WO2017007120A1 - Pharmaceutical composition for treating renal diseases, containing dipyridamole as active ingredient - Google Patents

Pharmaceutical composition for treating renal diseases, containing dipyridamole as active ingredient Download PDF

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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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dipyridamole
pharmaceutical composition
kidney disease
active ingredient
albumin
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PCT/KR2016/004847
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French (fr)
Korean (ko)
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이준용
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초당약품공업 주식회사
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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
    • A61K9/48—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.

Abstract

The present invention relates to a pharmaceutical composition for treating renal diseases, containing dipyridamole as an active ingredient. More specifically, the present invention relates to a pharmaceutical use, for treating renal diseases, of dipyridamole, by inhibiting the proliferation of mesangial cells and decreasing the excretion of urinary albumin, wherein the dipyridamole is currently used as a treatment use for the support of anticoagulant agents so as to prevent angina and thromboembolism and for the prevention of a stroke.

Description

디피리다몰을 유효 성분으로 함유하는 신장 질환 치료용 의약 조성물Pharmaceutical composition for treating renal disease containing dipyridamole as an active ingredient
본 발명은 디피리다몰을 유효 성분으로 함유하는 신장 질환 치료용 의약 조성물에 관한 것이다. 더욱 상세하게는 현재 협심증, 혈전 색전증 예방을 위한 항응고제의 보조 및 뇌졸중 예방을 위한 치료 용도로 사용되고 있는 디피리다몰의 메산지움 세포의 증식 억제, 비뇨 알부민 배설 감소를 통한 신장 질환 치료용 의약 용도 발명에 관한 것이다.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.
디피리다몰(dipyridamole)은 {2,6-비스(디에탄올아미노)-4,8-디피페리디노-피리미도[5,4-d]피리미딘}이라는 화학명을 지닌 화합물로서 그의 제조방법은 미국 특허공보 제3,031,450호에 최초로 개시된 바 있다.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.
디피리다몰은 1960년대 이후 관상동맥 확장제로서 사용되어 왔다. 또한 디피리다몰은 아데노신 유입의 억제로 인해 혈소판 응집 저해 활성을 지닌 것으로 보고되었으며 이러한 연구 결과로 인해 디피리다몰은 항혈전제로서 사용되어 왔다. Deepyridamole has been used as a coronary dilator since the 1960s. In addition, 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.
또한 제2차 유럽 뇌졸중 예방 연구(European Stroke Prevention Study 2)에서 발표된 문헌에서는 디피리다몰에 의한 단독 치료가 뇌졸증의 위험을 감소시키는 데에 저용량 아스피린만큼 효과적이고 디피리다몰과 아스피린과의 병용 치료가 아스피린 단독 치료보다 2배 이상 효과적이라는 것이 개시되어 있다[J Neurof Sci. (1996) 143, pp.1-13; Neurology (1998) 51, pp.17-19 참조].In addition, the literature published in the second European Stroke Prevention Study 2 found that dipyridamole alone treatment is as effective as low-dose aspirin in reducing the risk of stroke and a combination of dipyridamole and aspirin. Has been shown to be twice as effective as aspirin alone [J Neurof Sci. (1996) 143, pp. 1-13; Neurology (1998) 51, pp. 17-19].
이때 디피리다몰은 다중 기전을 통해 혈전증을 억제하는 것으로 여겨진다. 초기 연구에 따르면 디피리다몰은 강력한 내생성 항-혈전성 화합물인 것으로 알려진 아데노신의 흡수를 억제하는 것으로 규명되었다. 또한 디피리다몰은 사이클릭 AMP를 억제하여 세포내 c-AMP를 증가시키는 것으로 규명되었다.It is believed that 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.
한편 디피리다몰에 의한 유리 라디칼 형성의 억제는 실험상의 간 섬유증에서 피브리노겐 생성을 억제하고(Hepatology (1996) 24, pp.855-864) 아미노뉴클레오사이드 신병증을 앓고 있는 실험 동물에서 산소 라디칼 및 단백뇨를 감소시키는 것으로 보고되어 왔다(Eur. J. Clin. Invest. (1998) 28, pp.877-883; Renal Physiol. (1984) 7, pp.218-226).Inhibition of free radical formation by dipyridamole, on the other hand, inhibits fibrinogen production in experimental liver fibrosis (Hepatology (1996) 24, pp. 855-864) and in the experimental animals suffering from aminonucleoside nephropathy It has been reported to reduce proteinuria (Eur. J. Clin. Invest. (1998) 28, pp. 877-883; Renal Physiol. (1984) 7, pp. 218-226).
