KR20190054544A - Composition for promoting or inducing a bone differentiation included silk protein and method for enhancing a bone differentiation using the same - Google Patents
Composition for promoting or inducing a bone differentiation included silk protein and method for enhancing a bone differentiation using the same Download PDFInfo
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- KR20190054544A KR20190054544A KR1020170151223A KR20170151223A KR20190054544A KR 20190054544 A KR20190054544 A KR 20190054544A KR 1020170151223 A KR1020170151223 A KR 1020170151223A KR 20170151223 A KR20170151223 A KR 20170151223A KR 20190054544 A KR20190054544 A KR 20190054544A
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- promoting
- bone differentiation
- stem cells
- silkworm
- fibroin
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Abstract
Description
본 발명은 실크단백질을 포함하는 줄기세포의 뼈분화 촉진 또는 유도용 조성물에 관한 것으로서, 보다 상세하게는 실크단백질로 품종별 누에 유래 피브로인 또는 세리신을 이용한 줄기세포의 뼈분화 촉진 또는 유도용 조성물에 관한 것이다.The present invention relates to a composition for promoting or inducing bone differentiation in a stem cell comprising a silk protein, and more particularly, to a composition for promoting or inducing bone differentiation using silk protein, silkworm-derived fibroin or sericin will be.
뼈(bone)는 인체의 연조직과 체중을 지탱해주고 내부기관을 둘러싸서 내부 장기를 외부의 충격으로부터 보호한다. 또한, 근육이나 장기를 구조적으로 지탱할 뿐만 아니라 체내의 칼슘이나 다른 필수 무기질, 즉 인이나 마그네슘과 같은 물질을 저장하는 인체의 중요한 부분 중 하나이다. 따라서 성장이 끝난 성인의 뼈는 멈추지 않고 죽는 날 까지 오래된 뼈는 제거되고 새로운 뼈로 대체하는 생성과 흡수 과정을 매우 역동적, 지속적으로 반복 재생 하면서 균형을 유지하게 된다. 이를 골재형성(bone remodeling) 이라고 한다. 오래된 뼈는 제거되고 새로운 뼈로 대체하는 뼈의 순환(turnover)은 성장과 스트레스에 의해서 일어나는 뼈의 미세한 손상을 회복시키고 적절히 뼈의 기능을 유지하는데 필수적이다.The bone supports the body's soft tissues and body weight and surrounds the internal organs to protect the internal organs from external impact. It is also an important part of the human body that not only supports the muscles or organs but also stores calcium or other essential minerals in the body, such as phosphorus or magnesium. Thus, adult bones do not stop growing until they die, and the old bones are removed and the new bone replaces the production and absorption process very dynamically, continuously and repeatedly. This is called bone remodeling. The old bone is removed and replaced with a new bone, the turnover of the bone is necessary to restore the fine damage of the bone caused by growth and stress and to maintain proper bone function.
뼈를 구성하는 세포는 뼈의 항상성을 유지하는 골세포(osteocyte), 뼈를 형성하는 골모세포(osteoblast), 뼈를 흡수하는 파골세포(osteoclast), 그리고 뼈의 말단의 관절기능을 담당하는 연골세포(chondrocyte) 등이 있으며, 성장이 완료된 골(骨)에서도 해면골은 파골세포에 의해서 흡수되면 다른 표면에서는 골모세포에 의해서 새로운골이 형성되면서 재형성되게 된다. 이러한 골형성과 골흡수의 균형이 깨어지면 골질환으로 진행되는데, 이러한 골질환으로 난치성 골질환에는 골다공증(osteoporosis), 불유합(non-union) 골절, 골괴사증(osteonecrosis), 골연화증(osteomalacia), 골결손 등이 있다. 또한, 무혈성대퇴골괴사(Avascular necrosis of the Femoral Head)는 외상, 음주, 스테로이드제 복용 등의 원인으로 고관절을 이루는 대퇴골 골두에 혈액 공급이 중단되어 뼈가 파괴되는 난치성 골질환으로, 이 질환은 미국에서는 연간 20,000명, 한국에서는 연간 4,000명~5,000명의 발병률을 보이며, 대부분 20-50세 발생하며 평균 30대 후반에서 발생률 높은 것으로 알려져 있다. 또한, 골다공증은 골소공증 또는 골 조송증이라고도 하며, 정상인에 비해 골량이 현저히 감소된 상태로 골의 구성성분의 양적 감소를 주 병변으로 하는 대사성 골 질환을 의미한다. 일반적으로 골다공증의 병태 자체는 무증상 또는 경미한 증상인 경우가 많지만, 일단 골절이 생기면 일반적으로 치료가 곤란하고, 골접합술을 시술해도 충분하게 회복되기가 어렵다.The cells that make up the bones are osteocytes that maintain the homeostasis of the bones, osteoblasts that form the bones, osteoclasts that absorb the bones, and cartilage cells that play the joint functions of the ends of the bones (chondrocyte), and in the bone that has been grown, the cancellous bone is absorbed by the osteoclasts, and on the other surface, the new bone is formed by the osteoblasts and is reformed. When the balance between osteogenesis and bone resorption is broken, the disease progresses to osteopathy. Osteoporosis, non-union fracture, osteonecrosis, osteomalacia, osteoporosis, There are deficiencies. In addition, avascular necrosis of the femoral head is a refractory osteoarthritis in which the bone is destroyed by stopping the blood supply to the femoral head that constitutes the hip joint due to trauma, alcohol and steroid use. 20,000 per year, and 4,000-5,000 per year in Korea. The incidence is generally 20-50 years old, with an average rate in the late 30s. Osteoporosis is also referred to as osteoporosis or osteoporosis. It refers to a metabolic bone disease in which the bone mass is significantly reduced compared with that of a normal person, and a major decrease in the bone constituent is the main lesion. In general, the condition of osteoporosis itself is often asymptomatic or mild. However, once a fracture occurs, it is generally difficult to treat and it is difficult to recover enough even after the operation of osteosynthesis.
