WO2020032426A1 - 티아민 유도체를 포함하는 혈관 또는 판막 석회화의 예방 또는 치료용 조성물 - Google Patents
티아민 유도체를 포함하는 혈관 또는 판막 석회화의 예방 또는 치료용 조성물 Download PDFInfo
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- WO2020032426A1 WO2020032426A1 PCT/KR2019/009015 KR2019009015W WO2020032426A1 WO 2020032426 A1 WO2020032426 A1 WO 2020032426A1 KR 2019009015 W KR2019009015 W KR 2019009015W WO 2020032426 A1 WO2020032426 A1 WO 2020032426A1
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- calcification
- valve
- vascular
- preventing
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Definitions
- the present invention relates to a composition for the prevention, improvement or treatment of vascular or valve calcification, and more particularly, to a composition for the prevention, improvement or treatment of vascular or valve calcification comprising a thiamine derivative.
- the present invention was made by the task number NRF-2017R1A2B3006406 under the support of the Ministry of Science and Technology Information and Communication, the research management specialized organization of the project is the Korea Research Foundation, the research project name is “medium research”, the project title is "Mitochondrial vesicle membrane ( New Treatment Mechanism for Chronic Inflammation and Metabolic Syndrome through Mitochondria-Associated ER Membrane (MAM) Interaction and Pyruvate Dehydrogenase Kinase (PDK) Activity ", Host Organization is Kyungpook National University ⁇ 2022.02.28.
- the present invention was made by the task number HI16C1501 under the support of the Ministry of Health and Welfare of the Republic of Korea, the research and management institution of the task is the Korea Health Industry Development Institute, the research project name is “leading lateralization research project”, the research title is “leading diabetes mellitus And Metabolic Disease Research Project ", the lead institution is Kyungpook National University Hospital, and the research period is 2016.04.01. ⁇ 2021.03.31.
- Blood vessels are circulatory organs that continuously regulate the movement of body fluids, supply oxygen and nutrients to tissues, and receive and process carbon dioxide or waste products from tissues.
- Vascular calcification is a deposit of minerals such as calcium and phosphoric acid in the blood vessels, increase the stiffness of the blood vessels cause vascular rupture. Vascular calcification is commonly found in patients with atherosclerosis, diabetes mellitus, and chronic renal failure. The loss of calcium accumulation inhibitors, induction of bone formation, nucleation complexes in blood, and cell death are the main causes of vascular calcification. Is not yet known.
- cardiovascular calcification contributes to the exacerbation of hypertension, heart failure, acute coronary syndrome and valve disease, leading to various complications (heart sudden death, myocardial infarction, angina pectoris and ischemic heart failure).
- cardiovascular calcification contributes to the exacerbation of hypertension, heart failure, acute coronary syndrome and valve disease, leading to various complications (heart sudden death, myocardial infarction, angina pectoris and ischemic heart failure).
- the exact mechanism of vascular calcification is not yet known, and the prevention and treatment for this has not yet been developed.
- the present inventors have made diligent research efforts to develop compositions for the prevention, improvement or treatment of vascular or valve calcification. As a result, the present invention was completed by clarifying that thiamine derivatives have an inhibitory effect on vascular calcification.
- a pharmaceutical composition for the prevention or treatment of vascular or valve calcification comprising thiamine derivatives and pharmaceutically acceptable salts thereof.
- Another object of the present invention is to provide a food composition for improving vascular or valve calcification, including thiamine derivatives and salts thereof.
- Another object of the invention is to provide a method for preventing or treating vascular or valve calcification comprising administering to a subject a pharmaceutical composition comprising a thiamine derivative and a pharmaceutically acceptable salt thereof.
- Still another object of the present invention is to provide a therapeutic use for vascular or valve calcification of a pharmaceutical composition comprising a thiamine derivative and a pharmaceutically acceptable salt thereof.
- the present inventors made diligent research efforts to develop a composition for preventing, improving or treating vascular or valve calcification. As a result, it was found that thiamine derivative has an inhibitory effect on vascular calcification.
- the present invention provides a pharmaceutical composition for preventing or treating vascular or valve calcification, including a thiamine derivative and a pharmaceutically acceptable salt thereof, a food composition for improving vascular or valve calcification, including a thiamine derivative and a salt thereof, and a thiamin derivative.
- the present invention relates to a method for preventing / treating vascular or valve calcification using a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, and a therapeutic use of vascular or valve calcification thereof.
- One aspect of the present invention relates to a pharmaceutical composition for preventing or treating vascular or valve calcification, including a thiamine derivative represented by the following Chemical Formula 1 and a pharmaceutically acceptable salt thereof.
- R 1 is , And Any one selected from the group consisting of,
- R 2 is , , And Any one selected from the group consisting of.
- R 1 is R 2 is or Can be.
- R 1 is R 2 is In the case of the thiamin derivative is fursulthiamine (thiamine tetrahydrofurfuryl disulfide).
- R 1 is R 2 is In the case of the thiamine derivative is allithiamine (Allithiamine; thiamine allyl disulfide).
- R 1 is R 2 is In the case of the thiamine derivative is Benfortiamine (S-Benzoylthiamine O-monophospate).