신장 질환은 비뇨 알부민 배설 이상으로 정의되는 만성 질환으로 건강한 사람의 경우 비뇨 알부민 배설율은 40mg/24시간 이하이다. 신장 병증의 임상 단계는 미량의 단백뇨, 중증의 단백뇨 및 말기 신장 질환(ESRD)으로 구분된다. 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).
따라서 본 발명자들은 디피리다몰의 단백뇨 감소 효과를 확인하기 위해 디피리다몰의 사구체 내의 메산지움(Mesangium) 세포의 증식 억제 효과를 시험관 내에서 측정해보고 또한 비뇨 알부민 배설에 미치는 영향을 동물 실험을 통해 측정함으로써 디피리다몰의 신장 질환 치료 및 예방 효과를 확인함으로써 본 발명을 완성하게 된 것이다. Therefore, in order to confirm the effect of dipyridamole on proteinuria reduction, 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.
따라서 본 발명이 해결하고자 하는 과제는 디피리다몰의 단백뇨 감소 효과를 확인하기 위해 디피리다몰의 사구체 내의 메산지움 세포의 증식 억제 효과를 시험관 내에서 측정코자 한 것이다. 또한 비뇨 알부민 배설에 미치는 영향을 동물 실험을 통해 측정코자 한 것이다. 디피리다몰의 신장 질환 치료 및 예방 효과를 확인함으로써 디피리다몰을 유효 성분으로 함유하는 신장 질환 치료용 의약 조성물을 개발코자 것이다.Therefore, 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. In addition, the effect of urinary albumin excretion was measured through animal experiments. By identifying the therapeutic and prophylactic effects of dipyridamole for the kidney disease, a pharmaceutical composition for treating kidney disease containing dipyridamole as an active ingredient will be developed.
본 발명의 목적은 디피리다몰을 유효 성분으로 함유하는 신장 질환 치료용 의약 조성물에 있어서, 상기 디피리다몰은 시험관 내에서 메산지움 세포의 증식을 억제하고, 시험 동물 내에서 비뇨 알부민 배설을 감소시킴으로써 신장 질환을 치료함을 특징으로 하는 의약 조성물을 제공하는 것이다. 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.
이때 상기 신장 질환은 당뇨병성 신증, IgA신증, 만성 사구체신염, 급성진행성 신염, 네프로제 증후군, 소상 사구체 경화증, 막성 증식성 사구체신염, 루프스 신염 또는 자반병성 신염에서 선택된 하나의 질환임을 특징으로 한다. In this case, 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.
또한 상기 의약 조성물은 당뇨병성 신증에 있어서 비뇨 알부민 배설을 감소시킴으로써 신장 질환을 치료함을 특징으로 한다. In addition, the pharmaceutical composition is characterized by treating kidney disease by reducing urinary albumin excretion in diabetic nephropathy.
또한 상기 의약 조성물은 IgA신증, 만성 사구체신염, 소상 사구체 경화증 또는 막성 증식성 사구체신염에서 메산지움 세포 증식을 억제시킴으로써 신장 질환을 치료함을 특징으로 한다.In addition, 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.
본 발명의 효과는 디피리다몰의 단백뇨 감소 효과를 확인하기 위해 디피리다몰의 사구체 내의 메산지움 세포의 증식 억제 효과를 시험관 내에서 측정하고 또한 비뇨 알부민 배설에 미치는 영향을 동물 실험을 통해 측정함으로써 디피리다몰의 신장 질환 치료 및 예방 효과를 제공코자 한 것이다. 디피리다몰을 유효 성분으로 함유하는 신장 질환 치료용 의약 조성물을 제공하는 것이다. 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.
본 발명은 디피리다몰을 유효 성분으로 함유하는 신장 질환 치료용 의약 조성물에 있어서, 상기 디피리다몰은 시험관 내에서 메산지움 세포의 증식을 억제하고, 시험 동물 내에서 비뇨 알부민 배설을 감소시킴으로써 신장 질환을 치료함을 특징으로 하는 의약 조성물에 관한 것이다. 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.
