KR101428512B1 - A pharmaceutical composition for treating and preventing bonedisease containing methyl vanillate - Google Patents
A pharmaceutical composition for treating and preventing bonedisease containing methyl vanillate Download PDFInfo
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- KR101428512B1 KR101428512B1 KR1020120024550A KR20120024550A KR101428512B1 KR 101428512 B1 KR101428512 B1 KR 101428512B1 KR 1020120024550 A KR1020120024550 A KR 1020120024550A KR 20120024550 A KR20120024550 A KR 20120024550A KR 101428512 B1 KR101428512 B1 KR 101428512B1
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Abstract
본 발명은 골질환 예방 및 치료용 약학조성물에 관한 것으로 좀 더 상세하게는 메틸 바닐레이트(Methyl vanillate)를 유효성분으로 함유하는 골 질환 예방 및 치료용 약학조성물에 관한 것이다. 본 발명에 의한 조성물은 천연물로부터 유래되어 부작용이 없고, 뼈의 분해 억제가 아닌 형성을 촉진하여 기존의 뼈 분해억제제의 단점을 보완하여 골다공증 및 관련 질병의 치료에 효과적이다.The present invention relates to a pharmaceutical composition for preventing and treating bone diseases, and more particularly, to a pharmaceutical composition for preventing and treating bone diseases containing methyl vanillate as an active ingredient. The composition according to the present invention is derived from a natural product and has no side effects. It is effective for the treatment of osteoporosis and related diseases by complementing the disadvantages of the existing bone decomposition inhibitor by promoting the formation rather than inhibiting the degradation of the bone.
Description
본 발명은 메틸 바닐레이트를 유효성분으로 함유하는 골질환 예방 및 치료용 약학조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing and treating bone diseases containing methyl vanillate as an active ingredient.
골다공증이란 뼈의 화학적 조성에는 변화가 없고, 단위용적 내의 골량의 감소를 초래하여 경미한 충격에도 쉽게 골절을 일으킬 수 있는 질환을 말한다. 현재 골다공증 치료제의 대부분은 병의 증상을 완화하거나 진행을 막는 것이 목표라 주로 골흡수 억제제(antiresorptive drug)로 골 손실을 지연시키는 작용을 한다. 현재 사용하는 골다공증 치료제는 파골세포(골 흡수에 관여하는 세포)의 기능을 약화시켜 뼈 손실을 막아주는 비스포스포네이트(Bisphosphonates) 제제가 주류를 이루며, 머크사(社)의 `포사맥스`, 프록터갬블사(社)의 `악토넬` 등이 있다. 하지만 이들 치료제는 뼈를 형성을 촉진하는 것이 아닌 분해 억제제로 지속적인 사용시 뼈를 푸석푸석하게 하여 지속적인 사용시 추가적인 골절을 유도할 수 있기 때문에 근본적인 치료는 될 수 없는 상황으로 대체제가 절실한 실정이다.Osteoporosis is a disease in which there is no change in the chemical composition of the bone and a decrease in bone mass in the unit volume, which can easily cause fracture even in a slight impact. Currently, the majority of osteoporosis treatment drugs to alleviate the symptoms or prevent the progression of the goal is mainly antiresorptive drug (antiresorptive drug) to delay the action of bone loss. Currently, osteoporosis treatment drugs are bisphosphonates, which inhibit bone loss by weakening the functions of osteoclasts (bone resorption-related cells). Merck's Fosamax, Procter Gamble, And "Actonel". However, these treatments do not promote the formation of bones, but as a decomposition inhibitor, it is necessary to replace the bone because it can induce additional fractures in continuous use.
최근 들어 뼈의 형성과 관련된 여러 종류의 단백질과 유전자의 기능이 밝혀짐으로써 이러한 단백질 및 유전자들을 표적으로 하는 `뼈 형성 촉진제`의 개발에 대한 다양한 시도가 다국적 제약회사나 국내에서 이루어지고 있다.