이제까지 골다공증, 골절을 비롯한 골질환의 예방제 및/또는 치료제로서, 칼슘 제제, 에스트로겐 제제, 선택적 에스트로겐 수용체 조절약(SERM), 활성형 비타민 D3 제제, 비타민 K 제제, 이프리플라본 제제, 칼시토닌 제제, 비스포스포네이트 제제, 부갑상선 호르몬 제제, 단백 동화 호르몬 제제, 골형태 유도 인자(BMP), 또는 섬유아세포 증식 인자(FGF) 등이 임상적으로 사용되거나, 또는 임상 응용이 시도되어 왔으나, 이와 같이 다수의 약제가 사용되고 있음에도 불구하고, 골질환의 환자수는 해마다 증가되고 있는 실정이며, 따라서 이런 난치성 골 질환을 효율적으로 치료하기 위한 새로운 개념의 치료제 개발이 절실히 요구되고 있다.As a preventive and / or therapeutic agent for bone diseases including osteoporosis, fracture, etc., there has been proposed a pharmaceutical composition containing a calcium preparation, an estrogen preparation, a selective estrogen receptor modulating agent (SERM), an active vitamin D3 preparation, a vitamin K preparation, an ipriflavone preparation, a calcitonin preparation, a bisphosphonate preparation, (BMP), fibroblast growth factor (FGF), etc. have been clinically used or clinical applications have been tried. However, even though a large number of medicines are used in this way The number of patients with bone disease is increasing year by year. Therefore, it is urgently required to develop a new concept of therapeutic agent for efficiently treating such refractory bone diseases.
골 질환에 대한 전통적인 치료법으로는 자가골 이식(autografting)과 동종골 이식(allografting) 그리고 인조골이식(artificial bone grafting) 등이 있지만, 골 채취 부위의 감염, 혈종 등과 같은 합병증 유발(자가골이식), 공여자로부터의 질병 전염 가능성(동종골 이식), 근본적인 골 생성이 되지 않는(인조골 이식) 문제점을 가지고 있다. 이와 같이 종래의 골형성 메카니즘 및 이들 메카니즘에 작용하여 골형성에 효과적으로 기여하는 물질들은 고가여서 용이하게 적용이 쉽지 않으며, 천연물질에서 유래된 것이 아니어서 부작용도 있는 바, 현재는 인체 무해하면서 뼈분화 촉진효능은 우수함과 동시에 저렴하여 용이하게 이용할 수 있는 소재자체 개발이 필요한 실정이다.Traditional therapies for bone disease include autografting, allografting, and artificial bone grafting. However, complications such as infections at the site of bone harvesting, hematomas (autogenous bone graft) (Allograft), and a problem that does not result in fundamental bone formation (artificial bone graft). As described above, the conventional bone formation mechanisms and the substances that contribute to the bone formation by effectively acting on these mechanisms are not easily applied due to their high cost, and they are not derived from natural materials and have side effects. Therefore, It is necessary to develop a material that is excellent in promoting effect and at the same time inexpensive and easy to use.
본 발명의 목적은 인체무해하면서 용이하고 저렴하게 뼈분화를 촉진하거나 유도할 수 있는 줄기세포의 뼈분화 촉진 또는 유도용 조성물을 제공하는 데에 있다.It is an object of the present invention to provide a composition for promoting or inducing bone differentiation of a stem cell which is capable of promoting or inducing bone differentiation easily and inexpensively while being harmless to the human body.
상기 목적을 달성하기 위한 본 발명의 줄기세포의 뼈분화 촉진 또는 유도용 조성물은, 누에 유래 피브로인 또는 세리신 중 어느 하나이상을 유효성분으로 포함하는 것이 특징이다. To achieve the above object, the composition for promoting or inducing bone differentiation of stem cells according to the present invention comprises at least one of silkworm derived from silkworm as an active ingredient.
또한, 상기 피브로인과 세리신은 모든 품종(대성잠, 금옥잠, 백옥잠, 골드실크, 연녹잠)에서 줄기세포의 뼈분화 촉진 또는 유도효과를 나타내며, 특히 피브로인의 경우에는 상대적으로 상기 누에의 품종 중 대성잠, 금옥잠, 백옥잠 중 어느 하나이상에서 그 효능이 더 우수하게 나타내며, 세리신의 경우에는 상기 누에의 품종 중 금옥잠에서 그 효능이 더 우수하게 나타내는 것이 특징이다. In addition, the fibroin and sericin exhibit bone-differentiation promoting or inducing effects on stem cells in all varieties (Daesung, Geumokam, Baekokam, Goldsilk, Yeonwonjam), and in particular fibroin, The efficacy is more excellent in at least one of Daesung sleep, Geumok sleep, and Baekok sleep, and in the case of sericin, the efficacy of the silkworm among the varieties of silkworm is more excellent.
