WO2011122899A2 - Pharmaceutical composition for inhibiting platelet aggregation or for thrombolysis - Google Patents

Pharmaceutical composition for inhibiting platelet aggregation or for thrombolysis Download PDF

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WO2011122899A2
WO2011122899A2 PCT/KR2011/002267 KR2011002267W WO2011122899A2 WO 2011122899 A2 WO2011122899 A2 WO 2011122899A2 KR 2011002267 W KR2011002267 W KR 2011002267W WO 2011122899 A2 WO2011122899 A2 WO 2011122899A2
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platelet aggregation
triflusal
ibudilast
pharmaceutical composition
inhibiting platelet
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PCT/KR2011/002267
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French (fr)
Korean (ko)
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WO2011122899A3 (en
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곽수종
정춘식
권순경
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Kwak Soo Jong
Jeong Choon Sik
Kwon Soon Kyoung
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Publication of WO2011122899A2 publication Critical patent/WO2011122899A2/en
Publication of WO2011122899A3 publication Critical patent/WO2011122899A3/en

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a pharmaceutical composition for inhibiting platelet aggregation or thrombolysis and a method for inhibiting platelet aggregation or thrombolysis.
  • Abnormal activation of the platelet aggregation system causes blood vessel thrombus formation, and thrombus generated in closed vessels such as arteries, veins or microvascular vessels prevents the smooth flow of blood in the blood vessels.
  • Platelet adhesion and aggregation are major factors in vascular thrombosis, and thrombi can grow to a size sufficient to block arterial vessels.
  • Blood clots may also form in stagnant or low blood flow velocity regions within the vein. Venous blood clots can easily detach from their location and travel through the circulatory system, resulting in occlusion of other blood vessels, such as the pulmonary artery.
  • arterial thrombosis causes serious disease due to local obstruction, and venous thrombosis mainly causes distant occlusion, or embolism.
  • medications with platelet aggregation inhibition or thrombolytic action include thrombosis, diseases associated with embolism such as myocardial infarction, angina, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, peripheral or deep vein thrombosis, and optional blood vessels.
  • PTCA percutaneous coronary angioplasty
  • Aspirin which is widely used clinically for the purpose of preventing thrombus formation at home and abroad, is known to prevent thrombus formation by inhibiting platelet aggregation when a small amount is continuously taken.
  • aspirin may cause side effects such as gastritis and bleeding depending on the dose and duration of administration.
  • a significant proportion of patients with aspirin resistance who do not adequately inhibit platelet aggregation even with aspirin have been reported.
  • Clopidogrel a platelet aggregation inhibitor that acts to reduce platelet aggregation and thrombus formation by inhibiting platelet aggregates (calcium, serotonin, fibrinogen, etc.) induced by ADP, and is the second most used after aspirin, has practical side effects as well as resistance.
  • Thienopyridine has been shown to increase the incidence of strongly life-threatening thrombocytopenic purpura (Bennett, CL et al . N. Engl. J. Med ., (2000) 342 (1771-1777).
  • ReoPro (7E3) drugs have been shown to have clinical efficacy associated with impressive but bleeding, and increased risk of requiring transfusions occasionally ( N. Engl. J. Med., (1994) 330: 956-961 ). Therefore, there is a need to develop a product having fewer problems and side effects and excellent efficacy.
  • triflusal (2-acetoxy-4-trifluoromethyl benzoic acid) is a compound having the structure of Formula 1 below, thrombus including the complications caused by thrombosis, embolism prevention and treatment, platelet aggregation suppression, heart after surgery It is a platelet aggregation inhibitor used in arrhythmia thrombosis and atherosclerosis dysfunction. Triflusal has a much lower risk of gastrointestinal bleeding than aspirin, which is a platelet aggregation inhibitor similar in chemical structure to aspirin.
  • Triflusal also inhibits platelet cyclooxygenase (COX), similar to aspirin, which not only inhibits thromboxane A2 production, but also cAMP and phosphodiesterase (PDE). It is known to suppress (Murdoch D, et al., Drugs 2006, 66 (5), 671-92: Gonzalex-Correa JA, et al., Drug rev , 2006, 24, 11-24, Cesarone MR et al., Angiology 1999, 50, 455-463).
  • COX platelet cyclooxygenase
  • PDE phosphodiesterase
  • Ibudilast (Ibudilast; (3-isobutyryl-2-isopropylpyrazolo- [1,5a] -pyridine) has a structure of Formula 2 below, as a phosphodiesterase (PDE) inhibitor as a brain circulation disorder due to sequelae after cerebral infarction
  • PDE phosphodiesterase
  • Ibudillast is known to inhibit platelet aggregation by inhibiting cAMP phosphodiesterase, thereby increasing cAMP concentration and increasing NO or PGI 2 production in vascular endothelial cells.
  • the inventors of the present invention through the continuous research and development, when combined administration of ibudilast (Tbuflulast) and Triflusal (excellent platelet aggregation inhibitory effect) compared to the case of administering them alone, respectively It has been found that exhibiting a synergistic effect unpredictable and less bleeding risk, based on this provides a pharmaceutical composition for platelet aggregation or thrombolysis containing ibudilast and triflusal as an active ingredient.
  • the present invention also provides a method for inhibiting platelet aggregation or dissolving thrombi using a composition comprising ibudilast and triflusal as an active ingredient.
  • a pharmaceutical composition comprising ibudilast and triflusal of the present invention as an active ingredient and a method of administering the composition can be used to inhibit aggregation of platelets or to dissolve blood clots.
  • the composition is prepared to have the effects of both drugs to prevent and treat thromboembolic diseases including complications caused by thrombosis.
  • two components having different pharmacological mechanisms exert an effect, thereby widening the effect and therapeutic range, and exhibiting a strong therapeutic effect by synergy. As such, when the two components are used in combination, the therapeutic effect is increased, and thus the side effect can be lowered because the effect can be achieved with a smaller amount of administration when used alone.
  • the composite composition of the present invention has the advantage of low bleeding risk.
  • Diseases or symptoms that can be prevented or treated by the composition or method of the present invention include, for example, myocardial infarction, angina pectoris, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, peripheral vascular or deep vein thrombosis, and any blood vessels.
  • thrombosis Arterial thrombosis, venous thrombosis, ischemic cerebral infarction, arteriosclerosis, hypertension, pulmonary hypertension, cerebral infarction, stroke, chronic arterial obstruction, pulmonary infarction, cerebral embolism, renal embolism, pathological symptoms after thromboembolism and subarachnoid hemorrhage, percutaneous coronary angioplasty (PTCA) And thrombus formation at stent insertion, restenosis after stent placement, catheter thrombotic occlusion or reoccluding, acute coronary syndrome, TIA (transient cerebral ischemic attack or acute cerebrovascular syndrome), heart failure, chest pain due to ischemic etiology , Syndrome X, diabetes mellitus and the like.
  • PTCA percutaneous coronary angioplasty
  • Figure 1 shows the effect of the administration of ibudilast and / or triflusal in ADP induced platelet aggregation.
