KR20170005539A - Pharmaceutical composition for treating renal disease including dipyridamole as active ingredient - Google Patents
Pharmaceutical composition for treating renal disease including dipyridamole as active ingredient Download PDFInfo
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- KR20170005539A KR20170005539A KR1020150095683A KR20150095683A KR20170005539A KR 20170005539 A KR20170005539 A KR 20170005539A KR 1020150095683 A KR1020150095683 A KR 1020150095683A KR 20150095683 A KR20150095683 A KR 20150095683A KR 20170005539 A KR20170005539 A KR 20170005539A
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- South Korea
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- dipyridamole
- renal disease
- pharmaceutical composition
- active ingredient
- treating
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
Abstract
The present invention relates to a pharmaceutical composition for treating a renal disease containing dipyridamole as an active ingredient. More particularly, the present invention relates to a medicament for the treatment of renal disease by inhibiting the proliferation of mesangial cells of dipyridamole, reduction of urinary albumin excretion, and the like, which are currently used for the treatment of angina pectoris, an anticoagulant for the prevention of thromboembolism, .
Description
The present invention relates to a pharmaceutical composition for treating a renal disease containing dipyridamole as an active ingredient. More particularly, the present invention relates to a medicament for the treatment of renal disease by inhibiting the proliferation of mesangial cells of dipyridamole, reduction of urinary albumin excretion, and the like, which are currently used for the treatment of angina pectoris, anticoagulant therapy for prevention of thromboembolism, .
Dipyridamole is a compound having the chemical name {2,6-bis (diethanolamino) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine} Patent Publication No. 3,031,450.
Dipyridamole has been used as a coronary artery dilator since the 1960s. In addition, dipyridamole has been reported to inhibit platelet aggregation inhibition due to inhibition of adenosine entry. As a result of these studies, dipyridamole has been used as an antithrombotic agent.
In a second European Stroke Prevention Study (2), Dipyridamole alone has been shown to be as effective as low-dose aspirin in reducing the risk of stroke, combined with dipyridamole and aspirin Has been shown to be more than twice as effective as aspirin alone therapy [J Neurof Sci. (1996) 143, pp.1-13; Neurology (1998) 51, pp. 17-19].
It is believed that dipyridamole inhibits thrombosis through multiple mechanisms. Early 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 inhibit cyclic AMP and increase intracellular c-AMP.
Inhibition of free radical formation by dipyridamole inhibits fibrinogen production in experimental hepatic fibrosis (Hepatology (1996) 24, pp. 855-864). In experimental animals suffering from aminucleoside nephropathy, (1998) 28, pp. 877-883; Renal Physiol. (1984) 7, pp.218-226).
Renal disease is a chronic disease defined as abnormal urinary albumin excretion. In healthy people, urinary albumin excretion rate is less than 40 mg / 24 hours. The clinical stages of nephropathy are classified into microalbuminuria, severe proteinuria and end stage renal disease (ESRD).
Therefore, in order to confirm the effect of dipyridamole on proteinuria, the present inventors measured in vitro the effect of inhibiting proliferation of Mesangium cells in the glomeruli of dipyridamole, and measured the effect on urinary albumin excretion through animal experiments Thereby confirming the therapeutic and preventive effects of dipyridamole on kidney disease, thereby completing the present invention.
Therefore, a problem to be solved by the present invention is to measure in vitro the effect of suppressing the proliferation of mesangial cells in the glomeruli of dipyridamole in order to confirm the effect of decreasing the proteinuria of dipyridamole. In addition, the effect on urinary albumin excretion was measured through animal experiments. The present invention relates to a pharmaceutical composition for the treatment of renal diseases, which comprises dipyridamole as an active ingredient by confirming the therapeutic and preventive effects of dipyridamole on kidney disease.
It is an object of the present invention to provide a medicinal composition for treating a renal disease containing dipyridamole as an active ingredient, wherein the dipyridamole inhibits proliferation of mesangial cells in vitro and reduces urinary albumin excretion in a test animal Thereby treating a renal disease.
