵탄-2-일]-2,3,4,7,8,9,11,12,14,15,16,17-도데카하이드로-1H-사이클로펜타[[a]페난트렌-3-일] 하이드로젠 설페이트 ([(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] hydrogen sulfate)는 골수 세포의 파골세포로의 분화를 억제할 뿐만 아니라, 파골세포의 기능을 억제시키는 것을 알 수 있다.Through the above results according to the present invention [(3S, 8S, 9S, 10R, 13R, 14S, 17R) -10,13-dimethyl-17-[(2R) -6-methylheptan-2-yl] -2, 3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta [[a] phenanthren-3-yl] hydrogen sulfate ([(3S, 8S , 9S, 10R, 13R, 14S, 17R) -10,13-dimethyl-17-[(2R) -6-methylheptan-2-yl] -2,3,4,7,8,9,11,12, 14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-3-yl] hydrogen sulfate inhibits osteoblast differentiation as well as inhibits osteoclast function. have.
이상에서 본 발명에 대하여 상세하게 설명하였지만 본 발명의 권리범위는 이에 한정되는 것은 아니고, 청구범위에 기재된 본 발명의 기술적 사상을 벗어나지 않는 범위 내에서 다양한 수정 및 변형이 가능하다는 것은 당 기술분야의 통상의 지식을 가진 자에게는 자명할 것이다.Although the present invention has been described in detail above, the scope of the present invention is not limited thereto, and various modifications and variations can be made without departing from the technical spirit of the present invention described in the claims. It will be self-evident to those who have knowledge of.
Claims (18)
상기 스테롤 황산염은 하기 화화식 1로 표시되는 것이고,
상기 골 관련 질환은 골다공증(osteoporosis), 골연화증(osteomalacia), 골감소증(osteopenia), 골위축(bone atrophy), 섬유성골이형성증(fibrous dysplasia), 페이젯병(Paget's disease), 고칼슘혈증(hypercalcemia), 뼈의 종양성 파괴(neoplastic destruction), 암(cancer) 관련 골재흡수 질병, 골절(fracture), 골용해(osteolysis), 골관절염(osteoarthritis), 및 류머티스 관절염(rheumatoid arthritis)으로부터 구성된 군으로부터 선택되는 1종 이상인 것인, 약학 조성물.
[화학식 1]
A pharmaceutical composition for the prevention or treatment of bone-related diseases comprising sterol sulfate as an active ingredient,
The sterol sulfate is represented by the following formula 1,
The bone-related diseases include osteoporosis, osteomalacia, osteopenia, osteoopenia, bone atrophy, fibrous dysplasia, Paget's disease, hypercalcemia, hypercalcemia At least one member selected from the group consisting of neoplastic destruction, cancer-related bone resorption diseases, fractures, osteolysis, osteoarthritis, and rheumatoid arthritis Phosphorus, pharmaceutical composition.
[Formula 1]
상기 약학 조성물은 전조골세포의 조골세포로의 분화를 촉진하는 것인, 약학 조성물.
The method of claim 1,
The pharmaceutical composition is to promote the differentiation of osteoblasts into osteoblasts, pharmaceutical composition.
상기 약학 조성물은 골수 세포의 파골세포로의 분화를 억제하는 것인, 약학 조성물.
The method of claim 1,
The pharmaceutical composition is to inhibit the differentiation of bone marrow cells into osteoclast, pharmaceutical composition.
상기 골다공증은 노화에 의한 원발성 골다공증, 폐경에 의한 원발성 골다공증, 및 난소 적출술에 의한 원발성 골다공증으로 구성된 군으로부터 선택되는 1종 이상인 것인, 약학 조성물.
The method of claim 1,
The osteoporosis is one or more selected from the group consisting of primary osteoporosis due to aging, primary osteoporosis due to menopause, and primary osteoporosis by ovarian extraction.
상기 골다공증은 글루코코르티코이드 유발성 골다공증, 갑상선 기능 항진성 골다공증, 고정 유발성 골다공증, 헤파린 유발성 골다공증, 면역 억제 유발성 골다공증, 신부전에 따른 골다공증, 염증성 골다공증, 쿠싱 증후군에 따른 골다공증, 류마티스성 골다공증, 및 에스트로젠 합성 억제제에 의한 골다공증으로 이루어진 군에서 선택된 1종 이상인 것인, 약학 조성물.
The method of claim 1,
The osteoporosis is glucocorticoid-induced osteoporosis, hyperthyroidism osteoporosis, fixed-induced osteoporosis, heparin-induced osteoporosis, immunosuppressive osteoporosis, osteoporosis following renal failure, inflammatory osteoporosis, osteoporosis according to Cushing syndrome, rheumatoid osteoporosis, and It is one or more selected from the group consisting of osteoporosis by estrogen synthesis inhibitor, pharmaceutical composition.