- R 1 is R 2 is In the case of the thiamine derivative is Sulbutiamine (O-isobutyrylthiamine disulfide).
- the thiamine derivative has a fat-soluble property, so it is directly absorbed in the small intestine, and thus has a high bioavailability in liver, muscle, and nerve tissue.
- derivative refers to a compound obtained by chemically changing a part of the compound by introducing a functional group, introducing, oxidizing, reducing, or substituting an atom using a compound as a parent, and does not significantly change the structure and properties of the parent compound. Similar compounds, unless changed. Usually, it refers to a compound in which a hydrogen atom or a specific atomic group in the compound is substituted by another atom or atomic group.
- vascular or valve calcification is meant the formation, growth or deposition of extracellular matrix hydroxyapatite (calcium phosphate) crystal deposits in blood vessels or valves.
- the vascular or valve calcification may be due to valve disease, hyperlipidemia, aging, estrogen deficiency, angina pectoris, heart failure, kidney disease, uremia, diabetes, inflammatory disease or cardiovascular disease.
- the kidney disease may be, for example, glomerulonephritis, diabetic nephropathy, lupus nephritis, multiple upposin, nephritis, nephrolithiasis, renal tuberculosis or renal tumor.
- Such inflammatory diseases include, for example, asthma, allergic and non-allergic rhinitis, chronic and acute rhinitis, chronic and acute gastritis or enteritis, ulcerative gastritis, acute and chronic nephritis, acute and chronic hepatitis, chronic obstructive pulmonary disease , Pulmonary fibrosis, irritable bowel syndrome, inflammatory pain, migraine, headache, back pain, fibromyalgia, fascia disease, viral infections (eg, type C infections), bacterial infections, fungal infections, burns, surgical or dental surgery Wound, prostaglandin E excess syndrome, atherosclerosis, gout, arthritis, rheumatoid arthritis, ankylosing spondylitis, Hodgkin's disease, pancreatitis, conjunctivitis, iris, scleritis, uveitis, dermatitis, eczema or multiple sclerosis.
- asthma allergic and non-allergic rhinitis
- the cardiovascular disease may be, for example, myocardial disorder, primary cardiac arrest, ischemic heart failure, hypertension, ischemic heart disease, coronary artery disease, angina pectoris, myocardial infarction, atherosclerosis or arrhythmia.
- the vascular calcifications include calcification of coronary arteries, aorta and other blood vessels, and may be, for example, medial calcification or atherosclerotic calcification.
- the medial calcification can be used in the same sense as medial wall calcification or Moenckeberg's sclerosis, and means calcification by calcium deposited in the medial wall.
- Such mesenteric calcification is known to occur due to the development of bone formation promoting factors in the blood vessels due to diabetes, calcium metabolic abnormalities or kidney disease.
- the atherosclerotic calcification refers to calcification that occurs in atheromatous plaques along the inner membrane layer. This atherosclerotic calcification is known to be caused by the deposition of calcium directly on the atherosclerotic lesion site.
- the valve calcification may be, for example, aortic valve calcification.
- prevention in the present invention is meant any action that inhibits or delays the progression of vascular or valve calcification by administration of the pharmaceutical composition according to the present invention.
- Treatment in the present invention means any action that improves or advantageously changes the symptoms for vascular or valve calcification by administration of the pharmaceutical composition according to the present invention.
- salts in the present invention may be prepared by conventional methods in the art, for example, salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, or the like.
- inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, or the like.
- a salt of the acid with an organic acid such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestitic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin), or It is meant to react with alkali metal ions such as sodium and potassium to form their metal salts, or to react with ammonium ions to form another form of a pharmaceutically acceptable salt.
- organic acid such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestitic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin), or It is meant to react with alkali metal ions such as sodium and potassium to form their metal salts, or to react with ammonium ions to form another form of a pharmaceutical
- the pharmaceutical composition according to the present invention includes 3-aryl-1,2,4-triazole derivative represented by Formula 1 as an active ingredient, and may further include a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier is conventionally used in the preparation, and includes, but is not limited to, saline solution, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposomes, and the like. If necessary, other conventional additives such as antioxidants and buffers may be further included.
- diluents, dispersants, surfactants, binders, lubricants and the like may be additionally added to formulate injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
- Suitable pharmaceutically acceptable carriers and formulations can be preferably formulated according to the individual components using methods disclosed in Remington's literature.
- the pharmaceutical composition of the present invention is not particularly limited in formulation, but may be formulated as an injection, inhalant, or external skin preparation.
- compositions of the invention may be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage may be determined by the condition and weight of the patient, Depending on the degree, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
- the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
- pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level refers to the type of disease, severity, activity of the drug, It may be determined according to the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently and other factors well known in the medical field.
- the pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with a minimum amount without side effects, which can be readily determined by one skilled in the art.
- the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day.
- the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention by any method.
- Another aspect of the present invention relates to a food composition for improving vascular or valve calcification, including a thiamine derivative represented by Formula 1 below and a salt thereof.
- R 1 is , And Any one selected from the group consisting of,
- R 2 is , , And Any one selected from the group consisting of.
- R 1 is R 2 is or Can be.