Wherein the renal disease is one disease selected from diabetic nephropathy, IgA nephritis, chronic glomerulonephritis, acute progressive nephritis, nephrotic syndrome, pancreatic glomerulosclerosis, membranoproliferative glomerulonephritis, lupus nephritis or papillary nephritis.
Also, the pharmaceutical composition is characterized by treating renal disease by decreasing urinary albumin excretion in diabetic nephropathy.
The pharmaceutical composition is also characterized by treating renal disease by inhibiting mesangial cell proliferation in IgA nephropathy, chronic glomerulonephritis, pancreatic glomerulosclerosis or glomerular proliferative glomerulonephritis.
The effect of the present invention is to measure the effect of inhibiting proliferation of mesangial cells in the glomeruli of dipyridamole in vitro in order to confirm the effect of dipyridamole on proteinuria, It is intended to provide the treatment and prevention of kidney disease of lidarol. And a medicinal composition for treating a renal disease containing dipyridamole as an active ingredient.
The present invention relates to a pharmaceutical composition for treating a renal disease containing dipyridamole as an active ingredient, wherein the dipyridamole inhibits proliferation of mesangial cells in vitro and reduces urinary albumin excretion in a test animal, Which comprises administering a therapeutically effective amount of a compound of formula
Hereinafter, the present invention will be described in more detail.
Diseases that can be treated by administration of dipyridamole include one kidney selected from diabetic nephropathy, IgA nephropathy, chronic glomerulonephritis, acute advanced nephritis, nephrotic syndrome, pancreatic glomerulosclerosis, membranoproliferative glomerulonephritis, lupus nephritis or papillary nephritis Disease.
The dipyridamol pharmaceutical composition also reduces or alleviates renal disease by reducing urinary albumin excretion in diabetic nephropathy.
Most of the kidney disease is diabetic kidney disease. Diabetic nephropathy occurs in 35% to 40% of patients with type 1 diabetes mellitus and in 10% to 60% of patients with type 2 diabetes mellitus. Diabetic nephropathy is also the most common cause of end stage renal disease.
Appropriate antihypertensive therapy for patients with diabetic nephropathy has been reported to not only delay the rate of decline in the glomerular filtration rate of the patient but also significantly reduce renal and cardiovascular mortality through reduction of proteinuria in patients with type 1 diabetes mellitus [ : Lewis et al., N. Engl. J. Med. 1993, 329, 1456-1462).
Therefore, in the case of diabetic nephropathy, reduction of proteinuria such as urinary albumin excretion plays a very important role in treating or alleviating the disease, and the dipyridamol pharmaceutical composition of the present invention is effective for diabetic nephropathy such as diabetic rats And the effect of reducing urinary albumin and creatinine was confirmed by animal experiments.
On the other hand, the dipyridamol pharmaceutical composition treats or alleviates renal disease by inhibiting mesangial cell proliferation in IgA nephropathy, chronic glomerulonephritis, pancreatic glomerulosclerosis or membranous proliferative glomerulonephritis.
Mesangium cells are rapidly increased in their number of cells due to diseases such as glomerulonephritis, which leads to an increase in proteinuria such as urinary albumin. Therefore, the medicament for the treatment of kidney disease usually exhibits mesangial cell proliferation inhibitory effect, and the dipyridamol medicinal composition of the present invention also exhibits mesangial cell proliferation inhibitory effect in vitro.
Meanwhile, the dipyridamol 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.
Also, the dipyridamol pharmaceutical composition of the present invention can be a product disclosed in Korean Patent Application No. 10-2015-71452 of the present inventor, and a process for producing a core-shell sustained release pellet containing dipyridamole as an active ingredient.
I) spraying a solution containing 5 to 10 parts by weight of a methacrylic acid copolymer with 100 parts by weight of stearic acid as a core material, thereby forming a primary coating; Ii) spray coating a solution containing 50 to 150 parts by weight of dipyridamole on the primary coated pellets to form a secondary coating; Iii) thirdly coating the second coated pellets with a spraying solution comprising 3 to 7 parts by weight of the hydroformylose phthalate and 2 to 5 parts by weight of ethyl cellulose; And iv) drying and selecting the tertiary-coated pellets; and a core-shell sustained-release pellet containing dipyridamole as an active ingredient.