  • Figure 2 shows the effect of the administration of ibudilast and / or triflusal to arachidonic acid induced platelet aggregation.
  • the present invention is based on the finding that the combined administration of ibudilast and triflusal results in a synergistic increase in platelet aggregation inhibition efficacy compared to their administration alone.
  • the inventors of the present invention conducted a test using a platelet aggregation reaction model induced by ADP or arachidonic acid to confirm the platelet aggregation inhibitory effect by ibudilast and triflusal combined administration.
  • Experimental results on platelet aggregation induced by ADP confirmed that the combination of ibudilast and triflusal, which did not show an inhibitory effect when added alone, showed an inhibitory effect. It is an unpredictable effect from the result of administration.
  • the combination of ibudilast and triflusal at a concentration that inhibits ADP-induced platelet aggregation reaction shows a higher inhibition rate than the addition of the inhibitory effect that occurs when each drug is treated alone. It was confirmed that the inhibitory effect appeared synergistically (Table 1 and FIG. 1).
  • the present invention provides a pharmaceutical composition in which two components having different pharmacological mechanisms exert an effect, exhibit a synergistic platelet aggregation inhibition or thrombolytic effect, and less hemorrhagic side effects.
  • the present invention provides a pharmaceutical composition for inhibiting platelet aggregation or thrombolysis, which comprises ibudilast and triflusal as an active ingredient, and includes a pharmaceutically acceptable carrier.
  • the present invention provides a myocardial infarction, angina pectoris, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, peripheral vascular or deep vein thrombosis, and any blood vessel artery containing ibudilast and triflusal as active ingredients.
  • Thrombosis venous thrombosis, ischemic cerebral infarction, arteriosclerosis, hypertension, pulmonary hypertension, cerebral infarction, stroke, chronic arterial obstruction, pulmonary infarction, cerebral embolism, pathological symptoms after renal embolism, thromboembolism and subarachnoid hemorrhage, percutaneous coronary angioplasty (PTCA) and Thrombus formation during stent insertion, restenosis after stent placement, catheter thrombotic occlusion or redo occlusion, acute coronary syndrome, TIA (transient cerebral ischemic attack or acute cerebrovascular syndrome), heart failure, chest pain due to ischemic etiology, Provided is a composition for preventing or treating X syndrome or diabetes mellitus.
  • PTCA percutaneous coronary angioplasty
  • Thrombus formation during stent insertion restenosis after stent placement
  • catheter thrombotic occlusion or redo occlusion acute coronary syndrome
  • the present invention provides a method for inhibiting platelet aggregation or dissolving thrombi in vitro or in vivo using a composition comprising ibudilast and triflusal as an active ingredient.
  • kits for inhibiting platelet aggregation or thrombolytic dissolution comprising a composition comprising ibudilast and triflusal as an active ingredient.
  • the present invention also provides a myocardial infarction, angina pectoris, thrombophlebitis, arterial embolism, coronal administration, and the like, comprising administering a composition comprising a therapeutically effective amount of ibudilast and triflusal of the present invention as an active ingredient.
  • Cerebral arterial thrombosis peripheral or deep vein thrombosis, arterial thrombosis of any blood vessel, venous thrombosis, ischemic cerebral infarction, arteriosclerosis, hypertension, pulmonary hypertension, cerebral infarction, stroke, chronic arterial obstruction, pulmonary infarction, cerebral embolism, renal embolism, thromboembolism and astrocytes
  • Pathological symptoms after lower bleeding percutaneous coronary angioplasty (PTCA) and stent insertion, thrombus formation, restenosis after stent placement, catheter thrombotic occlusion or redostasis, acute coronary syndrome, TIA (transient cerebral ischemic attack or acute) Cerebrovascular syndrome), heart failure, chest pain caused by ischemic etiology, syndrome X or diabetes mellitus The ball.
  • PTCA percutaneous coronary angioplasty
  • stent insertion thrombus formation
  • restenosis after stent placement catheter thrombotic occlusion
  • the pharmaceutical composition of the present invention may be formulated in combination form by combining each drug alone or by mixing each drug. It is formulated and administered in a unit dosage form suitable for oral administration according to a conventional method in the pharmaceutical field.
  • Formulations for oral administration suitable for this purpose include, but are not limited to, hard and soft capsules, tablets, dragees, film coated tablets, uncoated tablets, enteric tablets, powders, suspensions, syrups, and the like.
  • Preparations for oral administration include, in addition to the two pharmacologically active ingredients, one or more pharmaceutically inert conventional carriers such as excipients such as starch, lactose, carboxymethylcellulose, kaolin, water, gelatin, alcohols, glucose And additional ingredients such as binders such as gum arabic, tragacanta rubber, disintegrants such as starch, dextrin, alginate, and lubricants such as talc, stearic acid, magnesium stearate, liquid paraffin, and the like. It doesn't work.
  • the pharmaceutical composition of the present invention may also add dissolution aids and the like for dissolution.
  • parenteral administration is not limited to the injection method such as subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.
  • parenteral formulations ibudilast and triflusal can be prepared in solution or suspension by mixing in water with stabilizers or buffers.
  • the pharmaceutical composition of the present invention can be used as a cyclodextrin clathrate for preventing restenosis after stent placement.
  • the pharmaceutical composition of the present invention can be used by applying to a biodegradable resin that is a stent material, or embedded in the stent itself.
  • kit for platelet aggregation inhibition or thrombolysis comprising the composition of the present invention may include reagents necessary for the drug to function in addition to ibutylast and triflusal.
  • the daily dosage of the composition according to the present invention may vary depending on various factors, such as the degree of symptoms, the onset, age, health condition, complications, etc. of the subject to be administered, generally based on adult ibudilast 1 -50 mg, preferably 5-30 mg, more preferably 10-30 mg, triflusal may be administered 25-1200 mg, preferably 100-900 mg, more preferably 300-900 mg.
  • the composition of the present invention can be prepared in the above dosage amount.
  • the composition of the present invention can be administered divided into 1 to 3 times a day.
  • the unit preparation prepared from the composition of the present invention may adjust the content of the component in consideration of the frequency of administration.
  • a unit formulation containing a composition according to the present invention may contain, for example, 10 mg of ibudilast and 300 mg of triflusal, which may be 1 to 3 times a day, 1 unit once (e.g., 1 Tablets or 1 capsule, etc.) may be administered.
  • the composition according to the invention comprises ibudilast: triflusal in a ratio of 1: 0.01 to 90, preferably 1: 0.1 to 30, more preferably 1:10 to 30 in molar ratio.
  • One embodiment of the present invention has the above composition ratio, 1-50 mg of ibudilast, preferably 5-30 mg, more preferably 10-30 mg, trilosal is 25-1200 mg, preferably 100-900 mg More preferably 300-900 mg.
  • Animals used in the experiment were 180-250 g of Sprague-Dawley male rats. Plasma was supplied from human fresh frozen plasma from Seoul National University Blood Bank.
