WO2022092884A1 - Composition pharmaceutique comprenant du 13-o-acétylphobol pour prévenir et traiter des maladies liées à l'os et une calcification vasculaire - Google Patents

Composition pharmaceutique comprenant du 13-o-acétylphobol pour prévenir et traiter des maladies liées à l'os et une calcification vasculaire Download PDF

Info

Publication number
WO2022092884A1
WO2022092884A1 PCT/KR2021/015405 KR2021015405W WO2022092884A1 WO 2022092884 A1 WO2022092884 A1 WO 2022092884A1 KR 2021015405 W KR2021015405 W KR 2021015405W WO 2022092884 A1 WO2022092884 A1 WO 2022092884A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
bone
preventing
acetylphobol
vascular calcification
Prior art date
Application number
PCT/KR2021/015405
Other languages
English (en)
Korean (ko)
Inventor
황기철
임소연
이세형
김상우
최정원
Original Assignee
가톨릭관동대학교산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020210055026A external-priority patent/KR102541582B1/ko
Application filed by 가톨릭관동대학교산학협력단 filed Critical 가톨릭관동대학교산학협력단
Publication of WO2022092884A1 publication Critical patent/WO2022092884A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention relates to a pharmaceutical composition for the prevention or treatment of bone disease and vascular calcification comprising 13-O-acetylphobol as an active ingredient.
  • Osteoporosis is a disease in which bone mass is reduced due to the imbalance between bone formation and bone resorption, and the risk of fracture continues to increase due to the degeneration of the microstructure of bone tissue. is the state The gap between the bone microstructures becomes wider and the microstructures become thinner, increasing the risk of easily fractured bones even with a small impact. Old age, lack of exercise, low body weight, smoking, low calcium diet, menopause, and ovarian resection are known causes of osteoporosis.
  • vascular calcification increases the stiffness of blood vessels, leading to vascular rupture, and cardiovascular system calcification contributes to exacerbation of hypertension, heart failure, acute coronary syndrome and valvular disease, and various complications (sudden cardiac death, myocardial infarction, angina and ischemic heart failure, etc.).
  • the exact mechanism of vascular calcification has not yet been elucidated, and thus a preventive and therapeutic agent for this has not yet been developed.
  • the present inventors have completed the present invention by confirming that 13-O-acetylphobol has such an effect as a result of an effort to discover a substance having an effective effect on both osteoporosis and vascular calcification.
  • the present inventors have discovered 13-O-acetylphobol as a substance having a therapeutic effect on bone-related diseases, for example, diseases such as osteoporosis.
  • diseases such as osteoporosis.
  • RANKL receptor activator of NK- ⁇ B ligand
  • osteoclast differentiation inducer an osteoclast differentiation inducer
  • the 13-O-acetylphobol was also treated with macrophages to convert into osteoclasts. It was found that differentiation was inhibited (FIG. 4).
  • the activity of differentiated osteoclasts was also inhibited by 13-O-acetylphobol ( FIG. 4 ).
  • one aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of bone diseases, comprising the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of Formula 1 is 13-O-acetylphobol (CAS 60857-08-1), also known as prostratin or 12-Deoxyphorbol-13-Acetate.
  • the bone disease is osteoporosis, periodontal disease, osteomalacia, osteopenia, bone defect, bone atrophy, osteonecrosis, fracture, osteolysis ( osteolysis), it may be selected from the group consisting of osteoarthritis and osteoporosis imperfecta, preferably osteoporosis.
  • osteoporosis refers to a state in which the mineral (especially calcium) and matrix constituting the bone are reduced, and the microstructure of the bone tissue is deteriorated, and as a result, the risk of fractures continuously increases.
  • osteoclast activity is increased more than osteoblastic activity, it occurs because the balance of bone remodeling is disturbed, and the causes include calcium malabsorption, vitamin D deficiency, drug side effects, lack of exercise, excessive drinking, menopause, and depression.
  • the amount of estrogen secretion decreases after menopause, active oxygen accumulates in the cells and bone loss is triggered.
  • the pharmaceutical composition for the prevention or treatment of bone disease may additionally have an inhibitory effect on vascular calcification.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and when formulated, commonly used fillers, extenders, It is prepared using a diluent or excipient such as a binder, a wetting agent, a disintegrant, and a surfactant.
  • a diluent or excipient such as a binder, a wetting agent, a disintegrant, and a surfactant.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, and the like, and such solid preparations include one or more compounds of the present invention and at least one excipient, for example, starch, calcium carbonate, water It is prepared by mixing sucrose or lactose or gelatin.
  • lubricants such as magnesium stearate talc are also used.
  • Liquid formulations for oral administration include suspensions, oral solutions, emulsions, or syrups.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • injectable esters such as ethyl oleate.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption of an active ingredient in the body, inactivation rate and excretion rate, disease type, and drugs used in combination, generally limited thereto
  • 0.001 mg to 200 mg preferably 0.01 mg to 100 mg, more preferably 0.2 mg to 50 mg per kg body weight can be administered.
  • the dosage is not intended to limit the scope of the present invention in any way.
  • Another aspect of the present invention provides a food composition for preventing or improving bone disease, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the food composition uses the same ingredients as the pharmaceutical composition for the prevention or treatment of bone diseases, overlapping content between the two is omitted to avoid excessive description of the specification.
  • the food composition may be provided in the form of powder, granule, tablet, capsule, syrup, beverage or pill, and is used together with other food or food additives in addition to the compound represented by Formula 1 as an active ingredient, a conventional method can be used appropriately.