The dipyridamol pharmaceutical composition of the present invention may be administered orally, topically, or in the form of an injection, although oral administration in the form of a capsule is most preferred.
Hereinafter, the present invention will be described in more detail by way of examples.
(Example 1) Inhibitory effect of dipyridamole on human mesangial cell proliferation in vitro
Normal and human mesangial cells to 1 × 10 4 cells / 200μL in a 96-well culture plate mesangial cells seeded in growth medium / well concentration, CO 2 incubator for culturing in (37 ℃, O 2: 5 : CO 2 = 95) did. One day after seeding, the mesangial cell basal medium containing 0.5% bovine serum albumin was washed and the medium was incubated with a specific concentration of human activated blood coagulation FXa factor (20 nM) and the test compound, dipyridamole (1 μM, 10 μM) Replaced with a mesangium cell-based medium containing 0.5% bovine serum albumin, and cultured in a CO 2 incubator for 110 hours. After incubation, the cells were washed with 250 [mu] L / well of Hanks' buffering buffer and stored frozen at -30 [deg.] C until the amount of DNA in the plate was measured. The amount of DNA was measured using a cell growth measurement kit with fluorescence intensity (measuring conditions: excitation wavelength: 480 nm; measurement wavelength: 520 nm).
The fluorescence intensity of the medium containing only the FXa factor (20 nM) without the dipyridamole as a test compound was 227.0 ± 3.5 and the fluorescence intensity of the medium containing dipyridamole (1 μM) and FXa factor (20 nM) was 206.2 ± 2.8 The fluorescence intensity of the medium containing dipyridamole (10 μM) and FXa factor (20 nM) was 178.3 ± 3.7. Thus, it was confirmed that the number of cells of mesangial cells was decreased by inhibiting mesangial cell proliferation in the medium in a dose dependent manner by the test compound Dipyridamol of the present invention.
(Example 2) Inhibitory effect on nephropathy progression in spontaneously diabetic mouse
6-week-old spontaneously diabetic mice (db / db mice) (20) and their non-diabetic mice (db / + m mice) (10) were used for animal studies. Spontaneously diabetic mice were divided into two groups (10 each). In the test group, 20 mg / kg of dipyridamole as a test compound suspended in 0.5% methylcellulose solution, 0.5% methylcellulose solution only in the control group and db / + m Mice were orally administered only 0.5% methylcellulose solution twice a day.
After 10 weeks of administration, each subject was earmuffed for 24 hours in the metabolic cage. Urine samples were analyzed for urinary albumin / creatinine ratio as an indicator of urinary protein by removing insoluble matter by centrifugation and adjusting urinary albumin concentration to urinary creatinine concentration. In addition, albumin / creatinine ratio in urine was calculated based on the following equation.
Urine albumin / creatinine ratio = urine albumin concentration / urine creatinine concentration
Urinary albumin concentration was measured using a kit for quantifying albumin in mouse urine, and creatinine concentration in urine was measured using a kit for creatinine measurement.
In non-diabetic mice (db / + m mice), albumin / creatinine ratio in urine was constantly 0.025. And 0.38 in the control spontaneously diabetic mouse (db / db mouse). In the case of spontaneously diabetic mouse (db / db mouse) in which the dipyridamole compound of the present invention was administered for 10 weeks, the urinary albumin / creatinine ratio was 0.20.
As a result, the content of albumin in the urine of the spontaneously diabetic mouse (db / db mouse) administered with dipyridamole as a test compound of the present invention for 10 weeks was measured by using a control spontaneously diabetic mouse (db / db mouse) Compared with that of the control group.
However, the amount of albumin in the urine of test-spontaneously diabetic mice (db / db mice) was about 7-fold higher than that of non-diabetic mice (db / + m mice) without diabetes.
(Example 3) Effect of dipyridamole on diabetic test albumin and creatinine urine reduction effect
Goto-Kakizaki (GK) diabetic rats were clinically administered ramipril (1 mg / kg / day) and dipyridamole compound (5 mg / kg / day), which were commercially available as diuretics over a period of 12 weeks. Drinking water and feed were fed under fasting conditions.