또한, 상기 피브로인과 세리신을 모두 포함할 경우에는 상기 피브로인과 세리신은 1:1 중량비로 포함되는 것이 특징이다.When both the fibroin and sericin are included, the fibroin and sericin are contained in a weight ratio of 1: 1.
본 발명이 이루고자 하는 기술적 과제들은 이상에서 언급한 기술적 과제들로 제한되지 않으며, 언급되지 않은 다른 기술적 과제들은 아래의 기재로부터 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not intended to limit the invention to the particular embodiments that are described. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not restrictive of the invention, There will be.
본 발명에 의해, 줄기세포의 뼈분화 촉진 또는 유도용 조성물이 제공됨에 따라, 종래 고가의 뼈분화유도물질(덱사미타손)을 대체할 수 있어 인체무해하면서 용이하고 저렴하게 뼈분화를 촉진하거나 유도할 수 있게 된다.According to the present invention, since a composition for promoting or inducing bone differentiation of stem cells is provided, it is possible to replace a conventional expensive bone differentiation inducing substance (dexamitone), thereby promoting bone differentiation or inducing bone differentiation easily and inexpensively, .
도 1은 누에 품종별로 얻어진 각 피브로인을 대상으로 Alizarin red 염색처리 후 줄기세포의 뼈세포 분화 및 유도효과를 나타낸 도면이다.
도 2는 누에 품종별로 얻어진 각 피브로인을 대상으로 Alizarin red 염색처리 후 시료를 탈색한 다음 비색법으로 정량하여 줄기세포의 뼈세포 분화 및 유도효과를 나타낸 그래프이다.
도 3은 누에 품종별로 얻어진 각 세리신을 대상으로 Alizarin red 염색처리 후 줄기세포의 뼈세포 분화 및 유도효과를 나타낸 도면이다.
도 4는 누에 품종별로 얻어진 각 세리신을 대상으로 Alizarin red 염색처리 후 시료를 탈색한 다음 비색법으로 정량하여 줄기세포의 뼈세포 분화 및 유도효과를 나타낸 그래프이다. FIG. 1 is a diagram showing bone cell differentiation and induction effect of stem cells after Alizarin red staining for each fibroin obtained for each silkworm. FIG.
FIG. 2 is a graph showing the bone cell differentiation and induction effect of the fibroblasts obtained for each silkworm cultivar by decoloring the sample after Alizarin red staining and quantitating it by the colorimetric method.
FIG. 3 is a diagram showing bone cell differentiation and induction effect of stem cells after Alizarin red staining for each sericin obtained for each silkworm. FIG.
FIG. 4 is a graph showing the bone cell differentiation and induction effects of the sericin obtained by decoloring the sample after Alizarin red staining for each silkworm obtained by the silkworm variety, and quantitatively determining it by the colorimetric method.
이하, 본 발명을 상세하게 설명하며, 본 발명의 요지를 불필요하게 흐릴 수 있는 공지 기능 및 구성에 대한 상세한 설명은 생략한다.DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in detail, and a detailed description of known functions and configurations that may unnecessarily obscure the gist of the present invention will be omitted.
본 발명은 실크단백질을 포함하는 줄기세포의 뼈분화 촉진 또는 유도용 조성물에 관한 것으로써, 보다 상세하게는, 실크단백질로 피브로인 또는 세리신 또는 이들 혼합물을 유효성분으로 포함하는 줄기세포의 뼈분화 촉진 또는 유도용 조성물을 제공하는 것이 특징이다. The present invention relates to a composition for promoting or inducing bone differentiation of a stem cell comprising a silk protein, and more particularly, to a composition for stimulating or differentiating stem cells comprising fibroin or sericin or a mixture thereof as an active ingredient, Thereby providing a composition for induction.
본 명세서에서 용어 “실크”는 견사 곤충이 토사하여 만든 섬유를 의미하며, 바람직하게는 누에(Bombyx mori)가 토사하는 가잠사를 의미한다. 실크 단백질은 피브로인 및 세리신으로 이루어져 있고, 피브로인과 세리신은 각각 평균 75%와 25%의 비율로 존재한다. 피브로인 단백질은 특이하게 글리신 및 알라닌 함량이 매우 높은 반면, 세리신은 피브로인과 전혀 다른 아미노산 조성을 나타내고 있으며, 세린이 전체 구성 아미노산 중의 1/3 이상을 차지하고 있다. 본 발명에서는 이러한 실크 단백질인 피브로인과 세리신을 모두 유효성분으로 적용하는 것으로써, 이는 누에의 품종별로 큰 차이가 있음을 확인하였다. As used herein, the term " silk " means a fiber produced by insect insect insect, preferably silkworm yarn to which silkworm (Bombyx mori) soil. The silk protein consists of fibroin and sericin, and fibroin and sericin are present in the ratio of 75% and 25%, respectively. Fibroin protein is particularly high in glycine and alanine content, while sericin has a completely different amino acid composition than fibroin, and serine occupies more than 1/3 of the total constituent amino acids. In the present invention, both silk protein fibroin and sericin are used as active ingredients, and it is confirmed that there is a large difference between the silkworm varieties.