Recently, various functions related to the formation of bone have been revealed, and various attempts have been made in the multinational pharmaceutical companies or in domestic for the development of `bone formation promoter` targeting these proteins and genes.
한편, Wnt/β-catenin 신호전달체계의 비정상적인 조절은 대장암과 간암과 같은 여러 암의 발생에 연관되어있다. 따라서 Wnt/β-catenin 신호전달체계는 항암제 개발에 표적으로 여겨지고 있다. 뿐만 아니라, Wnt 단백질의 receptors 중 하나인 Lrp5(low-density lipoprotein receptor-related protein 5)의 이상 (mutation)이 뼈 질량(bone mass)를 조절한다는 사실은 Wnt 신호전달계가 뼈와 관련이 있다는 사실을 보여주고 있고(Cell Signal., 2008. 20:999-1009.), 사람에게서 Lrp5유전자에 loss of function 돌연변이가 발생하면 (Wnt/β-catenin 신호전달계 비활성화) 골밀도 감소로 인해 나타나는 대표적인 유전질환인 OPPG (osteoporosis pseudoglioma syndrome)가 관찰된다고 보고되었으며(Cell 2001;107(4): 513-523.), 사람에게서 Lrp5유전자에 gain of function 돌연변이(G171V mutation )가 발생하면 (Wnt/β-catenin 신호전달계 활성화) bone mass 증가가 일어난다(Am J Hum Genet 1997;60 (6):1326-1332./ N Engl J Med 2002;346(20):1513-1521)고 보고되어 있다. 따라서, Wnt/β-catenin 신호전달계의 뼈 성장 및 골밀도 조절에 대한 관련성이 활발하게 연구되고 있으며, 골다공증 치료에 있어 효과적이고 안전한 약물 치료 표적으로 각광받고 있다(Boyden et al. N. Engl. J. Med. 2002; Little et al. Am. J. Hum. Genet. 2002; Einhorn et al., Science Translational Medicine, 2010; Yavropoulous et al., Exepert Review of Endocrinology and Metabolism, 2010; Wagner et al. Current Molecular Pharmacology, 2011).
On the other hand, abnormal regulation of the Wnt / β-catenin signaling pathway is associated with the development of multiple cancers, such as colorectal cancer and liver cancer. Therefore, the Wnt / β-catenin signaling system is considered as a target for the development of anticancer drugs. In addition, the fact that the mutation of Lrp5 (low-density lipoprotein receptor-related protein 5), one of the receptors of Wnt proteins, regulates bone mass, suggests that the Wnt signaling system is involved in bone ( Cell Signal ., 2008. 20 : 999-1009). When a loss of function mutation in the Lrp5 gene occurs in humans (inactivation of Wnt / β-catenin signaling pathway), OPPG (Wnt / β-catenin signal transduction system activation) in the Lrp5 gene in humans (Cell 2001; 107 (4): 513-523). It has been reported that osteoporosis pseudoglioma syndrome ) increased bone mass (Am J Hum Genet 1997; 60 (6): 1326-1332./N Engl J Med 2002; 346 (20): 1513-1521). Therefore, the relevance of the Wnt / β-catenin signal transduction system to bone regeneration and bone density regulation has been actively studied, and it has been regarded as an effective and safe drug treatment target in the treatment of osteoporosis (Boyden et al., N. Engl. 2010; Wagner et al. Current Molecular Pharmacology < RTI ID = 0.0 > et al., ≪ / RTI & , 2011).
이에 본 발명자들은 천연물인 지구자(Hovenia dulcis Thunb.)로부터 Wnt/β-카테닌 신호전달계를 활성화 시킬 수 있는 물질을 발견하여 골질환 치료 용도의 조성물을 개발하기에 이르렀다.Accordingly, the present inventors have discovered a substance capable of activating the Wnt / beta -catenin signal transduction system from a natural material ( Hovenia dulcis Thunb.) And developed a composition for treating bone diseases.
