WO2017007120A1 - Composition pharmaceutique pour le traitement des maladies rénales contenant du dipyridamole en tant qu'ingrédient actif - Google Patents

Composition pharmaceutique pour le traitement des maladies rénales contenant du dipyridamole en tant qu'ingrédient actif Download PDF

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Publication number
WO2017007120A1
WO2017007120A1 PCT/KR2016/004847 KR2016004847W WO2017007120A1 WO 2017007120 A1 WO2017007120 A1 WO 2017007120A1 KR 2016004847 W KR2016004847 W KR 2016004847W WO 2017007120 A1 WO2017007120 A1 WO 2017007120A1
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WO
WIPO (PCT)
Prior art keywords
dipyridamole
pharmaceutical composition
kidney disease
active ingredient
albumin
Prior art date
Application number
PCT/KR2016/004847
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English (en)
Korean (ko)
Inventor
이준용
Original Assignee
초당약품공업 주식회사
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Publication of WO2017007120A1 publication Critical patent/WO2017007120A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to a pharmaceutical composition for treating renal disease containing dipyridamole as an active ingredient. More specifically, in the invention of the use of medicaments for the treatment of renal disease through the inhibition of the proliferation of dipyridamole mesangium cells and the reduction of urinary albumin excretion, which are currently used for the treatment of angina, anticoagulants for the prevention of thromboembolism and for the prevention of stroke. It is about.
  • Dipyridamole is a compound with the chemical name ⁇ 2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine ⁇ . It is disclosed for the first time in Patent Publication No. 3,031,450.
  • Deepyridamole has been used as a coronary dilator since the 1960s.
  • dipyridamole has been reported to have platelet aggregation inhibitory activity due to inhibition of adenosine influx and dipyridamole has been used as an antithrombotic agent due to these studies.
  • dipyridamole inhibits thrombosis through multiple mechanisms. Initial studies have shown that dipyridamole inhibits the absorption of adenosine, which is known to be a potent endogenous anti-thrombotic compound. Dipyridamole was also found to increase intracellular c-AMP by inhibiting cyclic AMP.
  • Kidney disease is a chronic disease defined as more than urinary albumin excretion, with urinary albumin excretion less than 40 mg / 24 hours in healthy people.
  • the clinical stage of nephropathy is divided into trace proteinuria, severe proteinuria and terminal kidney disease (ESRD).
  • the present inventors measured the effect of inhibiting the proliferation of mesangium cells in glomeruli of dipyridamole in vitro and also measured the effect on urinary albumin excretion through animal experiments. By doing so, the present invention has been completed by confirming the effects of treating dipyridamole in the treatment and prevention of kidney disease.
  • the problem to be solved by the present invention is to determine the effect of inhibiting the proliferation of mesangium cells in glomeruli of dipyridamole in vitro in order to confirm the proteinuria reduction effect of dipyridamole.
  • the effect of urinary albumin excretion was measured through animal experiments.
  • An object of the present invention is a pharmaceutical composition for treating renal disease containing dipyridamole as an active ingredient, wherein the dipyridamole inhibits proliferation of mesangium cells in vitro and reduces urinary albumin excretion in test animals. It is to provide a pharmaceutical composition characterized by treating kidney disease.
  • the kidney disease is characterized by one disease selected from diabetic nephropathy, IgA nephropathy, chronic glomerulonephritis, acute progressive nephritis, neprogen syndrome, microsomal sclerosis, membranous proliferative glomerulonephritis, lupus nephritis or purpura nephritis.
  • the pharmaceutical composition is characterized by treating kidney disease by reducing urinary albumin excretion in diabetic nephropathy.
  • the pharmaceutical composition is characterized by treating kidney disease by inhibiting mesangium cell proliferation in IgA nephropathy, chronic glomerulonephritis, microglomerular sclerosis or membranous proliferative glomerulonephritis.
  • the effect of the present invention is to determine the effect of dipyridamole proteinuria reduction in vitro to determine the effect of inhibiting the proliferation of mesangial cells in the glomeruli of dipyridamole and to determine the effect on urinary albumin excretion through animal experiments
  • the purpose of the present invention is to provide a treatment and prevention effect of lidamol kidney disease. It is to provide a pharmaceutical composition for treating kidney disease containing dipyridamole as an active ingredient.
  • the present invention relates to a pharmaceutical composition for treating kidney disease containing dipyridamole as an active ingredient, wherein the dipyridamole inhibits proliferation of mesangium cells in vitro and reduces urinary albumin excretion in test animals. It relates to a pharmaceutical composition characterized in that to treat.
  • kidneys that can be treated through dipyridamole administration include one kidney selected from diabetic nephropathy, IgA nephropathy, chronic glomerulonephritis, acute progressive nephritis, nephrase syndrome, microglomerular sclerosis, membrane proliferative glomerulonephritis, lupus nephritis or purpura nephritis Disease.
  • the dipyridamole pharmaceutical composition also treats or alleviates kidney disease by reducing urinary albumin excretion in diabetic nephropathy.
  • Diabetic nephropathy affects 35-40% of patients with type 1 diabetes mellitus and 10-60% of patients with type 2 diabetes mellitus. Diabetic nephropathy is also the most common cause of end-stage renal disease.