  • Ibudillast was purchased from Wuxi Fortune (China), Triflusal from Zhejiang Apeloa (China), and other reagents were used as first-class reagents.
  • the sample to be measured for activity was dissolved in 0.5% EtOH (final concentration).
  • the test drugs were the highest solubilities.
  • Triflusal was tested to a final concentration of 1400 uM and ibudilast to a final concentration of 1000 uM.
  • Rats were inhaled anesthesia with diethyl ether, and all the platelets were used in a polystyrene (polystylene) or polyethylene container.
  • As an anticoagulant 2.2% trisodium citrate 0.1 volume was placed in a plastic syringe, and 0.9 volume of blood was collected from the heart. After carefully mixing the blood, centrifuged for 10 minutes at 200 ⁇ g at room temperature to obtain a supernatant PRP (platelet rich plasma). PRP was taken and the remaining layer was centrifuged at 1500 ⁇ g for 20 minutes to obtain PPP (Platelet poor plasma), and PRP was diluted with PPP to adjust platelet count to 350-450 ⁇ 10 6 / mL and used in the experiment.
  • PRP platelet rich plasma
  • the platelet aggregation inhibitory activity was measured with reference to the methods described in Transfus Apher Sci 2003, 28, 307-17 and Thromb Res 2000, 100, 511-8.
  • Platelet aggregometer (490X, Chrono-Log Corp., Havertown, PA, USA) was used and McNicol (Platelets-A Practical approach: Oirl Press at Oxford University Press, pp1-26, 1996) or Yun-Choi Reference was made to the method of HS et al. (Thromb Res, vol. 100, p511-518, 2000). Pul 500 Pul with a constant platelet count was incubated for 2 minutes in a 37 ° C. aggregometer and 5 ul of sample solution (or vehicle: 0.5% EtOH) was added while stirring at 1200 rpm. After 1 minute and 30 seconds, platelet aggregation was induced by adding 5 uL of ADP as a coagulant-inducing substance. The final concentration of ADP, a coagulant-inducing substance, was 2-3 uM. Platelet aggregation inhibition rate (%) was calculated
  • the concentrations of ibudilast and triflusal were 10 to 80%, respectively, against the coagulation-inducing substance ADP, and the inhibition rate when the two drugs were used together in the concentration range was%. Obtained. Aspirin was used as a positive control to predict the results of actual use by comparing the strength of complex samples. The test was repeated five times.
  • PRP and PPP were prepared in the same manner as described in Example 1 to measure platelet aggregation inhibition.
  • AA Arachidonic acid
  • the concentrations of ibudilast and triflusal were 10-80% of aggregation inhibitory concentration to AA, which is a coagulant-inducing substance, and the inhibition rate when two substances were added together in the concentration range was%. Obtained. Aspirin was used as a positive control to predict the results of actual use by comparing the strength of the composite samples. The test was repeated five times.
  • ibudilast 600 uM and Triflusal when administered to 300 uM alone or showed respectively 30 ⁇ inhibition rate of 8.0% and 23 ⁇ 9.0%, when co-administered with the two drugs, 86 + inhibition of 8.0% action Showed.
  • APPT, PT and TT assays were performed to investigate the anticoagulant activity of ibudilast and triflusal.
  • J. Ethnopharmacol. APTT was measured with reference to the method described in (2003, vol. 89, p101-5). After 3 ul of drug sample (or vehicle) was put in 100 ul of plasma and incubated for 2 minutes at 37 o C, 100 ul of aPTT reagent (STA PTT A 5, Stago) was added and then incubated for 3 minutes at 37 o C. After adding 100 ⁇ l of 0.025 M CaCl 2 , the time to plasma coagulation was measured by a fibrometer. All data were expressed in seconds.
  • J. Ethnopharmacol. PT was measured with reference to the method described in (2003, vol. 89, p101-5). 3 ul sample drug (or vehicle) in the plasma was placed in a 100 ul incubated for 3 minutes at 37 o C, PT reagents placed in advance by heating to 37 o C (Neoplastine® CI Plus2, Stago) was added to 200 ul and plasma clot The time to completion was measured with a fibrometer and all data were expressed in seconds.
  • Thromb. Res. TT was measured with reference to the methods described in 2000, 100, 511-8. Is added to the sample 3 ul drug (or vehicle) in the plasma was placed in a 100 ul incubated for 3 minutes at 37 o C, 37 o pre-TT reagent (STA®Thrombin2, Stago) was placed and heated to 200 C and ul plasma clot The time until was measured with a fibrometer and all data were expressed in seconds.
  • STA®Thrombin2, Stago 37 o pre-TT reagent
  • Examples 1 and 2 two drugs, ibudilast and triflusal, were used in combination to show the synergistic effect of platelet aggregation. prolonging the aPTT, PTVIII or TT time was observed. In addition, the simultaneous treatment of two drugs was used to observe the effect of prolonging the blood coagulation time at the concentration showing the synergistic effect of platelet aggregation inhibition. Heparin was used as a positive control and the results were predicted in actual use by comparing the strength of complex samples.
  • composition comprising ibudilast and triflusal had blood anticoagulant action was examined by prolonging the coagulation time for the endogenous, exogenous and common coagulation systems.
  • aPTT, PT, and TT time were extended by 80.2%, 106.6%, and 171.7%, respectively, at concentrations of 0.05 ⁇ 2 U / ml, resulting in a strong anticoagulant effect. This indicates that the risk of bleeding is quite high and therefore requires great care in use.
  • Treatment with ibudilast or triflusal alone did not affect PT and aPTT time or showed a weak extension of less than 10%, while extending the TT time by 12 to 18%, resulting in an extended blood clotting time by the common system. It showed a coagulation effect, but not so much compared to the control.
  • PT and aPTT time showed an extension of 10% or less when ibudilast and triflusal were co-administered, while the TT time was 19-23% longer than that of monotherapy. From this, the combination of ibudilast and triflusal is expected to reduce the risk of bleeding while prolonging the TT time, which is a common system in the coagulation mechanism, to compensate for the platelet aggregation inhibitory effect of these substances (Table 3).
  • Ibudillast, triflusal, lactose, microcrystalline cellulose and low-substituted hydroxypropyl cellulose were mixed, the povidone was dissolved in water, added, and granulated in a conventional manner. After drying, it was established, mixed with magnesium stearate and purified.
  • This preparation is taken 3 times a day, 1 tablet once.
  • Ibudillast, triflusal, lactose, microcrystalline cellulose and low-substituted hydroxypropyl cellulose were mixed, the povidone was dissolved in water, added, and granulated in a conventional manner. After drying, it was established, mixed with magnesium stearate and purified.
  • This tablet was film-coated in accordance with a conventional method with a film coating liquid in which Opadry 85G68914 white and titanium oxide were dispersed in an organic solvent.
  • This preparation is taken 3 times a day, 1 tablet once.
  • Ibudillast, triflusal, lactose, microcrystalline cellulose and low-substituted hydroxypropyl cellulose were mixed, the povidone was dissolved in water, added, and granulated in a conventional manner. After drying, it was established, mixed with magnesium stearate and purified. This tablet was dragged with gelatin, white sugar, precipitated calcium carbonate and hydroxypropylmethylcellulose 2906 in a conventional manner.