본 발명은 Wnt/β-카테닌 신호전달계를 활성화 시킬 수 있는 물질을 포함하는 골질환 치료 용도의 조성물을 제공하는 것을 목적으로 한다.It is an object of the present invention to provide a composition for treating bone diseases comprising a substance capable of activating a Wnt / beta -catenin signaling system.
상기 목적을 달성하기 위하여 본 발명의 일 구체예에서 메틸 바닐레이트(Methyl vanillate)를 유효성분으로 함유하는 골 질환 예방 및 치료용 약학조성물을 제공한다. 상기 골 질환은 이에 한정하지 않지만 골다공증(osteoporosis), 골연화증(osteomalacia), 구루병, 섬유성 골염, 무형성 골질환 및 대사성 골질환으로 구성된 군으로부터 선택된 어느 하나인 것을 특징으로 하고, 상기 메틸 바닐레이트는 Wnt/β-카테닌 신호전달계의 활성을 촉진하는 것을 특징으로 하며, 상기 메틸 바닐레이트는 Wnt/β-카테닌 신호전달계 활성에 의한 뼈 형성을 촉진하는 것을 특징으로 하며, 상기 골 질환이 골다공증(osteoporosis)인 것을 특징으로 하며, 상기 약학조성물은 경구, 비경구, 동맥내, 피내, 경피, 근육내, 복강내, 정맥내, 피하 및 비내 투여될 수 있다.
In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing and treating bone diseases, which comprises methyl vanillate as an active ingredient. The bone disease may be, but is not limited to, any one selected from the group consisting of osteoporosis, osteomalacia, rickets, fibrous bone disease, intractable bone disease and metabolic bone disease, / beta -catenin signal transduction system, wherein the methyl vanillylate promotes bone formation by Wnt / beta -catenin signal transduction system activity, wherein the bone disease is osteoporosis And the pharmaceutical composition may be administered orally, parenterally, intraarterally, intradermally, percutaneously, intramuscularly, intraperitoneally, intravenously, subcutaneously, and intranasally.
일 구체예에서 메틸 바닐레이트(Methyl vanillate)를 유효성분으로 함유하는 탈모 질환의 예방 및 치료용 약학조성물을 제공한다. 상기 메틸 바닐레이트는 Wnt/β-카테닌 신호전달계의 활성을 촉진하는 것을 특징으로 하고, 상기 조성물은 경구, 비경구, 동맥내, 피내, 경피, 근육내, 복강내, 정맥내, 피하 및 비내 투여 될 수 있으며, 상기 조성물은 크림, 젤, 패취, 분무제, 연고제, 경고제, 로션제, 리니멘트제, 파스타제 또는 카타플라스마제 제형일 수 있으며, 상기 탈모 질환은 이에 한정하지 않지만 휴지기 탈모증, 원형 탈모증, 생장기 모발 탈모증, 외상성 탈모증, 반흔성 탈모증 또는 비반흔성 탈모증일 수 있다.
In one embodiment, there is provided a pharmaceutical composition for preventing and treating hair loss diseases containing methyl vanillate as an active ingredient. Wherein said methyl vanillyl promotes the activity of a Wnt /? -Catenin signaling system, said composition being administered orally, parenterally, intraarterially, intradermally, transdermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, And the composition may be a cream, gel, patch, spray, ointment, warning agent, lotion, liniment, pasta or cataplasma formulation, Alopecia, alopecia areata, traumatic alopecia, cicatric alopecia or non-cicatric alopecia.
일 구체예에서 메틸 바닐레이트(Methyl vanillate)를 유효성분으로 함유하는 상처 치료용 약학조성물을 제공한다. 상기 메틸 바닐레이트는 Wnt/β-카테닌 신호전달계의 활성을 촉진하는 것을 특징으로 하고, 상기 조성물은 경구, 비경구, 동맥내, 피내, 경피, 근육내, 복강내, 정맥내, 피하 및 비내 투여될 수 있으며, 상기 조성물은 크림, 젤, 패취, 분무제, 연고제, 경고제, 로션제, 리니멘트제, 파스타제 또는 카타플라스마제 제형일 수 있으며, 상기 상처는 일반적인 외상 또는 욕창인 것을 특징으로 한다.