본 발명의 바람직한 구현예에 따르면, 본 발명의 뼈분화 촉진 또는 유도용 조성물의 유효성분으로 포함되는 실크 피브로인 또는 실크 세리신은 각각 누에고치로부터 분리해 낸 후 동결건조 한 후, 줄기세포를 배양하는 최적 배지에 각각 넣고 희석하여 본 발명의 유효성분으로 적용하는 것이 특징이다.According to a preferred embodiment of the present invention, the silk fibroin or silk sericin, which is an active ingredient of the composition for promoting or inducing bone differentiation of the present invention, is separated from the cocoon and freeze-dried, And they are diluted to be applied as an active ingredient of the present invention.
본 발명의 바람직한 또 다른 구현예에 따르면, 상기와 같이 분리된 피브로인과 세리신을 모두 유효성분으로 포함하는 것으로써 이때 상기 피브로인과, 상기 세리신은 1:1중량비로 혼합되는 것을 특징으로, 이는 피브로인 또는 세리신 단독적용 에도 본 발명이 목적하는 효능을 나타내긴 하나 그 보다 더 상승된 효능을 나타내는 것이 특징이다. 하기 실시예에서는 상기 피브로인과 세리신을 누에 품종별로 분리해 내어 이들의 뼈분화 촉진 또는 유도효능에 대해 어떠한 차이를 나타내는지에 대해 실시하고 그 결과를 개시하였다. According to another preferred embodiment of the present invention, the fibroin and sericin as described above are both included as active ingredients, wherein the fibroin and the sericin are mixed at a weight ratio of 1: 1, The present invention is also characterized in that the present invention exhibits a desired effect but shows an elevated effect even in the case of sericin alone. In the following examples, the fibroin and sericin were separated by silkworm cultivars to show differences in promoting or inducing bone differentiation, and the results were disclosed.
줄기세포(MSC)의 골분화 유도시 본 발명의 상기 누에 품종별 유래 피브로인 또는 세리신 또는 이들의 혼합물을 적용한 경우에 대조군에 비해 대성잠, 백옥잠, 금옥잠, 골드실크, 연녹잠 모두 유의성 있는 결과를 얻을 수 있었으며, 특히 피브로인의 여러 품종 중에서도 대성잠, 백옥잠 금옥잠에서 상대적으로 더 높은 뼈분화 효능을 나타냄이 확인되었으며, 세리신의 경우에는 여러 품종 중에서 상대적으로 금옥잠에서 뼈분화효능을 나타냄을 확인한 바, 누에의 각 품종별로도 나타내는 효능이 일부 차이가 남을 확인하였다.When fibroin or sericin derived from the silkworm cultivars of the present invention or a mixture thereof was used to induce bone differentiation of stem cells (MSCs), there was a significant difference in the results of the mature sleep, white moth, gold moth sleep, gold silk, Among the various breeds of fibroin, relatively high bone differentiation efficacy was observed in Daesungwam and Baekokwoongmokokwam, and sericin showed relatively high bone differentiation efficacy in various berries. As a result, it was confirmed that there was some difference in the efficacy of each silkworm varieties.
이러한 상기 유효성분들(피브로인 또는 세리신 또는 이들의 혼합물)은 인체 무해하면서 뼈분화 촉진효능은 우수하며, 저렴하게 용이하게 적용가능한 바, 약학조성물 또는 식품조성물의 소재로 충분히 사용될 수 있는 바, 본 발명은 이러한 실크 단백질을 함유하는 줄기세포의 뼈분화 촉진 또는 유도용 약학 조성물을 제공할 수 있다. 상기 약학 조성물은 통상의 방법에 따라 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다. 본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 추출물 또는 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 상기 견사단백질을 갖는 누에는 본 발명의 조성물에 0.1~100 중량%로 포함될 수 있다. Such effective components (fibroin or sericin or a mixture thereof) are excellent in promoting bone differentiation and harmless to human body, can be easily applied at low cost, and can be sufficiently used as a material for a pharmaceutical composition or a food composition. And a pharmaceutical composition for promoting or inducing bone differentiation of stem cells containing the silk protein can be provided. The pharmaceutical composition may further contain an appropriate carrier, excipient or diluent according to a conventional method. Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient, such as starch, calcium carbonate, sucrose, Lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like. The silkworm silk protein may be included in the composition of the present invention in an amount of 0.1 to 100% by weight.
본 발명의 조성물의 투여량은 치료받을 대상의 연령, 성별, 체중과, 치료할 특정 질환 또는 병리 상태, 질환 또는 병리 상태의 심각도, 투여경로 및 처방자의 판단에 따라 달라질 것이다. 이러한 인자에 기초한 투여량 결정은 당업자의 수준 내에 있으며, 일반적으로 투여량은 0.01㎎/㎏/일 내지 대략 2000㎎/㎏/일의 범위이다. 더 바람직한 투여량은 1㎎/㎏/일 내지 500㎎/㎏/일이다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. The dosage of the composition of the present invention will vary depending on the age, sex, body weight of the subject to be treated, the particular disease or condition to be treated, the severity of the disease or condition, the route of administration and the judgment of the prescriber. Dosage determinations based on these factors are within the level of ordinary skill in the art and generally the dosage ranges from 0.01 mg / kg / day to approximately 2000 mg / kg / day. A more preferable dosage is 1 mg / kg / day to 500 mg / kg / day. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.
본 발명의 조성물은 쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 주사에 의해 투여될 수 있다. 본 발명의 조성물은 독성 및 부작용이 없으므로 예방 목적으로 장기간 복용시에도 안심하고 사용할 수 있다. The composition of the present invention can be administered to mammals such as rats, livestock, humans, and the like in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection. Since the composition of the present invention has no toxicity and side effects, it can be safely used for prolonged use for preventive purposes.