- Formula 1 is the same as the pharmaceutical composition for preventing or treating vascular or valve calcification of the present invention described above, the common content between the two to omit the excessive complexity of the present specification, the description is omitted.
- the food composition of the present invention may be prepared in the form of powder, granules, tablets, capsules or beverages.
- powder for example, there are various foods, beverages, gums, teas, vitamin complexes, or health supplements of candy.
- the food composition of the present invention may include not only alithiamine, fursulthiamine, benfothiamine or salts thereof, but also components commonly added in preparing foods, and include, for example, proteins, carbohydrates, fats, nutrients, seasonings. And flavoring agents.
- examples of the above carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And sugars such as conventional sugars such as polysaccharides such as dextrin, cyclodextrin and the like and xylitol, sorbitol, erythritol.
- natural flavoring agents such as tauumatin, stevia extract (for example rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
- synthetic flavoring agents sacharin, aspartame, etc.
- the food composition of the present invention is prepared with a drink, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, tofu extract, jujube extract, licorice, in addition to alithiamine, fursulthiamine, benfothiamine or salts thereof Extracts and the like may be further included.
- Another aspect of the present invention relates to a method for preventing or treating vascular or valve calcification comprising administering to a subject a pharmaceutical composition comprising a thiamine derivative and a pharmaceutically acceptable salt thereof.
- the subject refers to a subject in need of treatment of a disease, and more specifically, to a mammal, such as a primate, a mouse, a dog, a cat, a horse, and a cow, which is human or non-human.
- a mammal such as a primate, a mouse, a dog, a cat, a horse, and a cow, which is human or non-human.
- Another aspect of the invention relates to the therapeutic use of vascular or valve calcification of a pharmaceutical composition
- a pharmaceutical composition comprising a thiamine derivative and a pharmaceutically acceptable salt thereof.
- the present invention relates to a pharmaceutical composition for preventing or treating vascular or valve calcification including thiamine derivative and pharmaceutically acceptable salt thereof, and a food composition for improving vascular or valve calcification including thiamine derivative and salt thereof.
- the composition of the present invention can be usefully used for the prevention, treatment or amelioration of vascular or valve calcification.
- FIG. 1 is a view showing the calcification inhibitory effect by Fursulthiamine (F) and Alithiamine (A) according to an embodiment of the present invention.
- Figure 2 is a diagram quantifying calcified calcium, in order to confirm the inhibitory effect of calcification by fursulthiamine and alithiamine according to an embodiment of the present invention.
- Figure 4 is a diagram quantifying the calcium deposited on the blood vessels, in order to confirm the inhibitory effect ( in vivo ) by fursulthiamine according to an embodiment of the present invention.
- Peripheral tissues were removed from the thoracic abdominal aorta isolated from male cattle, and endothelial cells of the vascular lining were removed. Divide the trimmed vessels into small pieces, Dulbecco's modified Eagle's medium (DMEM, Low Glucose, Thermo Fisher Scientific, USA) containing 20% Fetal Bovine Serum (FBS, Hyclone, Australia) After aligning the culture dish containing the, 37 °C, incubated for 3-4 weeks in a 5% CO 2 cell incubator. Freshly changed medium every two days, vascular smooth muscle cells extending around the vascular tissue were primary cultured.
- DMEM Dulbecco's modified Eagle's medium
- FBS Fetal Bovine Serum
- Vascular smooth muscle cells cultured in Preparation Example 1 were stabilized by subculture in DMEM (High Glucose) to which penicillin / streptomycin antibiotics and 10% FBS were added, and then inoculated 4 x 10 5 each in a 6-well culture dish. The next day of inoculation, inorganic phosphoric acid (Pi), or inorganic phosphoric acid and thiamine (Fursulthiamine or Allithiamine; 100 or 200 ⁇ M) were treated together. Incubate for 10 days with fresh media and drug replacement every 48 hours.
- DMEM High Glucose
- the medium was removed from the culture dish and washed three times with phosphate buffer saline (PBS). Then 4% paraformaldehyde was added and fixed at 4 ° C. for 15 minutes. After fixing, the mixture was washed twice with primary distilled water for 5 minutes, and treated with 5% silver nitrate (Silver Nitrate) for 20-30 minutes. After washing 2-3 times with primary distilled water, the degree of calcification was confirmed by an optical microscope (BX53 microscope, Olympus, Japan).
- PBS phosphate buffer saline
- the medium was removed from the culture dish and washed with PBS. Then treated with 0.6 N HCl, decalcification for 24 hours at 4 °C. The supernatant was recovered for use in quantifying calcium, protein was extracted from the cells using 0.1 N NaOH / 0.1% SDS, and quantified by BCA method.
- OD SAMPLE and OD BLANK represent the OD 612 nm value of the calcium sample and BLANK (water), and Slope represents the slope value of the measured absorbance graph.
- the inorganic phosphate-treated vascular smooth muscle cells increased the amount of calcium by inorganic phosphate, but treated with fursulthiamine (Fursulthiamine) and alliamine (Allithiamine) 100 and 200 ⁇ M respectively
- the amount of calcium increased by inorganic phosphate was decreased by fursulfamine and alithiamine treatment (* p ⁇ 0.01 vs Control; ** p ⁇ 0.01 vs Vehicle).