  • the reduction of proteinuria such as urinary albumin excretion plays a very important role in treating or alleviating the disease, and the dipyridamole pharmaceutical composition of the present invention is effective for such diabetic nephropathy.
  • the urinary albumin and creatinine reduction effect through administration to was confirmed through animal experiments.
  • the dipyridamole pharmaceutical composition treats or alleviates kidney disease by inhibiting mesangium cell proliferation in IgA nephropathy, chronic glomerulonephritis, microsomal sclerosis or membranous proliferative glomerulonephritis.
  • mesangium cells rapidly increase in number of cells due to diseases such as glomerulitis and thus increase the excretion of proteinuria such as urinary albumin. Therefore, in the case of medicines for the treatment of renal disease, the mesangium cell proliferation inhibitory effect is usually shown, and the dipyridamole pharmaceutical composition of the present invention also exhibited the mesangium cell proliferation inhibitory effect in vitro.
  • dipyridamole pharmaceutical composition of the present invention contains dipyridamole as an active ingredient and may include dipyridamole and one or more pharmaceutically acceptable carriers or excipients.
  • dipyridamole pharmaceutical composition of the present invention may be a formulation disclosed in Korean Patent Application No. 10-2015-71452 'Method for preparing core-shell sustained release pellets containing dipyridamole as an active ingredient'.
  • dipyridamole pharmaceutical composition of the present invention may be administered orally, topically, or in the form of an injection, but oral administration in the form of a capsule is most preferred.
  • the cells were washed with 250 ⁇ L / well of Hanks Adjustment Buffer and cryopreserved at ⁇ 30 ° C. until the amount of DNA in the plate was measured.
  • the DNA content was measured by fluorescence intensity (measurement condition: 480 nm excitation wavelength; 520 nm wavelength) using a cell proliferation measurement kit.
  • the fluorescence intensity of medium containing only FXa factor (20nM) containing no dipyridamole as a test compound was 227.0 ⁇ 3.5, and the fluorescence intensity of medium containing dipyridamole (1 ⁇ M) and FXa factor (20nM) was 206.2 ⁇ 2.8.
  • the fluorescence intensity of the medium containing dipyridamole (10 ⁇ M) and FXa factor (20 nM) was 178.3 ⁇ 3.7.
  • mice Six-week-old male spontaneously diabetic mice (db / db mice) (20 cases) and their non-diabetic mice (db / + m mice) (10 cases) were used for animal testing.
  • the spontaneously developed diabetic mice were divided into two groups (10 cases each), and in the test group, 20 mg / kg of dipyridamole, a test compound suspended in 0.5% methylcellulose solution, and 0.5% methylcellulose solution, db / + m in the control group. Mice were orally administered with 0.5% methylcellulose solution twice daily.
  • Albumin / creatinine ratio in urine Albumin concentration in urine / Creatinine concentration in urine
  • Urine albumin concentration was measured using a kit for quantifying trace albumin in mouse urine, and creatinine concentration in urine was measured using a kit for measuring creatinine.
  • the albumin / creatinine ratio in urine was consistently 0.025. 0.38 was shown for spontaneously diabetic mice (db / db mice) of the control group. Meanwhile, in the spontaneously developed diabetic mouse (db / db mouse) to which dipyridamole, a test compound of the present invention, was administered for 10 weeks, the albumin / creatinine ratio in urine was 0.20.
  • albumin content in urine of test group spontaneously diabetic mice is about 7 times higher than that of non-diabetic mice (db / + m mice) without diabetes.
  • Goto-Kakizaki (GK) diabetic rats were clinically administered ramipril (1 mg / kg / day) and dipyridamole compound (5 mg / kg / day) commercially available as a diuretic over a 12 week period. Drinking water and feed were fed under fasting conditions.
  • GK rats are a model of type 2 diabetes.
  • the control group received no drug, one test group received dipyridamole of the present invention, and the other test group received ramipril commercially available as a diuretic.
  • Table 1 shows the albumin and creatinine urinary excretion of each test group after 6 and 12 weeks of administration to GK rats.
  • the GK rats in the control group treated with no drug showed 103.9 mg / mmol in albumin / creatinine in the initial period of urine, but after 6 weeks they increased to 319.3 mg / mmol. After week, it increased to about 10 102.9 mg / mmol.
  • the albumin / creatinine content in urine was 20.7 mg / mmol, which was about 1/5 less than that in the original urine.
  • the albumin / creatinine content in the urine was 18.4 mg / mmol, which was confirmed to be maintained or reduced to about the same content after 6 weeks.
  • Test group 1 prepared a dipyridamole test compound solution at a dose of 10 mg / 10 ml / kg and was injected at a dose rate of 1 ml / min through the tail vein of ICR mice. After 24 hours, the live death of the mice was confirmed.
  • test group 2 a dipyridamole test compound solution was prepared at a dose of 50 mg / 10ml / kg and administered to ICR mice at the same administration method and rate
  • test group 3 a dipyridamole test compound solution was prepared at a dose of 100 mg / 10ml / kg.
  • the dipyridamole test compound solution was prepared at a dose of 200 mg / 10ml / kg, and administered to the ICR mice at the same administration method and rate.
  • Table 2 shows mortality after 24 hours of ICR mice in each test group.
  • Test group 1 Test group 2
  • Test group 3 Test group 4 death rate 0/5 0/5 0/5 0/5 0/5
  • the dipyridamole compound of the present invention did not cause any death even when administered to ICR mice at the maximum dose of 200 mg / 10 ml / kg.
  • the dipyridamole compound of the present invention was identified as a very safe drug for treating kidney disease.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)