또한, 본 발명은 상기와 같은 실크 단백질을 함유하는 줄기세포의 뼈분화 촉진 또는 유도용 식품 조성물도 제공할 수 있다. 이때 상기 실크 단백질은 본 발명의 식품 조성물에 0.001~100 중량%로 하여 첨가될 수 있다. 본 발명의 식품 조성물은 정제, 캡슐제, 환제 또는 액제 등의 형태를 포함하며, 본 발명의 조성물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 드링크제, 육류, 소세지, 빵, 캔디류, 스넥류, 면류, 아이스크림, 유제품, 스프, 이온음료, 음료수, 알코올 음료, 껌, 차 및 비타민 복합제 등이 있다. The present invention also provides a food composition for promoting or inducing bone differentiation of stem cells containing the silk protein as described above. The silk protein may be added to the food composition of the present invention in an amount of 0.001 to 100% by weight. The food composition of the present invention includes forms such as tablets, capsules, pills, and liquids. Examples of foods to which the composition of the present invention can be added include various kinds of drinks, meat, sausage, bread, , Noodles, ice cream, dairy products, soups, ionic drinks, beverages, alcoholic beverages, gums, tea and vitamin complexes.
이하에서는 실시예를 들어 본 발명에 관하여 더욱 상세하게 설명할 것이나, 이들 실시예는 단지 설명의 목적을 위한 것으로 본 발명의 보호 범위를 제한하고자 하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to examples, but these examples are for illustrative purposes only and are not intended to limit the scope of protection of the present invention.
<실시예 1 및 비교예 1 내지 4. 누에 품종별 유래 세리신을 포함하는 줄기세포의 뼈분화 촉진또는 유도용 조성물들 제조> <Example 1 and Comparative Examples 1 to 4. Preparation of compositions for promoting or inducing bone differentiation of stem cells comprising sericin derived from silkworm varieties>
먼저, 본 발명에 적용할 누에를 상기 표 1에 나타난 바와 같이 품종별로 준비하였다. 그 다음 각각의 품종별 누에에서 실크단백질인 세리신을 분리해내었다.First, silkworms to be applied to the present invention were prepared for each variety as shown in Table 1 above. Then, silk protein sericin was separated from each silkworm silkworm.
누에고치와 증류수의 비율을 1:30으로 하여 115℃에서 5시간 동안 반응을 시켜 얻은 용액으로 이 용액을 동결건조하여 세리신 분말을 제조하였으며, 이를 줄기세포의 최적 배지(하기 실험예1에 기재된 줄기세포 배양배지를 의미함)에 희석한 후, 이를 유효성분으로 포함하는 줄기세포의 뼈분화 촉진 또는 유도용 조성물들을 제조하였다. The resulting solution was lyophilized to give a solution of the silkworm powder prepared by mixing the silkworm cocoa powder and distilled water at a ratio of 1:30 at a temperature of 115 ° C for 5 hours. The resulting solution was lyophilized to prepare an optimal medium of the stem cells Cell culture medium), followed by preparing compositions for promoting or inducing bone differentiation of stem cells containing the same as an active ingredient.
<실시예 2 내지 4 및 비교예 5, 6. 누에 품종별 유래 피브로인을 포함하는 줄기세포의 뼈분화 촉진또는 유도용 조성물들 제조> <Examples 2 to 4 and Comparative Examples 5 and 6. Preparation of compositions for promoting or inducing bone differentiation of stem cells containing fibroin derived from silkworm varieties>
먼저, 본 발명에 적용할 누에를 상기 표 2에 나타난 바와 같이 품종별로 준비하였다. 그 다음 각각의 품종별 누에에서 실크단백질인 피브로인을 분리해내었다. First, silkworms to be applied to the present invention were prepared for each variety as shown in Table 2 above. Then, silk proteins, fibroin, were isolated from silkworms of each breed.
누에고치 150g을 sodium oleate 0.75g, sodium carbonate 0.45g과 증류수 8L를 40분 동안 100℃에서 끓이는 작업을 2회 실시하고 이후 증류수로만 100℃에서 끓이는 작업을 2회 실시하여 건조시켜 세리신이 제거된 순수한 피브로인을 얻었다. 이후, 물: 알콜: 염화칼슘 = 8: 2: 1(몰비율)의 용액 1L에 순수한 피브로인 35g을 넣어 85℃이상의 냉각장치가 귀된 히팅맨틀에서 7시간 동안 용해시키고, 투석막에 용해된 피브로인 용액을 넣어 3일동안 투석하여 염을 제거하여 순수한 피브로인 용액을 제조한 다음 이를 동결건조하여 피브로인 시료를 제작하였다. 본 발명에서 사용될 피브로인은 이렇게 제작된 동결건조 피브로인을 줄기세포의 최적 배지(하기 실험예1에 기재된 줄기세포 배양배지를 의미함)에 희석한 후, 이를 유효성분으로 포함하는 줄기세포의 뼈분화 촉진 또는 유도용 조성물들을 제조하였다. 150 g of silkworm cocoa was treated with 0.75 g of sodium oleate, 0.45 g of sodium carbonate and 8 L of distilled water for 40 minutes at 100 ° C for two times, followed by boiling at 100 ° C only for distilled water, followed by drying to remove sericin Fibroin was obtained. Thereafter, 35 g of pure fibroin was added to 1 L of a solution of water: alcohol: calcium chloride = 8: 2: 1 (molar ratio), and a cooling device at 85 ° C or more was dissolved in the heated heating mantle for 7 hours. Then, the fibroin solution dissolved in the dialysis membrane The solution was dialyzed for 3 days to remove the salt to prepare a pure fibroin solution, which was freeze-dried to prepare a fibroin sample. The fibroin to be used in the present invention is prepared by diluting the lyophilized fibroin prepared as described above in an optimal medium of stem cells (which means the stem cell culture medium described in Experimental Example 1), and then promoting bone differentiation Or inducing compositions were prepared.