  • This preparation is taken 3 times a day, 1 tablet once.
  • Ibudilast, triflusal, corn starch, lactose and magnesium stearate were mixed and then filled into capsules in the usual manner.
  • This preparation is taken 3 times a day, 1 tablet once.
  • Ibudillast, triflusal, lactose, microcrystalline cellulose and low-substituted hydroxypropyl cellulose were mixed, the povidone was dissolved in water, added, and granulated in a conventional manner. After drying, it was established, mixed with magnesium stearate and purified.
  • This tablet was prepared as an enteric tablet by a conventional method using methacrylic acid, an ethyl acrylate copolymer, propylene glycol, titanium oxide, and talc.
  • This preparation is taken 3 times a day, 1 tablet once.
  • a pharmaceutical composition comprising ibudilast and triflusal of the present invention as an active ingredient, a medicament comprising the composition, a kit and a method of administering the composition may be used to inhibit platelet aggregation or to dissolve blood clots.
  • Diseases or symptoms that can be prevented or treated by the composition or method of the present invention include, for example, myocardial infarction, angina pectoris, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, peripheral vascular or deep vein thrombosis, and any blood vessels.
  • thrombosis Arterial thrombosis, venous thrombosis, ischemic cerebral infarction, arteriosclerosis, hypertension, pulmonary hypertension, cerebral infarction, stroke, chronic arterial obstruction, pulmonary infarction, cerebral embolism, renal embolism, pathological symptoms after thromboembolism and subarachnoid hemorrhage, percutaneous coronary angioplasty (PTCA) And thrombus formation at stent insertion, restenosis after stent placement, catheter thrombotic occlusion or redo occlusion, acute coronary syndrome, TIA (transient cerebral ischemic attack or acute cerebrovascular syndrome), heart failure, chest pain due to ischemic etiology , Syndrome X, diabetes mellitus and the like.
  • PTCA percutaneous coronary angioplasty

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Abstract

The present invention relates to a pharmaceutical composition for inhibiting platelet aggregation or for thrombolysis. The present invention relates to a composition which has superior effectiveness and fewer side effects than conventional well-known pharmaceutical compositions for inhibiting platelet aggregation or for thrombolysis. The pharmaceutical composition for inhibiting platelet aggregation or for thrombolysis, according to the present invention, comprises ibudilast and triflusal as active ingredients due to the fact that ibudilast and triflusal have superior effectiveness in inhibiting platelet aggregation and thus exhibit synergistic effects and reduce the risk of bleeding when co-administered, as compared to respectively administering ibudilast and triflusal alone. The pharmaceutical composition of the present invention can be used in the prevention or treatment of various diseases and symptoms, for example, ischemic heart disease, ischemic cerebral infarction, arteriosclerosis, and thrombosis caused by the insertion of a stent, etc.

Description

혈소판 응집억제용 또는 혈전용해용 의약 조성물Pharmaceutical composition for inhibiting platelet aggregation or thrombolysis
본 발명은 혈소판 응집 억제용 또는 혈전용해용 의약 조성물 및 혈소판 응집억제 또는 혈전용해 방법에 관한 것이다. The present invention relates to a pharmaceutical composition for inhibiting platelet aggregation or thrombolysis and a method for inhibiting platelet aggregation or thrombolysis.
혈소판응집 시스템의 비정상적인 활성화는 혈관 내 혈전생성의 원인이 되며, 동맥, 정맥 또는 미세혈관 등 폐쇄혈관 내에 생성되는 혈전은 혈관 내 혈액의 원활한 흐름을 방해한다. 혈소판 부착 및 응집은 혈관 내 혈전증의 주요한 요인이며, 혈전은 동맥혈관을 막을 만큼 충분한 크기로 성장할 수 있다. 혈전은 또한 정맥 내의 정체 또는 저혈류 속도 지역에서 형성될 수 있다. 정맥혈전은 그 자체의 위치에서 쉽게 분리되어 순환계를 통해 이동할 수 있고 폐동맥 같은 다른 혈관의 폐색을 초래할 수 있다. 따라서, 동맥혈전은 국소폐색에 의한 심각한 질환을 야기하며, 정맥혈전은 주로 원거리 폐색, 또는 색전을 야기한다. Abnormal activation of the platelet aggregation system causes blood vessel thrombus formation, and thrombus generated in closed vessels such as arteries, veins or microvascular vessels prevents the smooth flow of blood in the blood vessels. Platelet adhesion and aggregation are major factors in vascular thrombosis, and thrombi can grow to a size sufficient to block arterial vessels. Blood clots may also form in stagnant or low blood flow velocity regions within the vein. Venous blood clots can easily detach from their location and travel through the circulatory system, resulting in occlusion of other blood vessels, such as the pulmonary artery. Thus, arterial thrombosis causes serious disease due to local obstruction, and venous thrombosis mainly causes distant occlusion, or embolism.
따라서, 혈소판 응집억제 또는 혈전용해 작용을 하는 의약은 혈전, 색전과 관련이 있는 질병들 즉, 심근경색, 협심증, 혈전성 정맥염, 동맥색전증, 관상 및 뇌동맥혈전증, 말초혈관 또는 심부정맥혈전증, 임의 혈관의 동맥 혈전증, 정맥혈전증,허혈성 뇌경색, 동맥경화, 고혈압, 폐고혈압, 뇌경색, 뇌졸증, 만성동맥폐색증, 폐경색, 뇌색전증, 신장색전증, 혈전색전증 및 지주막하 출혈 후의 병적 증상, 경피적 관상동맥 성형술(PTCA) 및 스텐트(stent) 삽입 시의 혈전 생성, 스텐트 설치 후의 재협착, 카테터 혈전성 폐색 또는 재폐색, 급성 관상동맥증후군, TIA(일과성 뇌허혈 발작 또는 급성 뇌혈관 증후군), 심부전증, 허혈성 병인에 의한 가슴통증, X 증후군, 진성당뇨병의 예방 및 치료에 사용될 수 있다.Thus, medications with platelet aggregation inhibition or thrombolytic action include thrombosis, diseases associated with embolism such as myocardial infarction, angina, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, peripheral or deep vein thrombosis, and optional blood vessels. Arterial thrombosis, venous thrombosis, ischemic cerebral infarction, arteriosclerosis, hypertension, pulmonary hypertension, cerebral infarction, stroke, chronic arterial obstruction, pulmonary infarction, pathologic embolism, renal embolism, thromboembolism and subarachnoid hemorrhage, percutaneous coronary angioplasty (PTCA ) And thrombus formation at stent insertion, restenosis after stent placement, catheter thrombotic occlusion or reoccluding, acute coronary syndrome, TIA (transient cerebral ischemic attack or acute cerebrovascular syndrome), heart failure, chest due to ischemic etiology It can be used for the prevention and treatment of pain, syndrome X, diabetes mellitus.