In one embodiment, there is provided a pharmaceutical composition for the treatment of wounds containing methyl vanillate as an active ingredient. Wherein said methyl vanillyl promotes the activity of a Wnt /? -Catenin signaling system, said composition being administered orally, parenterally, intraarterially, intradermally, transdermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, And the composition may be a cream, a gel, a patch, a spray, an ointment, a warning agent, a lotion, a liniment, a pasta or a cataplasm, and the wound is a general trauma or a pressure ulcer .
일 구체예에서 메틸 바닐레이트(Methyl vanillate)를 유효성분으로 함유하는 대사성 질환 예방 및 치료용 약학조성물을 제공한다. 상기 메틸 바닐레이트는 Wnt/β-카테닌 신호전달계의 활성을 촉진하는 것을 특징으로 하고, 상기 조성물은 경구, 비경구, 동맥내, 피내, 경피, 근육내, 복강내, 정맥내, 피하 및 비내 투여되는 것을 특징으로 하며, 상기 대사성 질환은 이에 한정하지 않지만 당뇨병, 고지혈증, 지방간, 심혈관 질환, 동맥경화증 및 비만인 것을 특징으로 한다.
In one embodiment, there is provided a pharmaceutical composition for the prevention and treatment of metabolic diseases containing methyl vanillate as an active ingredient. Wherein said methyl vanillyl promotes the activity of a Wnt /? -Catenin signaling system, said composition being administered orally, parenterally, intraarterially, intradermally, transdermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, The metabolic diseases include, but are not limited to, diabetes, hyperlipidemia, fatty liver, cardiovascular disease, arteriosclerosis, and obesity.
일 구체예에서, 메틸 바닐레이트(Methyl vanillate)를 유효성분으로 함유하는 골 질환 예방 및 개선용 건강기능식품을 제공한다.
In one embodiment, there is provided a health functional food for prevention and improvement of bone diseases containing methyl vanillate as an active ingredient.
일 구체예에서, 메틸 바닐레이트(Methyl vanillate)를 유효성분으로 함유하는 탈모 질환의 예방 및 개선용 건강기능식품을 제공한다.
In one embodiment, a health functional food for prevention and improvement of hair loss diseases containing methyl vanillate as an active ingredient is provided.
일 구체예에서 메틸 바닐레이트(Methyl vanillate)를 유효성분으로 함유하는 탈모 질환의 예방 및 개선용 화장품조성물을 제공한다.
In one embodiment, there is provided a cosmetic composition for preventing and ameliorating hair loss diseases containing methyl vanillate as an active ingredient.
일 구체예에서 메틸 바닐레이트(Methyl vanillate)를 유효성분으로 함유하는 상처 치료용 건강기능식품을 제공한다.
In one embodiment, a health functional food for treating wounds containing methyl vanillate as an active ingredient is provided.
일 구체예에서 메틸 바닐레이트(Methyl vanillate)를 유효성분으로 함유하는 대사성 질환 치료용 건강기능식품을 제공한다.
In one embodiment, there is provided a health functional food for treating metabolic diseases containing methyl vanillate as an active ingredient.
본 발명의 Wnt/β-catenin 신호전달계는 뼈 성장 및 골밀도 조절에 대한 관련성 이외에도 발모, 상처 치유 및 지방 분화(대사성 질환)에도 관련이 있다.
The Wnt / β-catenin signal transduction system of the present invention is related to hair growth, wound healing, and lipid differentiation (metabolic diseases) in addition to bone growth and bone density regulation.