<실시예 5. 본 발명의 누에 유래 피브로인+세리신을 포함하는 뼈분화 촉진 또는 유도용 조성물11 제조> <Example 5: Preparation of composition 11 for promoting or inducing bone differentiation containing silkworm derived fibroin + sericin>
누에 품종 중 피브로인과 세리신이 모두 뼈분화 촉진 또는 유도 효과를 나타내는 품종이 금옥잠인 것으로 확인 된 바, 금옥잠으로부터 피브로인과 세리신을 분리하였다.Among the silkworm varieties, both fibroin and sericin were found to be a beryllium that exhibited bone differentiation promoting or inducing effects, and fibroin and sericin were separated from kaolin.
그 다음 상기 분리해 낸 피브로인과 세리신을 1:1 중량비로 혼합하여 이를 유효성분으로 포함하는 본 발명의 줄기세포의 뼈분화 촉진 또는 유도용 조성물을 제조하였다. Then, the separated fibroin and sericin were mixed at a weight ratio of 1: 1 to prepare a composition for promoting or inducing bone differentiation of the stem cells of the present invention containing the same as an active ingredient.
<실험예 1. 누에 품종별 피브로인 또는 세리신의 줄기세포의 골분화 촉진 또는 유도능 확인> EXPERIMENTAL EXAMPLE 1: Confirmation of promoting or inducing bone differentiation of fibroin or sericin in silkworm variety according to silkworm varieties.
1. 실험방법1. Experimental Method
줄기세포를 24well plate에 65,000cell/well 배양하였다. 줄기세포가 80%이상 채워질 때까지 배양하고 여기에 뼈세포로 분화를 유도하기 위해 Dexamethasone과 β-glycerophospate를 첨가하여 뼈세포 분화를 유도하였다. 배양 초기부터 실크단백질을 0~10-6로 첨가해 준 실험군을 분화후라 하였다. 분화를 유도한 다음 3주 동안 배양하고 실크 단백질이 포함된 배양배지는 3일 간격으로 교체해 주었다. 실크 단백질 0%는 줄기세포를 배양하고 같은 방법으로 분화를 유도한 것으로 단지 실크단백질만 첨가하지 않은 대조군이다. 이렇게 분화유도 후 3주가 지난 세포를 Alizarin S로 염색하여 뼈세포 분화정도를 확인하였으며, 세포의 미네랄에 부착된 alizarin red의 양을 정량하기 위해서 10% cetylphyridinium chloride를 이용해서 염색된 Alizarin을 용해하여 562 nm에서 비색법으로 정량하였다. 모든 실험은 4번 반복 수행하였다.Stem cells were cultured on a 24-well plate at 65,000 cells / well. Bone marrow differentiation was induced by adding Dexamethasone and β-glycerophospate to induce differentiation into bone cells. From the beginning of the culture, the experimental group to which silk protein was added at 0 to 10 -6 was referred to as "differentiation". After induction of differentiation, the cells were cultured for 3 weeks, and the culture medium containing the silk protein was replaced every 3 days. 0% of silk protein was cultured stem cells and induces differentiation in the same way. It is a control group not containing only silk protein. The cells were stained with Alizarin S for 3 weeks after induction of differentiation, and the degree of osteoclast differentiation was determined. In order to quantify the amount of alizarin red adhered to the cell minerals, the stained Alizarin was dissolved in 10% cetylphyridinium chloride to obtain 562 nm by the colorimetric method. All experiments were repeated 4 times.
2. 실험결과2. Experimental results
상기 실험결과, 도 1 내지 4에 나타나 있듯이, 피브로인과 세리신 모두 줄기세포의 골분화 촉진 또는 유도능을 나타냄을 확인하였으며, 특히 세리신은 누에 품종 중에서도 금옥잠에서 분리해 낸 세리신에서 가장 효능이 우수하였으며, 피브로인은 누에 품종 중에서도 대성잠, 백옥잠, 금옥잠 3종에 대해서 분리해낸 피브로인이 가장 효능이 우수하게 나타남을 확인하였다. As a result, as shown in FIGS. 1 to 4, both fibroin and sericin showed the ability to stimulate or induce bone differentiation of stem cells. Among the silkworm varieties, sericin was most effective in sericin isolated from granola , And fibroin among the silkworm varieties were identified as the most efficacious fibroin isolated from three species of Daesung, Baekok, and Geumokam.
<실험예 2. 금옥잠에서 분리해 낸 피브로인과 세리신 혼합상태에서의 줄기세포의 골분화 촉진 또는 유도능 확인> <Experimental Example 2> Confirmation of promoting or inducing osteogenic differentiation of stem cells in a mixed state of fibroin and sericin,
1. 실험방법1. Experimental Method
상기 실험예 1과 같은 방법을 적용하여 실험하였다.The same experiment as in Experimental Example 1 was applied to the experiment.