  • the mixing amount of the active ingredient may be suitably determined according to the intended use thereof, for example, prophylactic, health or therapeutic treatment.
  • the effective dose of the active ingredient contained in the food composition may be used according to the effective dose of the pharmaceutical composition, but in the case of long-term intake for health and hygiene purposes or health control, it may be less than the above range, It is certain that the active ingredient can be used in an amount beyond the above range because there is no problem in terms of safety.
  • the food composition includes ingredients commonly added during food production, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents.
  • examples of the above-mentioned carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose, oligosaccharides and the like; and polysaccharides such as conventional sugars such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • flavoring agents natural flavoring agents and synthetic flavoring agents can be used.
  • citric acid, fructose liquid, sugar, glucose, acetic acid, malic acid, fruit juice, etc. may be additionally included in addition to the active ingredient of the present invention.
  • 13-O-acetylphobol also has an inhibitory effect on vascular calcification. Accordingly, another aspect of the present invention provides a pharmaceutical composition for preventing or treating vascular calcification, and a food composition for preventing or improving, comprising the compound of Formula 1 as an active ingredient.
  • Vascular calcification is a symptom in which minerals such as calcium phosphate are deposited in the blood vessels and harden the blood vessels, which increases the stiffness of the blood vessels, leading to vascular rupture.
  • cardiovascular calcification contributes to the exacerbation of hypertension, heart failure, acute coronary syndrome and valvular disease, leading to various complications (sudden cardiac death, myocardial infarction, angina pectoris and ischemic heart failure, etc.).
  • the exact mechanism of vascular calcification has not yet been elucidated, and thus a preventive and therapeutic agent for this has not yet been developed.
  • the pharmaceutical composition uses the same components as the pharmaceutical composition for the prevention or treatment of bone diseases, overlapping content between the two is omitted to avoid excessive description of the specification.
  • Another aspect of the present invention provides a composition for inhibiting osteoclast differentiation in vitro using the compound represented by Formula 1 above.
  • the compound represented by Formula 1 effectively inhibits the differentiation of macrophages into osteoclasts induced by RANKL treatment, and thus can be used for inhibiting osteoclast differentiation.
  • 13-O-acetylphobol inhibits the differentiation of macrophages into osteoclasts, inhibits osteoclast activity, and has the effect of inhibiting vascular calcification, thus preventing or treating bone disease and/or vascular calcification It can be usefully used for
  • Figure 2 shows the results of quantifying the actual intracellular calcium concentration after treatment with 13-O-acetylphobol while inducing calcification in human arterial smooth muscle cells.
  • 3 is a result of TRAP staining after treatment with 13-O-acetylphobol while differentiating macrophages into osteoclasts (A) and the ratio of TRAP+ osteoclasts having 3 or more, or 10 or more nuclei in one cell. It is the result of confirming (B).
  • 4 is a result of measuring the activity of osteoclasts after treatment with 13-O-acetylphobol while differentiating macrophages into osteoclasts.
  • FIG. 5 shows the results of intracellular calcium staining after treatment with 13-O-acetylphobol or oleic acid while inducing calcification in human arterial smooth muscle cells.
  • Example 1 Inhibitory effect of vascular calcification
  • Human aortic smooth muscle cells which are vascular cells capable of differentiating into calcified cells by intra-arterial pathological stimulation, were dispensed on the plate and treated with calcified cell differentiation medium (including angiotensin II) for 14 days.
  • 13-O-acetylphobol (0.01, 0.05, 0.1, 0.5, 1 and 2 ⁇ g/ml) was treated every 3 days.
  • the differentiated cells were fixed with a fixing solution at room temperature for 5 minutes and washed several times with distilled water.
  • a substrate solution of sodium tartrate and acid phosphatase was mixed, and the prepared mixture was treated with cells to stain tartrate-resistant acid phosphate (TRAP), an osteoclast differentiation marker. Staining was carried out at 37° C. for 15 to 45 minutes after covering the plate to prevent drying. After that, the dye was discarded and the reaction was stopped by washing with distilled water three times, and after observing it under a microscope, the number of stained cells was counted using the Image J program by taking pictures.
  • TRIP stain tartrate-resistant acid phosphate
  • the ratio of TRAP + osteoclasts having 3 or more (N ⁇ 3), or 10 or more (N ⁇ 10) nuclei in one cell was calculated.
  • the ratio of TRAP + osteoclasts having 3 or more (N ⁇ 3), or 10 or more (N ⁇ 10) nuclei in the 13-O-acetylphobol treatment group was significantly higher in the 13-O-acetylphobol treatment group compared to the control group treated only with RANKL It was confirmed that the decrease (FIG. 3B).
  • a bone resorption assay kit (CSR-BRA-48KIT, COSMOBIO) was used. Specifically, RAW264.7 cells were seeded on a culture dish coated with a bone imitation matrix containing a calcium-phosphate layer, and differentiation was induced by treatment with RANKL, an osteoclast differentiation inducer, at a concentration of 40 ng/ml. After that, culture was performed for a total of 4 days while changing the medium every 2 days, and 13-O-acetylphobol was treated together when the medium was replaced. After 6 days, the osteoclasts attached to the culture dish were removed by treatment with 5% sodium hypochlorite for 5 minutes. The culture dish was further washed with water and dried, and after taking a picture of each well, the pit area formed by osteoclasts decomposing the bone imitation matrix was measured as image J. The degradation area is proportional to the activity of osteoclasts.