Wnt/β-카테닌 신호전달계는 모낭의 형성을 촉진하고(WNT signals are required for the initiation of hair follicle development. Andl T, et al. (2002) Dev Cell. 2: 643-653.), 모발주기의 성장기 동안 발현하는 유전자들을 유지하고 활성화하는데 중요한 역할을 하며(Wnt signaling maintains the hair-inducing activity of the dermal papilla. Kishimoto J, et al. (2000) Genes Dev 14: 1181-1185), 줄기세포로부터 케라티노사이트로의 분화를 촉진한다(β-catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Huelsken J, et al. (2001) Cell 105: 533-545)고 보고되어 있다.
The Wnt / β-catenin signaling pathway promotes the formation of hair follicles (WNT signals are required for the initiation of hair follicle development. Andl T, et al. (2002) Dev Cell 2: 643-653) (Wnt signaling maintains the hair-inducing activity of the dermal papilla. Kishimoto J, et al. (2000) Genes Dev 14: 1181-1185). (2001) Cell 105: 533-545), which has been reported to induce differentiation into latent cells (β-catenin controls hair follicle morphogenesis and stem cell differentiation in the skin.
또한, Wnt/β-카테닌 신호전달계는 TGF-β 신호전달계의 활성화를 통해 상처 치유를 강화하고(Effect of Wnt signaling pathway on wound healing. Zhang DL, et al. (2009) Biochem Biophys Res Commun. 378:149-151), 상처 치유 과정에서 중요한 조절자로 알려진 근섬유아세포의 형성을 촉진한다(Wnt3a Induces Myofibroblast Differentiation by Upregulating TGF-β Signaling Through SMAD2 in a β-Catenin-Dependent Manner. Jon MC, et al. (2011) Plos ONE. 6: e19809)고 보고되어 있다.
In addition, the Wnt / beta -catenin signaling system enhances wound healing through activation of the TGF-beta signaling pathway (Zhang DL, et al. (2009) Biochem Biophys Res Commun. 378: 149-151), facilitating the formation of myofibroblasts, known as important regulators in wound healing processes (Wnt3a Induces Myofibroblast Differentiation by Upregulating TGF-β Signaling Through SMAD2 in a β-Catenin-Dependent Manner Jon MC, et al. Plos ONE. 6: e19809).
마지막으로 Wnt 신호전달계는 β-카테닌의 안정화를 통해 지방전구세포로부터 지방으로의 분화를 저해하는 것으로 잘 알려져 있고(Wnt Signaling Inhibits Adipogenesis through β-Catenin-dependent and -independent Mechanisms Jennifer AK, et al. (2005) Wnt Signaling Inhibits Adipogenesis through β-Catenin-dependent and -independent Mechanisms. J Biol Chem 280: 24004-24010), Wnt 신호전달계는 3T3-L1 지방 전구세포의 지방으로의 분화를 억제한다고 보고되어 있다(Inhibition of Adipogenesis by Wnt Signaling. Sarah ER, et al. (2000) Science 289: 950-953).
Finally Wnt signaling systems are well known to inhibit the differentiation of adipose precursor cells into fat through stabilization of β-catenin (Wnt Signaling Inhibits Adipogenesis through β-catenin-dependent and -independent Mechanisms Jennifer AK, et al. (2005) The Wnt signaling system has been reported to inhibit the differentiation of 3T3-L1 adipocyte precursors into adipocytes (see, for example, Inhibition of Adipogenesis (Adipogenesis through Adipogenesis through β-catenin-dependent and -independent Mechanisms. J Biol Chem 280: 24004-24010) by Wnt Signaling. Sarah ER, et al. (2000) Science 289: 950-953).
본 발명의 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.
The compositions of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of pharmaceutical compositions.
본 발명의 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있으며, 추출물을 포함하는 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 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 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 단순 희석제인 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(propylene glycol), 폴리에틸렌 글리콜, 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.
The composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method Examples of carriers, excipients and diluents that can be contained in the composition including the extract include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, 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 administration 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.