다양한 혈소판응집억제제 또는 혈전용해제 개발을 위한 연구가 진행되었다. 아스피린 및 디피리다몰과 같은 일부 제제가 예방적 항혈전제로 사용되었다. 현재 국내외에서 혈전생성 예방의 목적으로 임상적으로 널리 사용되고 있는 아스피린은 소량을 지속적으로 복용할 경우 혈소판의 응집을 억제하여 혈전생성을 예방하는 것으로 알려져 있다. 그러나, 아스피린은 복용량, 복용기간에 따라 위염의 발생, 출혈 등의 부작용의 위험이 있다. 또한, 아스피린을 복용하여도 혈소판응집을 적절하게 억제하지 못하는 아스피린 저항성 (aspirin resistance) 증상을 보이는 환자의 비율이 상당히 보고되었다. Research has been conducted to develop various platelet aggregation inhibitors or thrombolytic agents. Some agents, such as aspirin and dipyridamole, have been used as prophylactic antithrombotic agents. Aspirin, which is widely used clinically for the purpose of preventing thrombus formation at home and abroad, is known to prevent thrombus formation by inhibiting platelet aggregation when a small amount is continuously taken. However, aspirin may cause side effects such as gastritis and bleeding depending on the dose and duration of administration. In addition, a significant proportion of patients with aspirin resistance who do not adequately inhibit platelet aggregation even with aspirin have been reported.
아스피린 다음으로 많이 사용되고 있고 ADP에 의해 유도되는 혈소판 응집물질(칼슘, 세로토닌, 피브리노겐 등)을 억제해 혈소판 응집 및 혈전형성을 감소시키는 작용을 하는 혈소판 응집억제제인 클로피도그렐은 실제적인 부작용을 가질 뿐 아니라 저항성의 문제점이 있는 것으로 나타났고, 티에노피리딘의 경우 강력하게 생명을 위협하는 혈전성 혈소판감소성 자반증의 발병률을 증가시키는 것으로 나타났다(Bennett, C.L. 등 N. Engl. J. Med., (2000) 342:1771-1777). ReoPro(7E3) 약물은 임상효능은 인상적이나 과도한 출혈, 때때로 수혈을 필요로 할 만큼의 증가된 위험과 관련이 있다는 것이 밝혀졌다(N. Engl. J. Med., (1994) 330:956-961). 따라서, 기존의 제품이 갖는 문제점 및 부작용이 적고 효능이 우수한 제품의 개발이 필요하다. Clopidogrel, a platelet aggregation inhibitor that acts to reduce platelet aggregation and thrombus formation by inhibiting platelet aggregates (calcium, serotonin, fibrinogen, etc.) induced by ADP, and is the second most used after aspirin, has practical side effects as well as resistance. Thienopyridine has been shown to increase the incidence of strongly life-threatening thrombocytopenic purpura (Bennett, CL et al . N. Engl. J. Med ., (2000) 342 (1771-1777). ReoPro (7E3) drugs have been shown to have clinical efficacy associated with impressive but bleeding, and increased risk of requiring transfusions occasionally ( N. Engl. J. Med., (1994) 330: 956-961 ). Therefore, there is a need to develop a product having fewer problems and side effects and excellent efficacy.
한편, 트리플루살(Triflusal; 2-acetoxy-4-trifluoromethyl benzoic acid)은 하기 화학식1의 구조를 갖는 화합물으로서, 혈전증에 의한 합병증을 포함한 혈전, 색전 질환 예방 및 치료제, 혈소판 응집억제, 외과수술 후 심부정맥 혈전증 및 동맥 경화성 기능장애에 사용되는 혈소판응집억제 약물이다. 트리플루살은 화학구조가 아스피린과 매우 유사한 혈소판응집 억제작용물질이나 아스피린보다 위장출혈 위험성이 월등히 낮다. 또한 트리플루살은 아스피린과 유사하게 혈소판의 시클로옥시게나제 (cyclooxygenase(COX))를 억제하여 트롬복산A2(Thromboxane A2) 생성을 억제할 뿐 아니라 cAMP, 포스포디에스터라제 (phosphodiesterase(PDE))를 억제한다고 알려져 있다(Murdoch D, 등, Drugs 2006, 66(5), 671-92: Gonzalex-Correa JA,등, Drug Rev, 2006, 24, 11-24, Cesarone MR 등, Angiology 1999, 50, 455-463).On the other hand, triflusal (2-acetoxy-4-trifluoromethyl benzoic acid) is a compound having the structure of Formula 1 below, thrombus including the complications caused by thrombosis, embolism prevention and treatment, platelet aggregation suppression, heart after surgery It is a platelet aggregation inhibitor used in arrhythmia thrombosis and atherosclerosis dysfunction. Triflusal has a much lower risk of gastrointestinal bleeding than aspirin, which is a platelet aggregation inhibitor similar in chemical structure to aspirin. Triflusal also inhibits platelet cyclooxygenase (COX), similar to aspirin, which not only inhibits thromboxane A2 production, but also cAMP and phosphodiesterase (PDE). It is known to suppress (Murdoch D, et al.,Drugs 2006, 66 (5), 671-92: Gonzalex-Correa JA, et al.,Drug rev, 2006, 24, 11-24, Cesarone MR et al.,Angiology 1999, 50, 455-463).
화학식 1
Figure PCTKR2011002267-appb-C000001
 Formula 1
Figure PCTKR2011002267-appb-C000001
이부딜라스트 (Ibudilast;(3-isobutyryl-2-isopropylpyrazolo- [1,5a]-pyridine)는 하기 화학식2의 구조를 가지며, 포스포디에스터라제(PDE) 저해제로서 뇌경색 후유증에 따른 뇌순환장애로 인한 어지럼증의 개선에 사용되는 약물이다. 이부딜라스트는 cAMP 포스포디에스터라제를 억제하여 cAMP 농도를 증가시킬 뿐 아니라 혈관내피 세포에서 NO나 PGI2의 생성을 증가시켜 혈소판응집을 억제하는 것으로 알려져 있다 (Kishi Y 등, Cardiovasc Drug Rev 2001, 19, 215-225).Ibudilast (Ibudilast; (3-isobutyryl-2-isopropylpyrazolo- [1,5a] -pyridine) has a structure of Formula 2 below, as a phosphodiesterase (PDE) inhibitor as a brain circulation disorder due to sequelae after cerebral infarction Ibudillast is known to inhibit platelet aggregation by inhibiting cAMP phosphodiesterase, thereby increasing cAMP concentration and increasing NO or PGI 2 production in vascular endothelial cells. (Kishi Y et al., Cardiovasc Drug Rev 2001, 19, 215-225).