이하 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
디피리다몰 투여를 통해 치료할 수 있는 질환은 당뇨병성 신증, IgA신증, 만성 사구체신염, 급성진행성 신염, 네프로제 증후군, 소상 사구체 경화증, 막성 증식성 사구체신염, 루프스 신염 또는 자반병성 신염에서 선택된 하나의 신장 질환이다. Diseases 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.
또한 디피리다몰 의약 조성물은 당뇨병성 신증에 있어서 비뇨 알부민 배설을 감소시킴으로써 신장 질환을 치료 또는 경감시킨다. The dipyridamole pharmaceutical composition also treats or alleviates kidney disease by reducing urinary albumin excretion in diabetic nephropathy.
신장질환의 대부분은 당뇨병성 신장질환이다. 당뇨병 신장병증은 1형 진성 당뇨병을 앓는 환자의 35∼40%가 발생하며 2형 진성 당뇨병을 앓는 환자의 10∼60%가 발생한다. 또한 당뇨병셩 신장병증은 말기 신장 질환의 가장 공통적인 원인이다.Most of the kidney disease is diabetic kidney disease. 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.
당뇨병성 신장병증을 지닌 환자에게 적절한 항고혈압 치료는 환자의 사구체 여과율의 감퇴 속도를 지연시킬 뿐만 아니라 1형 진성 당뇨병 환자의 단백뇨의 감소를 통한 신장 및 심혈관 사망률을 상당히 감소시키는 것으로 보고되고 있다[문헌: Lewis et al., N. Engl. J. Med. 1993, 329, 1456-1462].Appropriate antihypertensive therapy for patients with diabetic nephropathy has been reported to not only slow the rate of decline of glomerular filtration rate in patients but also significantly reduce renal and cardiovascular mortality through the reduction of proteinuria in patients with type 1 diabetes mellitus. Lewis et al., N. Engl. J. Med. 1993, 329, 1456-1462.
따라서 당뇨병성 신장병증의 경우 비뇨 알부민 배설과 같은 단백뇨의 감소가 그 질환을 치료 또는 경감시키는데 매우 중요한 역할을 하며 본 발명의 디피리다몰 의약 조성물의 경우 이와 같은 당뇨병성 신장병증에 유효함을 당뇨병 래트에 투여를 통한 비뇨 알부민 및 크레아티닌 감소 효과를 동물 실험을 통해 확인하였다. Therefore, in the case of diabetic nephropathy, 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.
한편 디피리다몰 의약 조성물은 IgA신증, 만성 사구체신염, 소상 사구체 경화증 또는 막성 증식성 사구체신염에서 메산지움 세포 증식을 억제시킴으로써 신장 질환을 치료 또는 경감시킨다. Meanwhile, 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.
메산지움 세포는 사구체염과 같은 질환에 의해 그 세포의 수가 급격하게 증가하고 이에 따라 비뇨 알부민과 같은 단백뇨의 배출이 증가된다. 따라서 신장 질환 치료용 의약품의 경우 통상 메산지움 세포 증식 억제효과를 나타내며 본 발명의 디피리다몰 의약 조성물 역시 시험관 내에서 메산지움 세포 증식 억제효과를 나타내었다.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.
한편 본 발명의 디피리다몰 의약 조성물은 유효 성분으로서 디피리다몰을 함유하며 디피리다몰과 약제학적으로 허용될 수 있는 하나 이상의 담체 또는 부형제를 포함할 수 있다. Meanwhile, the 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.
또한 본 발명의 디피리다몰 의약 조성물은 본 발명자의 대한민국 특허출원 10-2015-71452호 '디피리다몰을 유효 성분으로 함유하는 코어-쉘형 서방성 펠렛의 제조방법'에 개시된 제제일 수 있다. In addition, the 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'.