본 발명의 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나 바람직한 효과를 위해서, 본 발명의 조성물은 1일 0.2 내지 200 ㎎/kg으로, 바람직하게는 2 내지 100 ㎎/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.
The preferred dosage of the composition of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the composition of the present invention is preferably administered at 0.2 to 200 mg / kg, preferably 2 to 100 mg / kg per 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, 생쥐, 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(intracerebroventricular) 주사에 의해 투여될 수 있다.
The composition of the present invention may be administered to mammals such as rats, mice, 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 or intracerebroventricular injections.
본 발명의 화합물을 포함하는 조성물은 골질환, 상처, 탈모 및 대사성질환 예방 및 개선을 위한 약제, 식품 및 음료 등에 다양하게 이용될 수 있다. 본 발명의 화합물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.
The composition containing the compound of the present invention can be used variously for medicines, foods and beverages for prevention and improvement of bone diseases, wounds, hair loss and metabolic diseases. Examples of foods to which the compound of the present invention can be added include various foods, beverages, gums, tea, vitamin complexes, health supplements and the like, and they can be used in powder, granule, tablet, have.
본 발명의 식품 또는 음료 중의 상기 화합물의 양은 일반적으로 본 발명의 건강식품조성물은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ㎖를 기준으로 0.02 내지 5 g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다.
The amount of the compound in the food or beverage of the present invention is generally from 0.01 to 15% by weight of the total food weight of the health food composition of the present invention, and the health beverage composition comprises 0.02 to 5 g, Can be added at a ratio of 0.3 to 1 g.
본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에 액체성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당 알콜이다. 상술한 것 이외의 향미제로서 천연 향미제 (타우마틴, 스테비아 추출물 (예를 들어, 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.
The health functional beverage composition of the present invention has no particular limitation on the liquid ingredient besides the above-mentioned compound as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary drinks. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. As natural flavors other than those described above, natural flavoring agents (tau martin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 조성물들은 천연 과일 주스 및 과일 주스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above-mentioned composition, the composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compositions of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
본 발명은 지구자 추출물에서 유래된 Wnt/β-카테닌 신호전달계를 활성화 시킬 수 있는 물질을 포함하는 조성물로서 기존의 치료제에 비해 부작용이 적고 효과가 뛰어나다.The present invention relates to a composition comprising a substance capable of activating a Wnt / 3-catenin signal transduction system derived from a mitochondrial extract, and has less side effects and excellent effects than existing therapeutic agents.
도 1은 갈로카테킨에 의한 뼈의 성장을 보여주는 사진이다.
도 2 는 갈로카테킨에 의한 POB의 분화유도를 나타내는 사진이다.
도 3 내지 4는 갈로카테킨 및 메틸바닐레이트의 ALP활성 효과를 보여주는 사진 및 그래프이다.BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a photograph showing bone growth by gallocatechin.
2 is a photograph showing the induction of POB differentiation by gallocatechin.
Figures 3 to 4 are photographs and graphs showing the effect of ALP activity of gallocatechin and methyl vanillylate.
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 with reference to the following examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.
실시예 1. 갈로카테킨(Gallocatechin) 및 메틸 바닐레이트(Methyl vanillate)의 준비Example 1 Preparation of Gallocatechin and Methyl vanillate
지구자 추출물에 갈로카테킨(Gallocatechin) 및 메틸 바닐레이트(Methyl vanillate)가 포함되어 있다는 보고를 바탕으로 sigma aldrich에서 구입하여 사용하였다(Chem Pharm Bull (Tokyo), 1996 Sep;44(9):1736-43; Yakugaku Zasshi. 1997 Feb;117(2):108-18; Arch Pharm Res. 2005 Jul;28(7):804-9).
(Chem. Pharm. Bull. Tokyo, 1996 Sep; 44 (9): 1736-7). Based on the report that gallocatechin and methyl vanillate are included in the extract of the kidneys, Arch Pharm Res 2005 Jul; 28 (7): 804-9).