- mice Seven 8- to 9-week-old C57BL / 6J mice were divided into five groups, and four groups (one group was used as a control group) were given high doses (9.0 x 10 5 IU) of vitamin D3 (Vit. D3) per day. Vascular calcification was induced by subcutaneous administration three times a day.
- mice were sacrificed, opened, and the surrounding tissues of the aorta were removed and separated, and then fixed in 4% PFA (paraformaldehyde) for 24 hours. After washing the fixed aorta, it was immersed in 5% silver nitrate solution and reacted with UV for 30 minutes.
- PFA paraformaldehyde
- mice were sacrificed, opened, and the tissues surrounding the aorta were removed and separated, and then frozen in liquid nitrogen.
- the frozen tissues were thawed, weighed to remove water, and then demineralized with 0.6N HCl solution.
- Calcium was quantified and calibrated by tissue weight in 0.6N HCl solution decalcified using a colormetric Ca quantification kit (Bioassay DICA-500).
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Abstract
본 발명은 티아민 유도체 및 이의 약제학적으로 허용 가능한 염을 포함하는 혈관 또는 판막 석회화의 예방 또는 치료용 약학적 조성물 및 티아민 유도체 및 이의 염을 포함하는 혈관 또는 판막 석회화의 개선용 식품 조성물에 관한 것으로, 본 발명의 조성물은 혈관 또는 판막 석회화의 예방, 치료 또는 개선 용도로 유용하게 사용될 수 있다.
Description
본 발명은 혈관 또는 판막 석회화의 예방, 개선 또는 치료용 조성물에 관한 것으로, 구체적으로는, 티아민 유도체를 포함하는 혈관 또는 판막 석회화의 예방, 개선 또는 치료용 조성물에 관한 것이다.
본 발명은 대한민국 과학기술정보통신부의 지원 하에서 과제번호 NRF-2017R1A2B3006406에 의해 이루어진 것으로서, 상기 과제의 연구관리전문기관은 한국연구재단, 연구사업명은 "중견연구", 연구과제명은 "미토콘드리아 연관 소포체 막 (Mitochondria-Associated ER Membrane, MAM) 상호작용 및 Pyruvate Dehydrogenase Kinase(PDK) 활성조절을 통한 만성염증·대사증후군의 새로운 치료기전", 주관기관은 경북대학교 글로컬산학협력단, 연구기간은 2017.03.01. ~ 2022.02.28.이다. 또한, 본 발명은 대한민국 보건복지부의 지원 하에서 과제번호 HI16C1501에 의해 이루어진 것으로서, 상기 과제의 연구관리전문기관은 한국보건산업진흥원, 연구사업명은 "선도형측성화연구사업", 연구과제명은 "선도형 당뇨병 및 대사성질환 연구사업단", 주관기관은 경북대학교병원, 연구기간은 2016.04.01. ~ 2021.03.31.이다.
본 특허출원은 2018년 8월 7일에 대한민국 특허청에 제출된 대한민국 특허출원 제10-2018-0092019호 및 2019년 7월 19일에 대한민국 특허청에 제출된 대한민국 특허출원 제10-2019-0087554호에 대하여 우선권을 주장하며, 상기 특허출원의 개시 사항은 본 명세서에 참조로서 삽입된다.
혈관은 체액의 이동을 지속적으로 조절하는 순환 기관으로, 산소 및 영양분 등을 조직에 공급하고, 이산화탄소나 노폐물을 조직으로부터 받아 처리하는 기능을 한다.
혈관 석회화(Vascular calcification)는 혈관에 칼슘 및 인산 등의 무기질이 침착된 것으로, 혈관의 경직도를 증가시켜 혈관 파열을 초래한다. 이러한 혈관 석회화는 동맥경화, 당뇨, 만성신부전 환자에게서 흔히 발견되며, 칼슘 축적 억제기 전의 소실, 골 형성 유도, 혈액 내 핵화 복합체, 및 세포사멸 등을 혈관 석회화의 주된 원인으로 보고 있으나, 그 정확한 기전은 아직까지 밝혀져 있지 않다.
특히, 심혈관계 석회화는 고혈압, 심부전, 급성 관상동맥증후군과 판막 질환의 악화에 기여하며, 이로 인한 여러 가지 합병증(심장 돌연사, 심근 경색, 협심증 및 허혈성 심부전 등)을 유발한다. 하지만, 언급된 바와 같이, 혈관 석회화의 정확한 기전은 아직까지 밝혀져 있지 않아 이에 대한 예방 및 치료제도 아직 개발되어 있지 않은 실정이다.
이에 따라, 혈관 또는 판막 석회화의 예방, 개선 또는 치료용 조성물에 관한 기술의 개발이 시급하다.
본 발명자들은 혈관 또는 판막 석회화의 예방, 개선 또는 치료용 조성물을 개발하고자 예의 연구 노력하였다. 그 결과, 티아민(Thiamine) 유도체가 혈관 석회화 억제 효과가 있음을 규명함으로써, 본 발명을 완성하게 되었다.