Landscapes

  • Health & Medical Sciences (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant du 13-O-acétylphobol en tant que principe actif pour prévenir et traiter des maladies liées à l'os et une calcification vasculaire. Le 13-O-acétylphobol supprime la différenciation des macrophages en ostéoclastes, inhibe l'activité des ostéoclastes et supprime la calcification vasculaire, ainsi le 13-O-acétylphobol peut être efficacement appliqué à de telles utilisations.
PCT/KR2021/015405 2020-10-29 2021-10-29 Composition pharmaceutique comprenant du 13-o-acétylphobol pour prévenir et traiter des maladies liées à l'os et une calcification vasculaire WO2022092884A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2020-0141668 2020-10-29
KR20200141668 2020-10-29
KR10-2021-0055026 2021-04-28
KR1020210055026A KR102541582B1 (ko) 2020-10-29 2021-04-28 13-ｏ-아세틸포볼을 포함하는 골질환 및 혈관석회화증 예방 또는 치료용 약학적 조성물

Publications (1)

Publication Number Publication Date
WO2022092884A1 true WO2022092884A1 (fr) 2022-05-05

Family

ID=81384268

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2021/015405 WO2022092884A1 (fr) 2020-10-29 2021-10-29 Composition pharmaceutique comprenant du 13-o-acétylphobol pour prévenir et traiter des maladies liées à l'os et une calcification vasculaire

Country Status (1)

Country Link
WO (1) WO2022092884A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050059180A (ko) * 2002-09-24 2005-06-17 페노스 게엠베하 당뇨병 및 심혈관 질환의 치료를 위한 단백질 키나제 ｃ알파의 저해용 조성물
KR20140117564A (ko) * 2012-01-18 2014-10-07 바이오석세스 바이오텍 컴퍼니 리미티드 포르볼 에스테르의 조성물 및 사용 방법
WO2017214394A2 (fr) * 2016-06-10 2017-12-14 The Regents Of The University Of California Procédés de traitement de perte osseuse

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050059180A (ko) * 2002-09-24 2005-06-17 페노스 게엠베하 당뇨병 및 심혈관 질환의 치료를 위한 단백질 키나제 ｃ알파의 저해용 조성물
KR20140117564A (ko) * 2012-01-18 2014-10-07 바이오석세스 바이오텍 컴퍼니 리미티드 포르볼 에스테르의 조성물 및 사용 방법
WO2017214394A2 (fr) * 2016-06-10 2017-12-14 The Regents Of The University Of California Procédés de traitement de perte osseuse