실시예 2. 동물실험을 통한 갈로카테킨(Gallocatechin) 및 메틸 바닐레이트(Methyl vanillate)의 효능 확인Example 2. Confirmation of the efficacy of gallocatechin and methyl vanillate by animal experiments
Wnt/β-카테닌 신호전달계를 활성화 시킬 수 있는 지구자 추출물의 8가지 성분 중 효과가 알려지지 않은 갈로카테킨 및 메틸 바닐레이트를 농도를 달리하여 뼈의 성장에 미치는 영향을 알아보기로 하였다.We investigated the effect of gallocatechin and methyl vanillate, which have no effect on the growth of bone, on the growth of Wnt / β - catenin signal transduction system.
오리엔트 바이오에서 공급받은 생후 4일된 쥐의 머리덮개뼈(Calvaria)에서 분화를 유도하면서 2nM의 갈로카테킨 및 0.2nM의 메틸 바닐레이트를 일주일간 처리하였다. 그 두께를 측정한 결과 대조군에 비해 갈로카테킨 및 메틸 바닐레이트를 처리한 군에서 머리덮개뼈의 두께가 증가되었음을 확인하였다(도 1). 또한 양성대조군(지구자 추출물)에 비하여 적은 양으로 머리덮개뼈의 두께가 증가되었음을 확인할 수 있었다.
Treated with 2 nM of gallocatechin and 0.2 nM of methyl vanillylate for one week, inducing differentiation in calvaria of 4-day old rats fed from Orient Bio. As a result of measuring the thickness thereof, it was confirmed that the thickness of the head lid bone was increased in the group treated with gallocatechin and methyl vanillate (FIG. 1). In addition, it was confirmed that the thickness of the head cover bone was increased by a small amount compared with that of the positive control group (the kidney extract).
또한, primary osteoblast(POB) 세포에 갈로카테킨 20μM을 처리하여 9일간 분화를 시켰다(도 2). 그리고 뼈의 활성화를 나타내는 ALP(alkaline phosphatase:염기성 인산분해효소)의 활성을 보기 위해 염색 결과, 갈로카테킨 및 메틸바닐레이트를 처리한 군에서 ALP의 발현이 높아진 것을 관찰할 수 있었다(도 3 내지 4).
In addition, primary osteoblast (POB) cells were treated with
실시예 3. 골질환 치료를 위한 추출물의 생체 내 투여Example 3 In vivo administration of extracts for treating bone diseases
대한실험공급센터에서 공급받은 6주령의 특정병원체부재(specific pathogen-free, SPF) SD계 랫트를 사용하여 급성독성실험을 하기와 같이 실시하였다. 각 그룹당 2마리씩의 동물에 상기 실시예 1의 갈로카테킨 및 메틸 바닐레이트를 1g/㎏의 용량으로 1회 경구 투여 후, 동물의 폐사여부, 임상증상 및 체중변화를 관찰하고 혈액학적 검사와 혈액생화학적 검사를 실시하였으며, 부검하여 육안으로 강장기와 흉강 장기의 이상 여부를 관찰하였다. 실험결과, 실험 물질을 투여한 모든 동물에서 특이할 만한 임상증상이나 폐사된 동물은 없었으며, 체중변화, 혈액검사, 혈액생화학 검사 및 부검 소견 등에서도 독성변화는 관찰되지 않았다. 이상의 결과, 본 발명의 추출물은 랫트에서 각각 1g/㎏까지도 독성변화를 나타내지 않았으며, 경구투여 최소치사량(LD 50 )은 1g/㎏이상인 안전한 물질로 판단됨을 확인할 수 있었다.