화학식 2
Figure PCTKR2011002267-appb-C000002
 Formula 2
Figure PCTKR2011002267-appb-C000002
종래 혈소판 응집 억제 또는 혈전용해를 위하여 사용되어 온 제제들은 약리기전에 따라 약리효과에 있어서 각기 장단점이 있으며 부작용의 발생문제가 심각하므로 새로운 개념의 약물개발이 절실하다. 따라서 본 발명에서는 약리기전이 다른 성분을 복합할 경우 약리기전의 범위가 넓어져 각각의 성분에서의 효능상 부족한 점을 보완할 수 있으며, 약효에 있어 상승효과를 발휘하여 치료효과를 극대화 할 가능성이 있다는 것에 착안하여, 기존의 제품이 갖고 있는 부작용을 최소화하면서 상승된 효과를 갖는 복합제제를 개발하는 것을 해결하고자 하는 과제이자 목적으로 한다. 따라서, 종래 알려진 것 보다 효능이 우수하고 부작용이 적은 혈소판 응집 억제용 복합 의약 조성물을 제공하는 것이 본 발명에서 해결하고자 하는 과제이다. Conventional agents that have been used for platelet aggregation inhibition or thrombolysis have advantages and disadvantages in terms of pharmacological effects and serious side effects. Therefore, in the present invention, when the pharmacological mechanism is combined with other components, the range of the pharmacological mechanism is widened to compensate for the lack of efficacy in each component, and the synergistic effect on the pharmacological effect may maximize the therapeutic effect. In view of the above, it is a problem and object to solve the development of a composite formulation having an elevated effect while minimizing the side effects of the existing product. Therefore, it is a problem to be solved by the present invention to provide a composite pharmaceutical composition for inhibiting platelet aggregation, which has better efficacy and less side effects than conventionally known.
상기 과제를 해결하기 위하여 본 발명의 발명자들은 부단한 연구개발을 통하여, 이부딜라스트(Ibudilast) 및 트리플루살(Triflusal)을 병용 투여할 경우 이들을 각각 단독으로 투여하는 경우와 비교하여 혈소판 응집저해 효능이 뛰어나 예측할 수 없었던 상승적인 효과를 발휘하며 출혈위험성이 적다는 것을 밝혀내고, 이를 기초로 이부딜라스트 및 트리플루살을 유효성분으로 포함하는 혈소판응집억제용 또는 혈전용해용 의약 조성물을 제공한다. In order to solve the above problems, the inventors of the present invention through the continuous research and development, when combined administration of ibudilast (Tbuflulast) and Triflusal (excellent platelet aggregation inhibitory effect) compared to the case of administering them alone, respectively It has been found that exhibiting a synergistic effect unpredictable and less bleeding risk, based on this provides a pharmaceutical composition for platelet aggregation or thrombolysis containing ibudilast and triflusal as an active ingredient.
또한, 본 발명은 이부딜라스트 및 트리플루살을 유효성분으로 포함하는 조성물을 사용하여 혈소판 응집을 억제 또는 혈전을 용해하는 방법을 제공한다.The present invention also provides a method for inhibiting platelet aggregation or dissolving thrombi using a composition comprising ibudilast and triflusal as an active ingredient.
본 발명의 이부딜라스트 및 트리플루살을 유효성분으로 포함하는 의약 조성물 및 상기 조성물을 투여하는 방법은 혈소판의 응집을 억제 또는 혈전을 용해하기 위하여 사용될 수 있다. A pharmaceutical composition comprising ibudilast and triflusal of the present invention as an active ingredient and a method of administering the composition can be used to inhibit aggregation of platelets or to dissolve blood clots.
국소혈류증가작용·항혈전작용·허혈성 뇌기능장해 개선작용 및 혈소판응집괴 해리작용이 강한 이부딜라스트와 혈소판의 시클로옥시게나제의 선택적인 억제를 통하여 트롬복산A2의 생성을 저해함으로써 혈소판 응집작용을 나타내고 항혈전작용 및 혈관확장 작용을 나타내는 트리플루살을 복합하여, 두 가지 약물의 작용효과를 모두 갖도록 제조된 조성물로 혈전증에 의한 합병증을 포함하는 혈전 색전질환을 예방하고 치료한다. 본 발명의 조성물은 약리기전이 다른 2 가지 성분이 효과를 발휘하여 작용효과 및 치료적 범위가 넓어지고, 상승작용으로 강력한 치료효과를 나타낸다. 이와 같이 두 가지 성분을 병용하면 치료 효과가 상승되므로 단독으로 사용할 때 보다 적은 양의 투여로 효과를 달성할 수 있으므로 부작용을 낮출 수 있다는 이점도 있다. 본 발명의 복합 조성물은 출혈위험성이 낮다는 장점이 있다.Platelet aggregation by inhibiting the production of thromboxane A2 through selective inhibition of ibudilast and platelet cyclooxygenase, which is effective in improving local blood flow, antithrombotic action, ischemic brain dysfunction, and platelet aggregation dissociation. In combination with triflusal, which exhibits antithrombotic and vasodilating effects, the composition is prepared to have the effects of both drugs to prevent and treat thromboembolic diseases including complications caused by thrombosis. In the composition of the present invention, two components having different pharmacological mechanisms exert an effect, thereby widening the effect and therapeutic range, and exhibiting a strong therapeutic effect by synergy. As such, when the two components are used in combination, the therapeutic effect is increased, and thus the side effect can be lowered because the effect can be achieved with a smaller amount of administration when used alone. The composite composition of the present invention has the advantage of low bleeding risk.
본 발명의 상기 조성물 또는 방법에 의하여 예방 또는 치료가 가능한 질병 또는 증상으로는 예를 들어, 심근경색, 협심증, 혈전성 정맥염, 동맥색전증, 관상 및 뇌동맥혈전증, 말초혈관 또는 심부정맥혈전증, 임의 혈관의 동맥 혈전증, 정맥혈전증,허혈성 뇌경색, 동맥경화, 고혈압, 폐고혈압, 뇌경색, 뇌졸증, 만성동맥폐색증, 폐경색, 뇌색전증, 신장색전증, 혈전색전증 및 지주막하 출혈 후의 병적 증상, 경피적 관상동맥 성형술(PTCA) 및 스텐트(stent) 삽입 시의 혈전 생성, 스텐트 설치 후의 재협착, 카테터 혈전성 폐색 또는 재폐색, 급성 관상동맥증후군, TIA(일과성 뇌허혈 발작 또는 급성 뇌혈관 증후군), 심부전증, 허혈성 병인에 의한 가슴통증, X 증후군, 진성당뇨병 등을 들 수 있다.Diseases or symptoms that can be prevented or treated by the composition or method of the present invention include, for example, myocardial infarction, angina pectoris, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, peripheral vascular or deep vein thrombosis, and any blood vessels. Arterial thrombosis, venous thrombosis, ischemic cerebral infarction, arteriosclerosis, hypertension, pulmonary hypertension, cerebral infarction, stroke, chronic arterial obstruction, pulmonary infarction, cerebral embolism, renal embolism, pathological symptoms after thromboembolism and subarachnoid hemorrhage, percutaneous coronary angioplasty (PTCA) And thrombus formation at stent insertion, restenosis after stent placement, catheter thrombotic occlusion or reoccluding, acute coronary syndrome, TIA (transient cerebral ischemic attack or acute cerebrovascular syndrome), heart failure, chest pain due to ischemic etiology , Syndrome X, diabetes mellitus and the like.