상기 스테롤 황산염은 10 내지 100 μM의 농도로 포함되는 것인, 약학 조성물.
The method of claim 1,
The sterol sulfate will be included in a concentration of 10 to 100 μM, pharmaceutical composition.
상기 스테롤 황산염은 하기 화화식 1로 표시되는 것이고,
상기 골 관련 질환은 골다공증(osteoporosis), 골연화증(osteomalacia), 골감소증(osteopenia), 골위축(bone atrophy), 섬유성골이형성증(fibrous dysplasia), 페이젯병(Paget's disease), 고칼슘혈증(hypercalcemia), 뼈의 종양성 파괴(neoplastic destruction), 암(cancer) 관련 골재흡수 질병, 골절(fracture), 골용해(osteolysis), 골관절염(osteoarthritis), 및 류머티스 관절염(rheumatoid arthritis)으로부터 구성된 군으로부터 선택되는 1종 이상인 것인, 식품 조성물.
[화학식 1]
As a food composition for the prevention or improvement of bone-related diseases comprising a sterol sulfate as an active ingredient,
The sterol sulfate is represented by the following formula 1,
The bone-related diseases include osteoporosis, osteomalacia, osteopenia, osteoopenia, bone atrophy, fibrous dysplasia, Paget's disease, hypercalcemia, hypercalcemia At least one member selected from the group consisting of neoplastic destruction, cancer-related bone resorption diseases, fractures, osteolysis, osteoarthritis, and rheumatoid arthritis Phosphorus, food composition.
[Formula 1]
상기 식품 조성물은 전조골세포의 조골세포로의 분화를 촉진하는 것인, 식품 조성물.
The method of claim 10,
The food composition is to promote differentiation of osteoblasts into osteoblasts, food composition.
상기 식품 조성물은 골수 세포의 파골세포로의 분화를 억제하는 것인, 식품 조성물.
The method of claim 10,
The food composition is to inhibit the differentiation of bone marrow cells into osteoclasts, food composition.
상기 스테롤 황산염은 하기 화화식 1로 표시되는 것이고,
상기 골재생은 골다공증(osteoporosis), 골연화증(osteomalacia), 골감소증(osteopenia), 골위축(bone atrophy), 섬유성골이형성증(fibrous dysplasia), 페이젯병(Paget's disease), 고칼슘혈증(hypercalcemia), 뼈의 종양성 파괴(neoplastic destruction), 암(cancer) 관련 골재흡수 질병, 골절(fracture), 골용해(osteolysis), 골관절염(osteoarthritis), 및 류머티스 관절염(rheumatoid arthritis)으로부터 구성된 군으로부터 선택되는 1종 이상의 질환에서의 골재생인 것인, 조성물.
[화학식 1]
A composition for promoting bone regeneration comprising a sterol sulfate as an active ingredient,
The sterol sulfate is represented by the following formula 1,
The osteoporosis (osteoporosis), osteomalacia (osteomalacia), osteopenia (osteopenia), bone atrophy (bone atrophy), fibrous dysplasia (Pageb's disease), hypercalcemia (hypercalcemia), bone species In one or more diseases selected from the group consisting of neoplastic destruction, cancer-related bone resorption diseases, fractures, osteolysis, osteoarthritis, and rheumatoid arthritis The bone regeneration of the composition.
[Formula 1]
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| JP2019565936A JP7154616B2 (en) | 2017-06-01 | 2018-05-30 | Pharmaceutical composition for prevention or treatment of bone-related diseases |
| CN201880036715.9A CN110809473A (en) | 2017-06-01 | 2018-05-30 | Pharmaceutical composition for preventing or treating bone-related diseases |
| EP18810528.2A EP3632447B1 (en) | 2017-06-01 | 2018-05-30 | Pharmaceutical composition for prevention or treatment of bone-related disease |
| PCT/KR2018/006174 WO2018221966A1 (en) | 2017-06-01 | 2018-05-30 | Pharmaceutical composition for prevention or treatment of bone-related disease |
| EP22177032.4A EP4098264A1 (en) | 2017-06-01 | 2018-05-30 | Pharmaceutical composition for prevention or treatment of bone-related disease |
| US17/575,162 US20220133690A1 (en) | 2017-06-01 | 2022-01-13 | Pharmaceutical Composition for Treatment of Bone-Related Disease |
| JP2022155528A JP2022185030A (en) | 2017-06-01 | 2022-09-28 | Pharmaceutical composition for prevention or treatment of bone-related diseases |
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