따라서, 본 발명의 목적은 티아민(Thiamine) 유도체 및 이의 약제학적으로 허용 가능한 염을 포함하는 혈관 또는 판막 석회화의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.
본 발명의 다른 목적은 티아민(Thiamine) 유도체 및 이의 염을 포함하는 혈관 또는 판막 석회화의 개선용 식품 조성물을 제공하는 것이다.
발명의 또 다른 목적은 티아민(Thiamine) 유도체 및 이의 약제학적으로 허용 가능한 염을 포함하는 약학적 조성물을 개체에 투여하는 단계를 포함하는 혈관 또는 판막 석회화의 예방 또는 치료방법을 제공하는 것이다.
본 발명의 또 다른 목적은 티아민(Thiamine) 유도체 및 이의 약제학적으로 허용 가능한 염을 포함하는 약학적 조성물의 혈관 또는 판막 석회화의 치료용도를 제공하는 것이다.
본 발명자들은 혈관 또는 판막 석회화의 예방, 개선 또는 치료용 조성물을 개발하고자 예의 연구 노력하였다. 그 결과, 티아민(Thiamine) 유도체가 혈관 석회화 억제 효과가 있음을 규명하였다.
본 발명은 티아민 유도체 및 이의 약제학적으로 허용 가능한 염을 포함하는 혈관 또는 판막 석회화의 예방 또는 치료용 약학적 조성물, 티아민 유도체 및 이의 염을 포함하는 혈관 또는 판막 석회화의 개선용 식품 조성물, 티아민 유도체 및 이의 약제학적으로 허용 가능한 염을 포함하는 약학적 조성물을 이용한 혈관 또는 판막 석회화의 예방/치료방법 및 이의 혈관 또는 판막 석회화의 치료용도에 관한 것이다.
이하, 본 발명을 더욱 자세히 설명하고자 한다.
본 발명의 일 양태는 하기 화학식 1로 표시되는 티아민(Thiamine) 유도체 및 이의 약제학적으로 허용 가능한 염을 포함하는 혈관 또는 판막 석회화의 예방 또는 치료용 약학적 조성물에 관한 것이다.
[화학식 1]
상기 화학식 1에서,
상기 화학식 1에서, R1이 이고, R2가 인 경우 상기 티아민 유도체는 푸르설티아민(Fursulthiamine; thiamine tetrahydrofurfuryl disulfide)이다.
본 발명에서 상기 티아민 유도체는 지용성의 성질을 가지고 있어, 소장에서 바로 흡수되므로 간과 근육, 신경 조직 등에서 높은 생체 이용률을 보이는 장점이 있다.
본 발명에서 "유도체"란 어떤 화합물을 모체로 하여 작용기를 도입, 산화, 환원, 원자의 치환 등을 통하여 화합물의 일부를 화학적으로 변화시켜서 얻어지는 화합물을 의미하며, 모체 화합물의 구조와 성질을 대폭 변하지 않는 한도에서 변화된 유사한 화합물이다. 보통은 화합물 중의 수소원자 또는 특정 원자단이 다른 원자 또는 원자단에 의하여 치환된 화합물을 말한다.
본 발명에서 "혈관 또는 판막 석회화"란 혈관 또는 판막 내에 세포외성 기질(matrix) 수산화인회석(hydroxyapatite)(인산칼슘)결정 침착물(crystal deposits)의 형성, 성장 또는 침착을 의미한다.
상기 혈관 또는 판막 석회화는 판막증, 고지혈증, 노화, 에스트로겐 부족, 협심증, 심부전, 신장질환, 요독증, 당뇨병, 염증 질환 또는 심혈관계 질환에 의한 것일 수 있다.
상기 신장 질환은, 예를 들어, 사구체 신장염, 당뇨병성신증, 루프스신염, 다발성의 우포신, 신맹신염, 신결석, 신결핵 또는 신종양일 수 있다.
상기 염증 질환은, 예를 들어, 천식, 알레르기성 및 비-알레르기성 비염, 만성 및 급성 비염, 만성 및 급성 위염 또는 장염, 궤양성 위염, 급성 및 만성 신장염, 급성 및 만성 간염, 만성 폐쇄성 폐질환, 폐섬유증, 과민성 대장 증후군, 염증성 통증, 편두통, 두통, 허리 통증, 섬유 근육통, 근막 질환, 바이러스 감염(예컨대, C형 감염), 박테리아 감염, 곰팡이 감염, 화상, 외과적 또는 치과적 수술에 의한 상처, 프로스타글라딘 E 과다 증후군, 아테롬성 동맥 경화증, 통풍, 관절염, 류머티즘성 관절염, 강직성 척추염, 호지킨병, 췌장염, 결막염, 홍채염, 공막염, 포도막염, 피부염, 습진 또는 다발성 경화증일 수 있다.
상기 심혈관계 질환은, 예를 들어, 심근장애, 원발성 심장정지, 허혈성 심부전, 고혈압, 허혈성 심장 질환, 관상동맥질환, 협심증, 심근경색증, 죽상경화증 또는 부정맥일 수 있다.
상기 혈관 석회화는 관상 동맥, 대동맥 및 기타 혈관의 석회화를 포함하며, 예를 들어, 중막성 석회화(medial calcification) 또는 죽상경화성 석회화(atherosclerotic calcification)일 수 있다.