실험 대상으로는 상기 실험예1에서 가장 우수한 효능을 나타내던 누에 품종인 금옥잠을 대상으로 분리해낸 피브로인과 세리신을 1:1 중량비로 혼합하여 본 실험을 수행하였다.As a test subject, fibroin and sericin isolated in a silkworm, a silkworm variety having the best efficacy in Experimental Example 1, were mixed at a weight ratio of 1: 1.
이때, 실크단백질인 세리신 또는 피브로인 또는 이들 혼합물을 적용할 시에는 10-5 농도 적용시에 Absorbance(562nm) 값을 측정하여 나타내었다.At this time, Absorbance (562 nm) was measured by applying silk protein sericin or fibroin or a mixture thereof at 10 -5 concentration.
2. 실험결과2. Experimental results
상기 실험결과, 하기 표 3과 같이 나타났다. The results of the experiment are shown in Table 3 below.
상기 표 3에 나타나 있듯이, 피브로인 또는 세리신 단독물질에 대해서도 대조구(실크단백질을 포함하지 않음) 대비 뼈분화 촉진효능을 나타내었으며, 피브로인과 세리신 혼합물에서는 상기 피브로인 또는 세리신 단독물질 대비 보다 상승된 줄기세포의 뼈분화 촉진 효과를 나타냄을 확인하였다. As shown in Table 3, fibroin or sericin alone exhibited bone-differentiation promoting effect in comparison with the control (not containing silk protein). In the fibroin and sericin mixture, the fibroin or sericin alone exhibited a higher level of stem cells than the fibroin or sericin alone It was confirmed that the effect of promoting bone differentiation was demonstrated.
결론적으로 상기와 같이 누에에서 유래된 피브로인 또는 세리신 또는 이들 혼합물에서 줄기세포의 뼈분화 촉진 또는 유도효과를 나타남에 따라 이를 포함하는 줄기세포의 뼈분화 촉진 도는 유도용 약학 조성물 또는 식품 조성물이 제공됨에 따라, 종래 고가의 뼈분화유도물질(덱사미타손)을 대체할 수 있어 인체무해하면서 용이하고 저렴하게 뼈분화를 촉진하거나 유도할 수 있게 된다.As a result, since fibroin or sericin derived from silkworm or the mixture thereof has the effect of promoting or inducing bone differentiation of stem cells as described above, the pharmaceutical composition or food composition for inducing bone differentiation promoting stem cells comprising the same , It is possible to replace or replace the expensive expensive bone differentiation inducing substance (dexamitone), thereby promoting or inducing bone differentiation easily and inexpensively while being harmless to the human body.
<제제예 1. 약학적 제제>≪ Formulation Example 1 >
실시예 5의 줄기세포의 뼈분화 촉진 또는 유도용 조성물 200g을 락토오스 175.9g, 감자전분 180g 및 콜로이드성 규산 32g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄해서 14 메쉬체를 통과시켰다. 이것을 건조시키고 여기에 감자전분 160g, 활석 50g 및 스테아린산 마그네슘 5g을 첨가해서 얻은 혼합물을 정제로 만들었다. 200 g of the composition for promoting or inducing bone differentiation of the stem cell of Example 5 was mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. To this mixture was added a 10% gelatin solution, which was pulverized and passed through a 14-mesh sieve. This was dried, and a mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into tablets.
<제제예 2. 건강기능식품 제조>≪ Formulation example 2. Preparation of health functional foods &
제제예 2-1. 조리용 양념의 제조Formulation Example 2-1. Manufacture of cooking seasonings
실시예 5의 줄기세포의 뼈분화 촉진 또는 유도용 조성물 1 중량%를 조리용 양념에 첨가하여 건강 증진용 조리용 양념을 제조하였다.1% by weight of a composition for promoting or inducing bone differentiation of stem cells of Example 5 was added to a cooking sauce to prepare a cooking sauce for health promotion.
제제예 1-2. 유제품(dairy products)의 제조Formulation Example 1-2. Manufacture of dairy products
실시예 5의 줄기세포의 뼈분화 촉진 또는 유도용 조성물 0.1 중량%를 우유에 첨가하고, 상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다.0.1% by weight of a composition for promoting or inducing bone differentiation of the stem cell of Example 5 was added to milk, and a variety of dairy products such as butter and ice cream were prepared using the milk.
상기의 본 발명은 바람직한 실시예를 중심으로 살펴보았으며, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자는 본 발명의 본질적 기술 범위 내에서 상기 본 발명의 상세한 설명과 다른 형태의 실시예들을 구현할 수 있을 것이다. 여기서 본 발명의 본질적 기술범위는 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention as defined by the appended claims. It will be possible. The essential technical scope of the present invention is set forth in the appended claims and any differences within the scope of equivalents thereof should be construed as being included in the present invention
Claims (16)
줄기세포의 뼈분화 촉진 또는 유도용 약학적 조성물.
A method for producing a silkworm comprising silkworm-derived fibroin as an active ingredient,
A pharmaceutical composition for promoting or inducing bone differentiation of stem cells.
상기 누에의 품종은 대성잠, 금옥잠, 백옥잠, 골든실크, 연록잠 중 어느 하나이상인 것이 특징인,
줄기세포의 뼈분화 촉진 또는 유도용 약학적 조성물.
The method according to claim 1,
The silkworm varieties are characterized by having at least one of the following characteristics:
A pharmaceutical composition for promoting or inducing bone differentiation of stem cells.