즉 1) 주석산 결정 100 중량부를 코어 물질로 하여 5∼10 중량부의 메타크릴산 공중합체를 포함하는 용액을 분무 분사시켜 1차 코팅시키는 단계; 2) 1차 코팅된 펠렛에 50∼150 중량부의 디피리다몰을 포함하는 용액을 분무 분사시켜 2차 코팅시키는 단계; 3) 2차 코팅된 펠렛에 3∼7 중량부의 히프로멜로오스 프탈레이트 및 2∼5 중량부의 에틸셀룰로오스를 포함하는 용액을 분무 분사시켜 3차 코팅하는 단계; 및 4) 3차 코팅된 펠렛을 건조 선별하는 단계;로 제조된 디피리다몰을 유효 성분으로 함유하는 코어-쉘형 서방성 펠렛의 형태일 수 있다. That is, 1) spray coating a solution containing 5 to 10 parts by weight of methacrylic acid copolymer by primary coating 100 parts by weight of tartaric acid crystals as a core material; 2) second coating by spray spraying a solution containing 50 to 150 parts by weight of dipyridamole to the first coated pellets; 3) tertiary coating by spray-spraying a solution containing 3 to 7 parts by weight of hypromellose phthalate and 2 to 5 parts by weight of ethyl cellulose to the secondary coated pellets; And 4) dry sorting the tertiary-coated pellet; and may be in the form of a core-shell sustained release pellet containing dipyridamole prepared as an active ingredient.
본 발명의 디피리다몰 의약 조성물은 경구 투여, 국소 투여, 주사제 형태로 투여할 수 있으나 캡슐제 형태의 경구 투여가 가장 바람직하다. The 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.
이하 실시예를 통해 본 발명을 더욱 상세히 설명한다. The present invention will be described in more detail with reference to the following examples.
(실시예 1) 디피리다몰의 시험관 내 인간 메산지움 세포증식 억제 효과Example 1 Inhibitory Effect of Dipyridamole In Vitro Human Mesangium Cell Proliferation
정상 인간 메산지움 세포를 96웰 배양 플레이트에 1×104 세포/200μL 메산지움 세포증식 배지/웰 농도로 씨딩하고, CO2 인큐베이터(37℃, O2 :CO2 =95:5)내에서 배양했다. 씨딩 1일후, 0.5% 소혈청 알부민을 포함하는 메산지움 세포 기초 배지를 세정하고, 배지를 특정 농도의 인간 활성화 혈액응고 FXa인자(20nM) 및 피험화합물인 디피리다몰(1μM, 10μM)을 포함하는 0.5% 소혈청 알부민 함유의 메산지움 세포 기초 배지로 치환하여 CO2 인큐베이터 내에서 110시간 배양했다. 배양 후, 세포를 행크스 조정 완충액 250μL/웰로 세정하고, 플레이트 내의 DNA량 측정까지 -30℃로 동결 보존했다. DNA량 측정은 세포증식 측정키트를 사용하여 형광강도(측정 조건: 여기파장 480nm; 측정 파장 520nm)로 측정했다. Normal human mesangium cells are seeded in 96-well culture plates at 1 × 10 4 cells / 200 μL mesangium cell proliferation medium / well concentration and incubated in CO 2 incubator (37 ° C., O 2 : CO 2 = 95: 5) did. After 1 day of seeding, the mesangium cell basal medium containing 0.5% bovine serum albumin was washed and the medium contained a specific concentration of human activated blood coagulation FXa factor (20 nM) and the test compound dipyridamole (1 μM, 10 μM). Substituted with mesangium cell basal medium containing 0.5% bovine serum albumin and incubated for 110 hours in a CO 2 incubator. After incubation, the cells were washed with 250 μL / 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.
피험화합물인 디피리다몰을 함유하지 않은 FXa 인자(20nM) 만을 포함한 배지의 형광강도는 227.0±3.5이었고 디피리다몰(1μM)과 FXa 인자(20nM)를 포함하는 배지의 형광강도는 206.2±2.8이었으며 디피리다몰(10μM)과 FXa 인자(20nM)를 포함하는 배지의 형광강도는 178.3±3.7이었다. 이를 통해 본 발명의 피험화합물 디피리다몰이 용량 의존적으로 배지 내에서 메산지움 세포 증식을 억제하여 메산지움 세포의 세포 수가 감소함을 확인하였다. 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 (1μM) and FXa factor (20nM) 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. Through this, the test compound dipyridamole of the present invention was dose-dependently inhibited mesangium cell proliferation in the medium, it was confirmed that the cell number of mesangium cells is reduced.