상기 중막성 석회화는 중막 벽 석회화(medial wall calcification) 또는 묀케베르그 경화증(Moenckeberg's sclerosis)과 동일한 의미로 사용될 수 있으며, 중막 벽 내에 침착된 칼슘에 의한 석회화를 의미한다. 이러한 중막성 석회화는 당뇨, 칼슘 대사기전 이상 또는 신장 질환 등으로 인하여 골 형성 촉진 인자들이 혈관에 발현되어 발생하는 것으로 알려져 있다.
상기 죽상경화성 석회화는 내막층을 따라 죽종성 플라크(artheromatous plaques)내에 발생하는 석회화를 의미한다. 이러한 죽상경화성 석회화는 죽상경화 병소 부위에 직접 칼슘이 침착되어 발생되는 것으로 알려져 있다.
상기 판막 석회화는, 예를 들어, 대동맥판막 석회화(Aortic valve calcification)일 수 있다.
본 발명에서 "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 혈관 또는 판막 석회화를 억제시키거나 이의 진행을 지연시키는 모든 행위를 의미한다.
본 발명에서 "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 혈관 또는 판막 석회화에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.
본 발명에서 약제학적으로 허용 가능한 염은 당해 기술분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면, 염산, 브롬화수소, 황산, 황산수소나트륨, 인산, 탄산 등의 무기산과의 염 또는 개미산, 초산, 옥살산, 벤조산, 시트르산, 타르타르산, 글루콘산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산(아스피린)과 같은 유기산과 함께 산의 염을 형성하거나, 또는 나트륨, 칼륨 등의 알칼리금속이온과 반응하여 이들의 금속염을 형성하거나, 또는 암모늄 이온과 반응하여 또 다른 형태의 약제학적으로 허용 가능한 염을 형성하는 것을 의미한다.
본 발명에 따른 약학적 조성물은 상기 화학식 1로 표시되는 3-아릴-1,2,4-트라이아졸 유도체를 유효성분으로 포함하며, 약학적으로 허용 가능한 담체를 더 포함할 수 있다. 상기 약학적으로 허용 가능한 담체는 제제시에 통상적으로 이용되는 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 사이클로덱스트린, 덱스트로즈 용액, 말토덱스트린 용액, 글리세롤, 에탄올, 리포좀 등을 포함하지만 이에 한정되지 않으며, 필요에 따라 항산화제, 완충액 등 다른 통상의 첨가제를 더 포함할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제, 윤활제 등을 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 적합한 약학적으로 허용되는 담체 및 제제화에 관해서는 레밍턴의 문헌에 개시되어 있는 방법을 이용하여 각 성분에 따라 바람직하게 제제화할 수 있다. 본 발명의 약학적 조성물은 제형에 특별한 제한은 없으나 주사제, 흡입제, 피부 외용제 등으로 제제화할 수 있다.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 얄려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래 의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.
구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1kg 당 0.001 내지 150mg, 바람직하게는 0.01 내지 100mg을 매일 또는 격일 투여하거나, 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감 될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.
본 발명의 다른 일 양태는 하기 화학식 1로 표시되는 티아민(Thiamine) 유도체 및 이의 염을 포함하는 혈관 또는 판막 석회화의 개선용 식품 조성물에 관한 것이다.
[화학식 1]
상기 화학식 1에서,
상기 화학식 1은 상술한 본 발명의 혈관 또는 판막 석회화의 예방 또는 치료용 약학적 조성물과 동일하므로, 이 둘 사이에 공통된 내용은 본 명세서의 과도한 복잡성을 피하기 위하여, 그 기재를 생략한다.
본 발명의 식품 조성물은 분말, 과립, 정제, 캡슐 또는 음료 등의 형태로 제조될 수 있다. 예컨대 캔디류의 각종 식품류, 음료, 껌, 차, 비타민 복합제, 또는 건강보조 식품류 등이 있다.
본 발명의 식품 조성물은 알리티아민, 푸르설티아민, 벤포티아민 또는 이들의 염뿐만 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함할 수 있으며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 [타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등]) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다. 예컨대, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 알리티아민, 푸르설티아민, 벤포티아민 또는 이들의 염 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 두충 추출액, 대추 추출액, 감초 추출액 등을 추가로 포함시킬 수 있다.
본 발명의 다른 일 양태는 티아민(Thiamine) 유도체 및 이의 약제학적으로 허용 가능한 염을 포함하는 약학적 조성물을 개체에 투여하는 단계를 포함하는 혈관 또는 판막 석회화의 예방 또는 치료방법에 관한 것이다.
상기 개체는 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말 및 소 등의 포유류를 의미한다.
본 발명의 또 다른 일 양태는 티아민(Thiamine) 유도체 및 이의 약제학적으로 허용 가능한 염을 포함하는 약학적 조성물의 혈관 또는 판막 석회화의 치료용도에 관한 것이다.
상기 조성물의 중복되는 내용은 본 명세서의 복잡성을 고려하여 생략한다.