Abstract

L'invention concerne une composition pharmaceutique pour traiter des maladies rénales, contenant du dipyridamole en tant qu'ingrédient actif. L'invention concerne, plus spécifiquement, l'utilisation pharmaceutique du dipyridamole pour le traitement des maladies rénales, par inhibition de la prolifération de cellules mésangiales et réduction de l'excrétion de l'albumine urinaire, le dipyridamole étant actuellement utilisé en tant que traitement pour le support d'agents anticoagulants de façon à empêcher l'angine de poitrine et la thrombo-embolie et à prévenir un accident vasculaire cérébral.
PCT/KR2016/004847 2015-07-06 2016-05-10 Composition pharmaceutique pour le traitement des maladies rénales contenant du dipyridamole en tant qu'ingrédient actif WO2017007120A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2015-0095683 2015-07-06
KR1020150095683A KR20170005539A (ko) 2015-07-06 2015-07-06 디피리다몰을 유효 성분으로 함유하는 신장 질환 치료용 의약 조성물

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WO2017007120A1 true WO2017007120A1 (fr) 2017-01-12

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WO (1) WO2017007120A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021077070A1 (fr) * 2019-10-18 2021-04-22 Yale University Compositions et méthodes d'inhibition d'anticorps pénétrant dans les cellules

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050018330A (ko) * 2003-08-13 2005-02-23 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 혈관장애의 치료 및 예방을 위한 디피리다몰,아세틸살리실산 및 안지오텐신 ⅱ 길항제의 용도
JP2005060359A (ja) * 2003-08-13 2005-03-10 Boehringer Ingelheim Pharma Gmbh & Co Kg 血管系病態の治療及び予防のためのジピリダモール、アセチルサリチル酸及びアンギオテンシンｉｉ拮抗薬の使用
US20130296331A1 (en) * 2010-11-26 2013-11-07 Technion Research And Development Foundation Ltd. Compositions and methods for ameliorating renal dysfunction induced by renal hypoperfusion or acute kidney injury

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050018330A (ko) * 2003-08-13 2005-02-23 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 혈관장애의 치료 및 예방을 위한 디피리다몰,아세틸살리실산 및 안지오텐신 ⅱ 길항제의 용도
JP2005060359A (ja) * 2003-08-13 2005-03-10 Boehringer Ingelheim Pharma Gmbh & Co Kg 血管系病態の治療及び予防のためのジピリダモール、アセチルサリチル酸及びアンギオテンシンｉｉ拮抗薬の使用
US20130296331A1 (en) * 2010-11-26 2013-11-07 Technion Research And Development Foundation Ltd. Compositions and methods for ameliorating renal dysfunction induced by renal hypoperfusion or acute kidney injury

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HILLIS, GRAHAMS ET AL.: "Dipyridamole Inhibits Human Mesangial Cell Proliferation", NEPHRON, vol. 78, no. 2, 1998, pages 172 - 178 *
YOON, JI SUNG: "Screening and Management of Diabetic Nephropathy", THE JOURNAL OF KOREAN DIABETES, vol. 14, 2013, pages 19 - 22, XP055345327 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021077070A1 (fr) * 2019-10-18 2021-04-22 Yale University Compositions et méthodes d'inhibition d'anticorps pénétrant dans les cellules

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