The acute toxicity test was carried out as described below using specific pathogen-free (SPF) SD rats of 6 weeks old supplied from the experimental supply center. Two animals per group were orally administered with 1 g / kg of gallocatechin and methyl vanillate of Example 1 once, followed by observation of animal mortality, clinical signs and weight changes, and hematology test and blood biochemistry The autopsy was performed, and autopsy was performed to observe whether or not the organs and thoracic organs were abnormal. As a result of the experiment, there were no clinical symptoms or dead animals in all animals treated with the test substance, and no toxic change was observed in weight change, blood test, blood biochemical test, and autopsy findings. As a result, it was confirmed that the extract of the present invention did not exhibit any toxicity at 1 g / kg or more in rats, and that the oral LDL was at least 1 g / kg.
상기 결과를 기초로 볼 때, 상기 화합물은 탈모(WNT signals are required for the initiation of hair follicle development. Andl T, et al. (2002) Dev Cell. 2: 643-653.참고), 상처(Effect of Wnt signaling pathway on wound healing. Zhang DL, et al. (2009) Biochem Biophys Res Commun. 378:149-151참고) 및 대사성 질환(Wnt Signaling Inhibits Adipogenesis through β-Catenin-dependent and -independent Mechanisms Jennifer AK, et al. (2005) 참고)에 효과가 있을 것으로 판단된다.
Based on the above results, it has been found that the compounds are useful in the treatment of hair loss (WNT signals are required for the initiation of hair follicle development. Andl T, et al. (2002) Dev Cell. 2: 643-653) Wnt signaling pathway on wound healing. Zhang DL, et al. (2009) Biochem Biophys Res Commun. 378: 149-151) and metabolic diseases (Wnt Signaling Inhibits Adipogenesis through β-Catenin-dependent and -independent Mechanisms Jennifer AK, et al. (2005)).
지금까지 예시적인 실시 태양을 참조하여 본 발명을 기술하여 왔지만, 본 발명의 속하는 기술 분야의 당업자는 본 발명의 범주를 벗어나지 않고서도 다양한 변화를 실시할 수 있으며 그의 요소들을 등가물로 대체할 수 있음을 알 수 있을 것이다. 또한, 본 발명의 본질적인 범주를 벗어나지 않고서도 많은 변형을 실시하여 특정 상황 및 재료를 본 발명의 교시내용에 채용할 수 있다. 따라서, 본 발명이 본 발명을 실시하는데 계획된 최상의 양식으로서 개시된 특정 실시 태양으로 국한되는 것이 아니며, 본 발명이 첨부된 특허청구의 범위에 속하는 모든 실시 태양을 포함하는 것으로 해석되어야 한다.While the present invention has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. You will know. In addition, many modifications may be made to adapt a particular situation and material to the teachings of the invention without departing from the essential scope thereof. Accordingly, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention be construed as including all embodiments falling within the scope of the appended claims.
Claims (25)
상기 약학 조성물은 경구, 비경구, 동맥내, 피내, 경피, 근육내, 복강내, 정맥내, 피하 또는 비내 투여되는 것을 특징으로 하는 골다공증 치료 또는 예방용 약학 조성물.The method according to claim 1,
Wherein the pharmaceutical composition is administered orally, parenterally, intraarterally, intradermally, percutaneously, intramuscularly, intraperitoneally, intravenously, subcutaneously or intranasally.
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| US14/758,053 US20160038555A1 (en) | 2011-03-31 | 2012-03-30 | Composition Containing Extracts of the Fruit of Hovenia Dulcis THUNB as an Active Ingredient for Preventing and Treating Bone Diseases |
| PCT/KR2012/002366 WO2012134214A2 (en) | 2011-03-31 | 2012-03-30 | Composition containing extracts of the fruit of hovenia dulcis thunb as an active ingredient for preventing and treating bone diseases |
| US16/111,527 US11219656B2 (en) | 2011-03-31 | 2018-08-24 | Method of using composition containing Hovenia dulcis Thunb. extract as active ingredient for prevention and treatment of bone diseases |
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| Nature product sciences, Vol.6(4), pages 155-160(2000년 공개) * |
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