(실시예 2) 자연발증 당뇨병 마우스의 신증 진전 억제 효과Example 2 Nephrotic Progression Inhibitory Effect of Spontaneously Diabetic Mice
6주령 수컷의 자연발증 당뇨병 마우스(db/db 마우스)(20예)와 그 비당뇨병성 마우스(db/+m 마우스)(10예)를 동물시험에 사용하였다. 자연발증 당뇨병 마우스는 2개의 군(각각 10예)으로 나누고 시험군에는 0.5% 메틸셀룰로스 용액에 현탁한 피험화합물인 디피리다몰 20mg/kg을, 대조군에는 0.5% 메틸셀룰로스 용액만을, db/+m 마우스에는 0.5% 메틸셀룰로스 용액만을 1일 2회 경구투여 하였다.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.
10주간 투여 후, 대사 케이지에서 각 개체의 24시간 축요를 행하였다. 소변 샘플은 원심분리에 의해 불용성 물질을 제거하고 소변중 알부민 농도를 소변중 크레아티닌 농도로 보정한 소변중 알부민/크레아티닌 비를 요단백량의 지표로서 평가했다. 또한 소변중 알부민/크레아티닌 비는 하기의 계산식에 기초하여 산출했다.After dosing for 10 weeks, each individual was given a 24-hour rest in a metabolic cage. Urine samples were evaluated by removing the insoluble material by centrifugation and adjusting the albumin concentration in urine to the creatinine concentration in urine as an indicator of urine protein. In addition, the albumin / creatinine ratio in urine was computed based on the following formula.
소변중 알부민/크레아티닌 비 = 소변중 알부민농도/소변중 크레아티닌민농도Albumin / creatinine ratio in urine = Albumin concentration in urine / Creatinine concentration in urine
소변중 알부민 농도는 마우스 소변중 미량 알부민 정량용 키트를 사용하여 측정하였고 소변중 크레아티닌 농도는 크레아티닌 측정용 키트를 사용하여 측정하였다.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.
비당뇨병성 마우스(db/+m 마우스)의 경우 소변중 알부민/크레아티닌 비는 일정하게 0.025를 나타내었다. 대조군의 자연발증 당뇨병 마우스(db/db 마우스)의 경우 0.38을 나타내었다. 한편 본 발명의 피험화합물인 디피리다몰을 10주간 투여한 자연발증 당뇨병 마우스(db/db 마우스)의 경우 소변중 알부민/크레아티닌 비는 0.20을 나타내었다.For nondiabetic mice (db / + m mice), 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.
이를 통해 본 발명의 피험화합물인 디피리다몰을 10주간 투여한 자연발증 당뇨병 마우스(db/db 마우스)의 소변중 알부민의 함량은 아무런 투약을 하지 않은 대조군 자연발증 당뇨병 마우스(db/db 마우스)에 비해 약 47%가 감소한 것을 확인하였다. The content of albumin in the urine of spontaneously-diabetic diabetic mice (db / db mice) to which dipyridamole, a test compound of the present invention, was administered for 10 weeks was administered to control spontaneously-diabetic diabetic mice that did not receive any administration. It was confirmed that the decrease of about 47%.
그러나 시험군 자연발증 당뇨병 마우스(db/db 마우스)의 소변중 알부민의 함량은 당뇨병을 지니지 않은 비당뇨병성 마우스(db/+m 마우스)에 비해 약 7배 정도가 증가한 함량이다. However, the albumin content in urine of test group spontaneously diabetic mice (db / db mice) is about 7 times higher than that of non-diabetic mice (db / + m mice) without diabetes.
(실시예 3) 디피리다몰의 당뇨병 시험동물 내 알부민 및 크레아티닌 뇨 감소 효과Example 3 Effect of Dipyridamole on Albumin and Creatinine Urine Reduction in Diabetic Test Animals
고토-가키자키(Goto-Kakizaki; GK) 당뇨병 래트에게 12주의 기간에 걸쳐서 이뇨제로 상용화된 라미프릴(1mg/kg/day)과 디피리다몰 화합물(5mg/kg/day)을 임상적으로 투여하였다. 음용수와 사료는 절식 조건 하에서 급이시켰다. 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.