도1은 이부딜라스트 및/또는 트리플루살의 투여가 ADP 유도 혈소판 응집반응에 미치는 영향을 나타낸 것이다.Figure 1 shows the effect of the administration of ibudilast and / or triflusal in ADP induced platelet aggregation.
도2는 이부딜라스트 및/또는 트리플루살의 투여가 아라키돈산 유도 혈소판 응집반응에 미치는 영향을 나타낸 것이다. Figure 2 shows the effect of the administration of ibudilast and / or triflusal to arachidonic acid induced platelet aggregation.
본 발명은 이부딜라스트 및 트리플루살의 병용투여가 이들의 단독 투여에 비하여 혈소판 응집 억제 효능이 상승적으로 증가한다는 것을 밝힌 것을 기초로 한다. The present invention is based on the finding that the combined administration of ibudilast and triflusal results in a synergistic increase in platelet aggregation inhibition efficacy compared to their administration alone.
본 발명의 발명자들은 이부딜라스트 및 트리플루살 복합투여에 의한 혈소판 응집억제효과를 확인하기 위하여 ADP 또는 아라키돈산에 의하여 유도되는 혈소판 응집반응 모델을 사용하여 시험을 실시하였다. ADP에 의해 유도된 혈소판 응집에 대한 실험 결과, 단독으로 첨가하였을 때 억제효과를 보이지 않았던 농도의 이부딜라스트 및 트리플루살을 병용처리하면 억제효과를 보인다는 것을 확인하였으며, 이는 상기 두 약물을 각각 단독으로 투여한 결과로부터 전혀 예측할 수 없는 효과이다. 또한, ADP 유도 혈소판 응집반응을 억제하는 농도의 이부딜라스트 및 트리플루살을 병용하여 처리하면, 각각의 약물을 단독으로 처리하였을 때 나타나는 억제효과를 더한 값보다 더 높은 억제율을 보여 두 약물을 병용 사용하면 억제효과가 상승적으로 나타난다는 것이 확인되었다(표 1 및 도 1). The inventors of the present invention conducted a test using a platelet aggregation reaction model induced by ADP or arachidonic acid to confirm the platelet aggregation inhibitory effect by ibudilast and triflusal combined administration. Experimental results on platelet aggregation induced by ADP confirmed that the combination of ibudilast and triflusal, which did not show an inhibitory effect when added alone, showed an inhibitory effect. It is an unpredictable effect from the result of administration. In addition, the combination of ibudilast and triflusal at a concentration that inhibits ADP-induced platelet aggregation reaction shows a higher inhibition rate than the addition of the inhibitory effect that occurs when each drug is treated alone. It was confirmed that the inhibitory effect appeared synergistically (Table 1 and FIG. 1).
아라키돈산으로 유도한 혈소판 응집 반응에 대해서도 두 약물을 병용 사용하면 억제효과가 상승적으로 나타난다는 것이 확인되었다(표2 및 도2).It was confirmed that the combination of the two drugs also showed a synergistic inhibitory effect on the arachidonic acid-induced platelet aggregation reaction (Table 2 and Figure 2).
한편, 이부딜라스트와 트리플루살의 두 종의 약물을 병용처리하여 혈소판 응집억제 작용의 상승효과를 보인 복합농도로 처리할 때 혈액응고시간의 연장효과가 있는지 관찰한 결과에 의하면, 혈액응고에 대한 aPTT (Activated Partial Thromboplastin Time) 및 PT(Prothrombin Time)의 경우 대조군과 비교하여10 % 이하로 연장되며 이는 각각의 약물을 단독으로 처리할 때와 비교하여 별 차이가 없는 것이었다. TT(Thrombin Time)의 경우, 두 종의 약물을 병용처리하면 대조군과 비교하여19 ~ 23 % 연장되어, 각각을 단독 처리할 때의 연장율(이부딜라스트 12.3~17%, 트리플루살 12.8~16.6%)) 보다 약간 증가되었으나 그 정도가 그리 크지 않았다. 이로부터, 이부딜라스트 및 트리플루살 병용처리는 혈액응고 기전 중 공통계인 TT시간 만을 연장시킨다는 것을 알 수 있었으며, aPTT, PT 및 TT를 모두 약80~170% 연장시키는 헤파린과 달리 출혈 위험성이 적을 것으로 추정된다(표3).　 On the other hand, according to the results of observing the effect of prolonging blood coagulation time when combined with two drugs, ibudilast and triflusal, in combination concentrations showing synergistic effect of platelet aggregation inhibition. Active Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) were extended to 10% or less compared to the control group, which showed no difference compared to treatment with each drug alone. In the case of TT (Thrombin Time), when two drugs are used in combination, they are extended by 19 to 23% compared to the control group, and the extension rate when each is treated alone (Ibudilast 12.3 to 17%, Triplerusal 12.8 to 16.6) %)) Is slightly increased, but not so much. From this, it can be seen that the combination of ibudilast and triflusal extends only TT time, which is a common system in the coagulation mechanism, and unlike heparin, which extends aPTT, PT, and TT by about 80% to 170%, the risk of bleeding is low. (Table 3).
이와 같은 실험결과로부터 본 발명은 일 실시예로서 약리기전이 다른 2 가지 성분이 효과를 발휘하여 상승적인 혈소판 응집 억제 또는 혈전용해 효과를 나타내며, 출혈성 부작용이 적은 의약 조성물을 제공한다. From the experimental results as described above, the present invention provides a pharmaceutical composition in which two components having different pharmacological mechanisms exert an effect, exhibit a synergistic platelet aggregation inhibition or thrombolytic effect, and less hemorrhagic side effects.
본 발명은 일 실시예로서 이부딜라스트 및 트리플루살을 유효성분으로 포함하고, 약제학적으로 허용되는 담체를 포함하는 혈소판응집억제용 또는 혈전용해용 의약 조성물을 제공한다. The present invention provides a pharmaceutical composition for inhibiting platelet aggregation or thrombolysis, which comprises ibudilast and triflusal as an active ingredient, and includes a pharmaceutically acceptable carrier.