After 6 and 12 weeks, albumin and cretinin excretion from GK rats was measured. GK rats are a model of type 2 diabetes. The control group did not receive any drug, one test group administered dipyridamole of the present invention, and another test group received ramipril that was commercialized as a diuretic.
Table 1 shows the albumin and creatinine excretion of each test group after 6 and 12 weeks of administration in GK rats.
As shown in Table 1, the albumin / creatinine content in the initial period urine was 103.9 mg / mmol in the control group GK rats in which no drug was administered, but increased to 319.3 mg / mmol after 6 weeks, And increased to about 1082.9 mg / mmol after about a week.
However, after administration of dipyridamole of the present invention at a dose of 5 mg / kg / day for 6 weeks, the albumin / creatinine content in the urine decreased to about 1/5 of that in the initial urine, which was 20.7 mg / mmol. After 12 weeks, the albumin / creatinine content in urine was 18.4 mg / mmol, which was maintained or decreased to almost the same level after 6 weeks.
Meanwhile, the albumin / creatinine content in urine increased gently in the test group in which laminifuril, a commercially available diuretic, was administered at a dose of 1 mg / kg / day, and the albumin / creatinine content in urine increased to 183.8 mg / mmol after 12 weeks . Thus, diuretics alone did not significantly reduce albumin and creatinine excretion in the urine of diabetic GK rats, but significantly reduced albumin and creatinine excretion as compared to control groups without any treatment.
(Example 4) Acute toxicity test
Twenty ICR male mice aged 7 weeks were divided into four groups. In test group 1, a dipyridamole test compound solution was prepared at a dose of 10 mg / 10 ml / kg and injected through the tail vein of ICR mice at a dose rate of 1 ml / min. After 24 hours, the mortality of the mice was confirmed. In the test group 2, the dipyridamole test compound solution was prepared at a dose of 50 mg / 10 ml / kg and administered to the ICR mice at the same administration method and rate. In test group 3, the dipyridamole test compound solution was prepared at a dose of 100 mg / And administered to the ICR mice at the same dosing method and rate. In test group 4, the dipyridamole test compound solution was prepared at a dose of 200 mg / 10 ml / kg and administered to ICR mice at the same administration method and rate.
Table 2 shows the mortality rates of ICR mice in each test group after 24 hours.
Therefore, no deaths occurred even when the dipyridamole compound of the present invention was administered to an ICR mouse at a maximum dose of 200 mg / 10 ml / kg. Thus, the dipyridamole compound of the present invention has been confirmed as a safe medicament for treating a renal disease.
Claims (4)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020150095683A KR20170005539A (en) | 2015-07-06 | 2015-07-06 | Pharmaceutical composition for treating renal disease including dipyridamole as active ingredient |
| PCT/KR2016/004847 WO2017007120A1 (en) | 2015-07-06 | 2016-05-10 | Pharmaceutical composition for treating renal diseases, containing dipyridamole as active ingredient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020150095683A KR20170005539A (en) | 2015-07-06 | 2015-07-06 | Pharmaceutical composition for treating renal disease including dipyridamole as active ingredient |
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| KR1020170025979A Division KR101736832B1 (en) | 2017-02-28 | 2017-02-28 | Pharmaceutical composition for treating renal disease including dipyridamole as active ingredient |
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| WO (1) | WO2017007120A1 (en) |
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| WO2021077070A1 (en) * | 2019-10-18 | 2021-04-22 | Yale University | Compositions and methods for inhibition of cell-penetrating antibodies |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20050018330A (en) * | 2003-08-13 | 2005-02-23 | 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 | Use of dipyridamole, acetylsalicylic acid and an angiotensin II antagonist for treatment and prevention of vascular events |
| JP2005060359A (en) * | 2003-08-13 | 2005-03-10 | Boehringer Ingelheim Pharma Gmbh & Co Kg | Use of dipyridamole, acetyl salicylic acid and angiotensin ii antagonist for treatment and prevention of vascular morbidity |
| 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 |
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