6주 및 12주 후에 GK 래트로부터의 알부민과 크레이티닌 배설을 측정하였다. GK 래트는 2형 당뇨병의 모델이다. 대조그룹은 아무런 약물을 투여하지 않았으며 하나의 시험그룹에는 본 발명의 디피리다몰을 투여하였고 또 다른 시험그룹에는 이뇨제로 상용화된 라미프릴을 투여하였다. After 6 and 12 weeks albumin and creatinine excretion from GK rats were measured. 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.
표 1은 GK 래트에 6주 및 12주 투여 후에 각각의 시험군의 알부민 및 크레아티닌 뇨 배설을 나타낸 표이다. Table 1 shows the albumin and creatinine urinary excretion of each test group after 6 and 12 weeks of administration to GK rats.
표 1
알부민/크레아티닌
mg/mmol
최초 6주 투여 12주 투여
대조그룹
평균 103.9 319.3 1082.9
표준오차(SEM) 19.6 64.4 170.1
개체수(N) 12 12 12
디피리다몰 투여그룹
평균 103.9 20.7 18.4
표준오차(SEM) 19.6 5.4 4.0
개체수(N) 12 12 12
라미프릴 투여그룹
평균 103.9 159.7 183.8
표준오차(SEM) 19.6 29.5 42.0
개체수(N) 12 12 12
Table 1
Albumin / creatinine
mg / mmol
first 6 weeks 12 weeks
Control group
Average 103.9 319.3 1082.9
Standard Error (SEM) 19.6 64.4 170.1
Number of individuals (N) 12 12 12
Dipyridamole administration group
Average 103.9 20.7 18.4
Standard Error (SEM) 19.6 5.4 4.0
Number of individuals (N) 12 12 12
Ramipril Dosing Group
Average 103.9 159.7 183.8
Standard Error (SEM) 19.6 29.5 42.0
Number of individuals (N) 12 12 12
표 1에 나타난 바와 같이 아무런 약물도 투여하지 않은 대조그룹의 GK 래트의 경우 최초시기 뇨 내의 알부민/크레아티닌 함량은 103.9mg/mmol이었으나 6주 후는 이보다 약 3배 증가한 319.3mg/mmol로 증가하였으며 12주 후에는 약 10배 증가한 1082.9mg/mmol로 증가하였다. As shown in Table 1, 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.
그러나 본 발명의 디피리다몰을 5mg/kg/day 용량으로 6주 투여후에는 뇨 내의 알부민/크레아티닌 함량이 20.7mg/mmol으로 최초 뇨 내의 함량보다 1/5 정도로 감소하였다. 또한 12주 투여 후에는 뇨 내의 알부민/크레아티닌 함량이 18.4mg/mmol로 6주 이후 거의 비슷한 함량으로 유지 또는 감소됨을 확인하였다. However, after 6 weeks of administration of dipyridamole of the present invention at a dose of 5 mg / kg / day, the albumin / creatinine content in urine was 20.7 mg / mmol, which was about 1/5 less than that in the original urine. In addition, after 12 weeks of administration, 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.
한편 현재 상용화된 이뇨제인 라미프릴을 1mg/kg/day 용량으로 투여한 시험그룹의 경우 뇨 내의 알부민/크레아티닌 함량이 완만하게 증가하여 12주 후에는 뇨 내의 알부민/크레아티닌 함량은 183.8mg/mmol 정도로 증가하였다. 이를 통해 이뇨제의 투여만으로는 당뇨병 GK 래트의 뇨 내의 알부민 및 크레아티닌 배설을 감소시킬 수는 없으나 아무런 처치를 하지 않은 대조 그룹에 비해서는 상당한 알부민 및 크레아티닌 배설의 감소를 확인한 것이다. On the other hand, in the test group administered the current commercial diuretic ramipril at a dose of 1mg / kg / day, the albumin / creatinine content in the urine increased slowly, and after 12 weeks, the albumin / creatinine content in the urine increased to 183.8mg / mmol. . This confirms that the administration of diuretics alone does not reduce albumin and creatinine excretion in the urine of diabetic GK rats, but significantly reduces albumin and creatinine excretion compared to the control group without any treatment.