본 발명은 티아민 유도체 및 이의 약제학적으로 허용 가능한 염을 포함하는 혈관 또는 판막 석회화의 예방 또는 치료용 약학적 조성물 및 티아민 유도체 및 이의 염을 포함하는 혈관 또는 판막 석회화의 개선용 식품 조성물에 관한 것으로, 본 발명의 조성물은 혈관 또는 판막 석회화의 예방, 치료 또는 개선 용도로 유용하게 사용될 수 있다.
도 1은 본 발명의 일 실시예에 따른 푸르설티아민(Fursulthiamine; F) 및 알리티아민(Allithiamine; A)에 의한 석회화 억제 효과를 나타낸 도이다.
도 2는 본 발명의 일 실시예에 따른 푸르설티아민 및 알리티아민에 의한 석회화 억제 효과를 확인하기 위하여, 석회화 된 칼슘을 정량한 도이다.
도 3은 본 발명의 일 실시예에 따른 푸르설티아민에 의한 석회화 억제 효과(in vivo)를 확인하기 위하여, 본 코사 염색(Von Kossa staining)을 수행한 결과이다.
도 4는 본 발명의 일 실시예에 따른 푸르설티아민에 의한 석회화 억제 효과(in vivo)를 확인하기 위하여, 혈관에 침착 된 칼슘을 정량한 도이다.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.
준비예 1. 혈관평활근세포(Vascular smooth muscle cells, VSMCs) 일차배양
수컷 소에서 분리한 흉복부 대동맥에서 주변 조직을 제거하고, 혈관 내벽의 내피세포를 제거하였다. 손질한 혈관을 작은 조각으로 나누고, 20 % 우태아혈청(Fetal Bovine Serum; FBS, Hyclone, Australia)이 포함된 둘베코수정이글배지(Dulbecco's modified Eagle's medium; DMEM, Low Glucose, Thermo Fisher Scientific, USA)를 넣은 배양 접시에 정렬한 후, 37 ℃, 5 % CO2 세포 배양기에서 3-4 주 동안 배양하였다. 2 일마다 배지를 새로 교체하면서, 혈관 조직 주위로 뻗어 나온 혈관평활근세포를 일차배양하였다.
준비예 2. 혈관평활근세포의 석회화 유도
상기 준비예 1에서 배양한 혈관평활근세포는 페니실린/스트렙토마이신 항생제 및 10 % FBS가 첨가된 DMEM(High Glucose)에서 계대배양(subculture)으로 안정화 시킨 후, 6-웰 배양 접시에 각 4Х105 개씩 접종하고, 접종 다음날 무기인산(Pi), 또는 무기인산 및 티아민(Fursulthiamine 또는 Allithiamine; 100 또는 200 μM)을 함께 처리하였다. 48 시간마다 배지와 약물을 새로 교체하면서 10 일 동안 배양하였다.
실험예 1. 혈관평활근세포의 석회화 확인
상기 준비예 2의 방법으로 석회화를 유도한 뒤, 배양 접시에서 배지를 제거하고 인산완충식염수(phosphate buffer saline; PBS)로 3 회 세척하였다. 그 다음 4 % 파라포름알데하이드(Paraformaldehyde)을 넣고 4 ℃에서 15 분간 고정하였다. 고정이 끝나면 1차 증류수로 5 분간 2 회 세척하고, 5 % 질산은(Silver Nitrate)을 처리 후 20-30 분 동안 자외선을 조사하여 발색하였다. 이후 1차 증류수로 2~3 회 세척한 뒤, 광학현미경(BX53 microscope, Olympus, Japan)으로 석회화 정도를 확인하였다.
도 1에서 확인할 수 있듯이, 무기인산만 처리한 혈관평활근세포(Pi)에서는 석회화(검은 점)가 증가하였으나, 푸르설티아민(Fursulthiamine; F) 및 알리티아민(Allithiamine; A)을 각각 100 및 200μM씩 함께 처리한 혈관평활근세포(Pi+F100μM, Pi+F200μM, Pi+A100μM 및 Pi+A200μM)에서는 석회화(검은 점)가 억제되었다.
실험예 2. 혈관평활근세포의 칼슘 정량
상기 준비예 2의 방법으로 석회화를 유도한 뒤, 배양 접시에서 배지를 제거하고 PBS로 세척하였다. 그 다음 0.6 N HCl을 처리하여 4 ℃에서 24 시간 동안 탈칼슘화(decalcification)시켰다. 상층액은 칼슘 정량에 사용하기 위하여 회수하였으며, 세포로부터 0.1 N NaOH/0.1 % SDS를 사용하여 단백질을 추출하고, BCA 방법을 이용하여 이를 정량 하였다.
QuantichromTM 칼슘 분석 키트(DICA-500, BioAssay System, USA)를 이용하여 612 nm에서 칼슘 샘플(Standard)의 흡광도를 측정하고 하기 계산식 1을 이용하여 칼슘 농도를 측정한 후, 그 값을 상기 정량한 단백질 양으로 나누어(보정)하여 최종적으로 칼슘을 정량 하였다.
[계산식 1]
(ODSAMPLE 및 ODBLANK은 칼슘 샘플 및 BLANK(물)의 OD612nm 값을 나타내며, Slope는 측정된 흡광도 그래프의 기울이 값을 나타냄.)