상기 누에의 품종은 대성잠, 금옥잠, 백옥잠 중 어느 하나이상인 것이 특징인,
줄기세포의 뼈분화 촉진 또는 유도용 약학적 조성물.
3. The method of claim 2,
The silkworm varieties are characterized by having at least one of the following characteristics:
A pharmaceutical composition for promoting or inducing bone differentiation of stem cells.
줄기세포의 뼈분화 촉진 또는 유도용 약학적 조성물.
Comprising sericin derived from silkworm as an active ingredient,
A pharmaceutical composition for promoting or inducing bone differentiation of stem cells.
상기 누에의 품종은 대성잠, 금옥잠, 백옥잠, 골든실크, 연록잠 중 어느 하나이상인 것이 특징인,
줄기세포의 뼈분화 촉진 또는 유도용 약학적 조성물.
5. The method of claim 4,
The silkworm varieties are characterized by having at least one of the following characteristics:
A pharmaceutical composition for promoting or inducing bone differentiation of stem cells.
상기 누에의 품종은 금옥잠인 것이 특징인,
줄기세포의 뼈분화 촉진 또는 유도용 약학적 조성물.
6. The method of claim 5,
The varieties of silkworms,
A pharmaceutical composition for promoting or inducing bone differentiation of stem cells.
줄기세포의 뼈분화 촉진 또는 유도용 약학적 조성물.
Which comprises sericin and fibroin derived from silkworm as an active ingredient,
A pharmaceutical composition for promoting or inducing bone differentiation of stem cells.
상기 세리신과 피브로인은 1:1 중량비로 포함되는 것이 특징인,
줄기세포의 뼈분화 촉진 또는 유도용 약학적 조성물.
8. The method of claim 7,
Wherein said sericin and fibroin are contained in a weight ratio of 1: 1.
A pharmaceutical composition for promoting or inducing bone differentiation of stem cells.
줄기세포의 뼈분화 촉진 또는 유도용 식품 조성물.
A method for producing a silkworm comprising silkworm-derived fibroin as an active ingredient,
A food composition for promoting or inducing bone differentiation of stem cells.
상기 누에의 품종은 대성잠, 금옥잠, 백옥잠, 골든실크, 연록잠 중 어느 하나이상인 것이 특징인,
줄기세포의 뼈분화 촉진 또는 유도용 식품 조성물.
10. The method of claim 9,
The silkworm varieties are characterized by having at least one of the following characteristics:
A food composition for promoting or inducing bone differentiation of stem cells.
상기 누에의 품종은 대성잠, 금옥잠, 백옥잠 중 어느 하나이상인 것이 특징인,
줄기세포의 뼈분화 촉진 또는 유도용 식품 조성물.
11. The method of claim 10,
The silkworm varieties are characterized by having at least one of the following characteristics:
A food composition for promoting or inducing bone differentiation of stem cells.
줄기세포의 뼈분화 촉진 또는 유도용 식품 조성물.
Comprising sericin derived from silkworm as an active ingredient,
A food composition for promoting or inducing bone differentiation of stem cells.
상기 누에의 품종은 대성잠, 금옥잠, 백옥잠, 골든실크, 연록잠 중 어느 하나이상인 것이 특징인,
줄기세포의 뼈분화 촉진 또는 유도용 식품 조성물.
13. The method of claim 12,
The silkworm varieties are characterized by having at least one of the following characteristics:
A food composition for promoting or inducing bone differentiation of stem cells.
상기 누에의 품종은 금옥잠인 것이 특징인,
줄기세포의 뼈분화 촉진 또는 유도용 식품 조성물.
14. The method of claim 13,
The varieties of silkworms,
A food composition for promoting or inducing bone differentiation of stem cells.
줄기세포의 뼈분화 촉진 또는 유도용 식품 조성물.
Which comprises sericin and fibroin derived from silkworm as an active ingredient,
A food composition for promoting or inducing bone differentiation of stem cells.
상기 세리신과 피브로인은 1:1 중량비로 포함되는 것이 특징인,
줄기세포의 뼈분화 촉진 또는 유도용 식품 조성물.16. The method of claim 15,
Wherein said sericin and fibroin are contained in a weight ratio of 1: 1.
A food composition for promoting or inducing bone differentiation of stem cells.
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Citations (3)
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|---|---|---|---|---|
| KR101236285B1 (en) | 2010-04-30 | 2013-02-26 | 대한민국 | Bone Graft Comprising Silk Fibroin Peptide as an Active Ingredient |
| KR101315202B1 (en) | 2011-05-19 | 2013-10-08 | 우리들생명과학 주식회사 | Composition for inducing a bone differentiation and method for enhancing a bone differentiation using the same |
| KR101472046B1 (en) | 2013-05-28 | 2014-12-16 | 주식회사 바이오알파 | An injectable composition for bone defects and a preparation method therof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101236285B1 (en) | 2010-04-30 | 2013-02-26 | 대한민국 | Bone Graft Comprising Silk Fibroin Peptide as an Active Ingredient |
| KR101315202B1 (en) | 2011-05-19 | 2013-10-08 | 우리들생명과학 주식회사 | Composition for inducing a bone differentiation and method for enhancing a bone differentiation using the same |
| KR101472046B1 (en) | 2013-05-28 | 2014-12-16 | 주식회사 바이오알파 | An injectable composition for bone defects and a preparation method therof |
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