(실시예 4) 급성 독성 시험 Example 4 Acute Toxicity Test
7주령의 ICR 수컷 마우스 20예를 4개의 군으로 나누었다. 시험군 1에는 10mg/10ml/kg 용량으로 디피리다몰 피험화합물 용액을 제조하고 ICR 마우스의 꼬리 정맥을 통해 투여 속도 1ml/분으로 주입하였다. 24시간 후 마우스의 생사를 확인하였다. 시험군 2에는 50mg/10ml/kg 용량으로 디피리다몰 피험화합물 용액을 제조하여 동일한 투여 방법 및 속도로 ICR 마우스에 투여하였으며 시험군 3에는 100mg/10ml/kg 용량으로 디피리다몰 피험화합물 용액을 제조하여 동일한 투여 방법 및 속도로 ICR 마우스에 투여하였고 시험군 4에는 200mg/10ml/kg 용량으로 디피리다몰 피험화합물 용액을 제조하여 동일한 투여 방법 및 속도로 ICR 마우스에 투여하였다. Twenty seven-week-old ICR male mice were divided into four groups. 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. In 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, and in test group 3, a dipyridamole test compound solution was prepared at a dose of 100 mg / 10ml / kg. Was administered to the ICR mice at the same administration method and rate, and in test group 4, 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.
표 2는 각각의 시험군 내의 ICR 마우스의 24시간 뒤 사망률을 나타낸 것이다. Table 2 shows mortality after 24 hours of ICR mice in each test group.
표 2
시험군 1 시험군 2 시험군 3 시험군 4
사망률 0/5 0/5 0/5 0/5
TABLE 2
Test group 1 Test group 2 Test group 3 Test group 4
death rate 0/5 0/5 0/5 0/5
따라서 본 발명의 디피리다몰 화합물은 최대 용량인 200mg/10ml/kg 용량으로 ICR 마우스에 투여한 경우에도 아무런 사망예가 발생하지 않았다. 이를 통해 본 발명의 디피리다몰 화합물은 매우 안전한 신장 질환 치료용 의약으로 확인되었다. Accordingly, 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. Through this, the dipyridamole compound of the present invention was identified as a very safe drug for treating kidney disease.

Claims (4)

  1. 디피리다몰을 유효 성분으로 함유하는 신장 질환 치료용 의약 조성물에 있어서, 상기 디피리다몰은 시험관 내에서 메산지움 세포의 증식을 억제하고, 시험 동물 내에서 비뇨 알부민 배설을 감소시킴으로써 신장 질환을 치료함을 특징으로 하는 의약 조성물.In the pharmaceutical composition for treating renal disease containing dipyridamole as an active ingredient, the dipyridamole inhibits proliferation of mesangium cells in vitro and treats kidney disease by reducing urinary albumin excretion in test animals. Pharmaceutical composition characterized in that.
  2. 제 1항에 있어서, 상기 신장 질환은 당뇨병성 신증, IgA신증, 만성 사구체신염, 급성진행성 신염, 네프로제 증후군, 소상 사구체 경화증, 막성 증식성 사구체신염, 루프스 신염 또는 자반병성 신염에서 선택된 하나의 질환임을 특징으로 하는 의약 조성물.The method of claim 1, wherein the kidney disease is one disease selected from diabetic nephropathy, IgA nephropathy, chronic glomerulonephritis, acute progressive nephritis, neprogen syndrome, microglomerular sclerosis, membranous proliferative glomerulonephritis, lupus nephritis or purpura nephritis Pharmaceutical composition characterized by the above-mentioned.
  3. 제 1항 또는 제 2항에 있어서, 상기 의약 조성물은 당뇨병성 신증에 있어서 비뇨 알부민 배설을 감소시킴으로써 신장 질환을 치료함을 특징으로 하는 의약 조성물.The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition treats kidney disease by reducing urinary albumin excretion in diabetic nephropathy.
  4. 제 1항 또는 제 2항에 있어서, 상기 의약 조성물은 IgA신증, 만성 사구체신염, 소상 사구체 경화증 또는 막성 증식성 사구체신염에서 메산지움 세포 증식을 억제시킴으로써 신장 질환을 치료함을 특징으로 하는 의약 조성물.The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition treats kidney disease by inhibiting mesangium cell proliferation in IgA nephropathy, chronic glomerulonephritis, microglomerular sclerosis or membranous proliferative glomerulonephritis.
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