도 2에서 확인할 수 있듯이, 무기인산만 처리한 혈관평활근세포(Vehicle)에서는 무기인산에 의해 칼슘의 양이 증가되었으나, 푸르설티아민(Fursulthiamine) 및 알리티아민(Allithiamine)을 각각 100 및 200μM씩 함께 처리한 혈관평활근세포에서는 무기인산에 의해 증가된 칼슘의 양이 푸르설티아민 및 알리티아민 처리에 의해 감소하였다(*p<0.01 vs Control; **p<0.01 vs Vehicle).
실험예 3.
In vivo
8~9주령 C57BL/6J 마우스를 7마리씩 총 5개 군으로 나누고, 4개 군(1개 군은 대조군으로 사용)에 고용량(9.0 x 105 IU)의 비타민 D3(Vit. D3)를 하루 1회 총 3일 동안 피하 투여하여 혈관석회화를 유도하였다.
이 중 3개 군에 대해서는 각각 10 mg/kg 및 30 mg/kg의 푸르설티아민(Fursulthiamine), 및 50mg/kg의 다이클로로아세테이트(dichloroacetate; DCA, 양성대조군)를 상기 비타민 D3 첫 투여 3일 전부터 경구 투여하기 시작하여 하루 1회 총 13일간 투여하였다.
3-1. Von Kossa 염색
먼저, 비타민 D3 투여 10일 후 마우스를 희생시켜 개복하고 대동맥 주변 조직을 깨끗이 제거하여 분리한 후, 4% PFA(paraformaldehyde)에 24시간 동안 고정하였다. 고정된 대동맥을 세척한 후 5% 질산은(Silver Nitrate) 용액에 담가 UV에 30분 동안 반응시켰다.
도 3에서 확인할 수 있듯이, 비타민 D3 그룹에서는 혈관 석회화의 증가로 인하여 대동맥의 대부분이 어둡게 착색된 반면, 양성 대조군인 DCA 그룹에서는 vehicle 그룹에 비해 착색된 부분이 확연히 감소하였다. 본원발명의 푸르설타민 그룹에서도 농도 의존적으로 착색된 부분이 감소(회복)되었는데, 특히 30 mg/kg 투여 그룹에서는 양성 대조군인 DCA 보다 회복 정도가 우수하였다.
3-2. 칼슘 정량
추가적으로, 상기 비타민 D3 투여 10일 후 마우스를 희생시켜 개복하고 대동맥 주변 조직을 깨끗이 제거하여 분리한 후, 액체 질소에 냉동하였다. 냉동된 조직을 해동하고 물기를 제거하여 무게를 잰 후, 0.6N HCl 용액으로 탈석회화를 진행하였다. colormetric Ca 정량 키트(Bioassay DICA-500)를 사용하여 탈석회시킨 0.6N HCl 용액에서 칼슘을 정량하고 조직 무게로 보정하였다.
도 4에서 확인할 수 있듯이, 비타민 D3 그룹에서는 비타민 D3를 주사하지 않은 대조군에 비하여 칼슘량이 10배 가까이 증가하였으나, 양성 대조군인 DCA 그룹에서 비타민 D3에 의해 증가하는 대동맥의 칼슘량이 유의적으로 감소하였다. 본원발명의 푸르설타민 그룹에서도 농도 의존적으로 칼슘량이 감소하였으며, 양성 대조군인 DCA 보다 그 정도가 우수하였다.
Claims (10)
- 제 1 항에 있어서, 상기 혈관 또는 판막 석회화는 판막증, 고지혈증, 노화, 에스트로겐 부족, 협심증, 심부전, 신장 질환, 요독증, 당뇨병, 염증 질환 및 심혈관계 질환으로 이루어진 군으로부터 선택된 것에 의한 것인, 혈관 또는 판막 석회화의 예방 또는 치료용 약학적 조성물.
- 제 1 항에 있어서, 상기 혈관 석회화는 중막성 석회화(medial calcification) 또는 죽상경화성 석회화(atherosclerotic calcification)인 것인, 혈관 또는 판막 석회화의 예방 또는 치료용 약학적 조성물.
- 제 1 항에 있어서, 상기 판막 석회화는 대동맥판막 석회화(Aortic valve calcification)인 것인, 혈관 또는 판막 석회화의 예방 또는 치료용 약학적 조성물.
- 제 6 항에 있어서, 상기 혈관 또는 판막 석회화는 판막증, 고지혈증, 노화, 에스트로겐 부족, 협심증, 심부전, 신장 질환, 요독증, 당뇨병, 염증 질환 및 심혈관계 질환으로 이루어진 군으로부터 선택된 것에 의한 것인, 혈관 또는 판막 석회화의 개선용 식품 조성물.
- 제 6 항에 있어서, 상기 혈관 석회화는 중막성 석회화(medial calcification) 또는 죽상경화성 석회화(atherosclerotic calcification)인 것인, 혈관 또는 판막 석회화의 개선용 식품 조성물.
- 제 6 항에 있어서, 상기 판막 석회화는 대동맥판막 석회화(Aortic valve calcification)인 것인, 혈관 또는 판막 석회화의 개선용 식품 조성물.
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