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEN DELONG; CHU FEIFAN; ZHANG GANGYU; WANG QINGQING; LI YING; ZHANG MENG; HE QI; YANG JUNZHENG; WANG HAIBIN; SUN PING; XU JIAKE; : "12-Deoxyphorbol 13-acetate inhibits RANKL-induced osteoclastogenesis via the attenuation of MAPK signaling and NFATc1 activation", INTERNATIONAL IMMUNOPHARMACOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 101, 7 October 2021 (2021-10-07), NL , XP086887244, ISSN: 1567-5769, DOI: 10.1016/j.intimp.2021.108177 *
LI ZHUO HAO, SI YU, XU GUO, CHEN XI MING, XIONG HAO, LAI LAN, ZHENG YI QING, ZHANG ZHI GANG: "High-dose PMA with RANKL and MCSF induces THP-1 cell differentiation into human functional osteoclasts in vitro", MOLECULAR MEDICINE REPORTS, SPANDIDOS PUBLICATIONS, GR, vol. 16, no. 6, 1 December 2017 (2017-12-01), GR , pages 8380 - 8384, XP055926492, ISSN: 1791-2997, DOI: 10.3892/mmr.2017.7625 *
WANG CATHY, STEER JAMES H, JOYCE DAVID A, YIP KIRK HM, ZHENG MING H, XU JIAKE: "2-O-tetradecanoylphorbol-13-acetate (TPA) Inhibits Osteoclastogenesis by Suppressing RANKL-Induced NF-␬B Activation", J BONE MINER RES, vol. 18, 1 January 2003 (2003-01-01), pages 2159 - 2168, XP055926488 *

Similar Documents

Publication Publication Date Title
KR100493836B1 (ko) 옥스카르바제핀을 포함하는 제약 조성물
EP0930889B1 (fr) EXTRAIT D'ECORCE DE CITRUS UTILISE EN TANT QU'INHIBITEUR DE 3-HYDROXY-3-METHYL-GLUTARYL COENZYME A (HMG CoA) REDUCTASE
US7371776B2 (en) Methods and compositions for treating cancer
US20110065658A1 (en) Method for treating hyperuricemia employing an sglt2 inhibitor and composition containing same
TW200914031A (en) Pharmaceutical composition comprising a SGLT2 inhibitor
EA022349B1 (ru) Фармацевтическая композиция, включающая ингибитор sglt2, ингибитор дпп-iv и другой антидиабетический агент, и ее применение
CZ303433B6 (cs) Použití ramiprilu, ramiprilátu nebo jejich farmaceuticky prijatelných derivátu
US6221357B1 (en) Flavonoids derived from citrus peels as collagen-induced platelet aggregation inhibitor
US20230270805A1 (en) A composition comprising an extract of alder tree or the isolated compounds therefrom for treating and preventing skeleton muscle-related disorder and the use thereof
WO2021201532A1 (fr) Composition de prévention, de soulagement ou de traitement du syndrome ménopausique chez la femme, contenant un extrait de rosa rugosa en tant que principe actif
CN117323323A (zh) 奇楠成分对ampk的激活作用
JP5562515B2 (ja) 骨疾患の予防及び／又は治療用組成物、その組成物を含有する機能性食品もしくは健康食品、並びにその組成物を有効成分とする医薬製剤
KR20200079203A (ko) 블루베리 추출물을 함유하는 골질환 예방 또는 치료용 조성물
WO2022092884A1 (fr) Composition pharmaceutique comprenant du 13-o-acétylphobol pour prévenir et traiter des maladies liées à l'os et une calcification vasculaire
US8466202B2 (en) Anthracenedione compounds
KR20040104626A (ko) 리파아제 억제제 및 글루코마난을 포함하는 약학 조성물
CN110799214A (zh) 利用碱化剂的血液净化
WO2021085849A1 (fr) Composition pharmaceutique comprenant un dérivé d'isoliquiritigénine destiné à la prévention ou le traitement des maladies osseuses.
KR102541582B1 (ko) 13-ｏ-아세틸포볼을 포함하는 골질환 및 혈관석회화증 예방 또는 치료용 약학적 조성물
EP1123304B1 (fr) Flavonoides derives d'ecorces d'agrumes en tant qu'inhibiteur d'agregation plaquettaire induite par le collagene
US11185553B2 (en) Pharmaceutical composition for preventing or treating ischemic-reperfusion injury comprising bile acids
WO2014084669A1 (fr) Composition pharmaceutique destinée à prévenir ou à traiter l'ostéoporose, contenant de la praéruptorine a ou un sel pharmaceutiquement acceptable de celle-ci à titre de principe actif
WO2005085223A1 (fr) Composition pour la prévention et/ou le traitement des maladies osseuses, alimentation fonctionnelle ou aliments diététiques contenant la composition et préparation médicale contenant la composition en tant qu’ingrédient actif.
WO2023204511A1 (fr) Composition pour la prévention ou le traitement de la calcification valvulaire
WO2023113356A1 (fr) Composition pour la prévention ou le traitement d'une calcification vasculaire, contenant un extrait de cornus controversa hemsl.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21886878

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21886878

Country of ref document: EP

Kind code of ref document: A1