또한, 본 발명은 다른 일 실시예로 이부딜라스트 및 트리플루살을 유효성분으로 포함하는 심근경색, 협심증, 혈전성 정맥염, 동맥색전증, 관상 및 뇌동맥혈전증, 말초혈관 또는 심부정맥혈전증, 임의 혈관의 동맥 혈전증, 정맥혈전증,허혈성 뇌경색, 동맥경화, 고혈압, 폐고혈압, 뇌경색, 뇌졸증, 만성동맥폐색증, 폐경색, 뇌색전증, 신장색전증, 혈전색전증 및 지주막하 출혈 후의 병적 증상, 경피적 관상동맥 성형술(PTCA) 및 스텐트(stent) 삽입 시의 혈전 생성, 스텐트 설치 후의 재협착, 카테터 혈전성 폐색 또는 재폐색, 급성 관상동맥증후군, TIA(일과성 뇌허혈 발작 또는 급성 뇌혈관 증후군), 심부전증, 허혈성 병인에 의한 가슴통증, X 증후군 또는 진성당뇨병의 예방 또는 치료용 조성물을 제공한다.In another embodiment, the present invention provides a myocardial infarction, angina pectoris, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, peripheral vascular or deep vein thrombosis, and any blood vessel artery containing ibudilast and triflusal as active ingredients. Thrombosis, venous thrombosis, ischemic cerebral infarction, arteriosclerosis, hypertension, pulmonary hypertension, cerebral infarction, stroke, chronic arterial obstruction, pulmonary infarction, cerebral embolism, pathological symptoms after renal embolism, thromboembolism and subarachnoid hemorrhage, percutaneous coronary angioplasty (PTCA) and Thrombus formation during stent insertion, restenosis after stent placement, catheter thrombotic occlusion or redo occlusion, acute coronary syndrome, TIA (transient cerebral ischemic attack or acute cerebrovascular syndrome), heart failure, chest pain due to ischemic etiology, Provided is a composition for preventing or treating X syndrome or diabetes mellitus.
또한, 본 발명은 다른 일 실시예로 이부딜라스트 및 트리플루살을 유효성분으로 포함하는 조성물을 사용하여 인비트로 또는 인 비보에서 혈소판 응집을 억제 또는 혈전을 용해하는 방법을 제공한다. In another aspect, the present invention provides a method for inhibiting platelet aggregation or dissolving thrombi in vitro or in vivo using a composition comprising ibudilast and triflusal as an active ingredient.
본 발명의 다른 일 실시예로서 이부딜라스트 및 트리플루살을 유효성분으로 포함하는 조성물을 포함하는 혈소판 응집의 억제 또는 혈전 용해를 위한 키트가 포함된다. As another embodiment of the present invention includes a kit for inhibiting platelet aggregation or thrombolytic dissolution comprising a composition comprising ibudilast and triflusal as an active ingredient.
또한, 본 발명은 다른 일 실시예로서 치료상 유효량의 본 발명의 이부딜라스트 및 트리플루살을 유효성분으로 포함하는 조성물을 투여하는 것을 포함하는 심근경색, 협심증, 혈전성 정맥염, 동맥색전증, 관상 및 뇌동맥혈전증, 말초혈관 또는 심부정맥혈전증, 임의 혈관의 동맥 혈전증, 정맥혈전증,허혈성 뇌경색, 동맥경화, 고혈압, 폐고혈압, 뇌경색, 뇌졸증, 만성동맥폐색증, 폐경색, 뇌색전증, 신장색전증, 혈전색전증 및 지주막하 출혈 후의 병적 증상, 경피적 관상동맥 성형술(PTCA) 및 스텐트(stent) 삽입 시의 혈전 생성, 스텐트 설치 후의 재협착, 카테터 혈전성 폐색 또는 재폐색, 급성 관상동맥증후군, TIA(일과성 뇌허혈 발작 또는 급성 뇌혈관 증후군), 심부전증, 허혈성 병인에 의한 가슴통증, X 증후군 또는 진성당뇨병을 예방 또는 치료하는 방법을 제공한다.In another embodiment, the present invention also provides a myocardial infarction, angina pectoris, thrombophlebitis, arterial embolism, coronal administration, and the like, comprising administering a composition comprising a therapeutically effective amount of ibudilast and triflusal of the present invention as an active ingredient. Cerebral arterial thrombosis, peripheral or deep vein thrombosis, arterial thrombosis of any blood vessel, venous thrombosis, ischemic cerebral infarction, arteriosclerosis, hypertension, pulmonary hypertension, cerebral infarction, stroke, chronic arterial obstruction, pulmonary infarction, cerebral embolism, renal embolism, thromboembolism and astrocytes Pathological symptoms after lower bleeding, percutaneous coronary angioplasty (PTCA) and stent insertion, thrombus formation, restenosis after stent placement, catheter thrombotic occlusion or redostasis, acute coronary syndrome, TIA (transient cerebral ischemic attack or acute) Cerebrovascular syndrome), heart failure, chest pain caused by ischemic etiology, syndrome X or diabetes mellitus The ball.
본 발명의 의약 조성물은 각각의 약물을 단독으로 제형화하여 병용하거나 각각의 약물을 혼합하여 복합제제 형태로 제형화 할 수 있다. 약제학적인 분야에서 통상적인 방법에 따라 경구투여에 적합한 단위투여형의 제제로 제형화시켜 투여한다. 이러한 목적에 적합한 경구투여용 제형에는 경질 및 연질 캅셀제, 정제, 당의정, 필름코팅정, 나정, 장용정, 산제, 현탁제, 시럽제 등이 포함되며 이로 제한되지 않는다. 경구투여용 제제에는 두 가지 약물학적 활성성분 이외에 하나 또는 그 이상의 약제학적으로 불활성인 통상적인 담체, 예를 들면 전분, 락토오즈, 카복시메틸셀룰로오즈, 카올린 등의 부형제, 물, 젤라틴, 알코올, 글루코오즈, 아라비아고무, 트라가칸타고무 등의 결합제, 전분, 덱스트린, 알기네이트 등의 붕해제, 탈크, 스테아르산, 마그네슘 스테아레이트, 유동 파라핀 등의 활탁제와 같은 추가의 성분제들이 포함될 수 있으며 이로 제한되지 않는다. 본 발명의 약학 조성물은 또한 용해를 위한 용해보조제 등을 첨가할 수도 있다. The pharmaceutical composition of the present invention may be formulated in combination form by combining each drug alone or by mixing each drug. It is formulated and administered in a unit dosage form suitable for oral administration according to a conventional method in the pharmaceutical field. Formulations for oral administration suitable for this purpose include, but are not limited to, hard and soft capsules, tablets, dragees, film coated tablets, uncoated tablets, enteric tablets, powders, suspensions, syrups, and the like. Preparations for oral administration include, in addition to the two pharmacologically active ingredients, one or more pharmaceutically inert conventional carriers such as excipients such as starch, lactose, carboxymethylcellulose, kaolin, water, gelatin, alcohols, glucose And additional ingredients such as binders such as gum arabic, tragacanta rubber, disintegrants such as starch, dextrin, alginate, and lubricants such as talc, stearic acid, magnesium stearate, liquid paraffin, and the like. It doesn't work. The pharmaceutical composition of the present invention may also add dissolution aids and the like for dissolution.
또한 본 발명의 의약 조성물은 비경구로 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육내주사 또는 흉부내 주사 등의 주입방식에 의하며 이로 제한되는 것은 아니다. 비경구 투여용 제형으로 제제화하기 위해서는 이부딜라스트 및 트리플루살을 안정제 또는 완충제와 함께 물에서 혼합하여 용액 또는 현탁액으로 제조할 수 있다. In addition, the pharmaceutical composition of the present invention can be administered parenterally, and parenteral administration is not limited to the injection method such as subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. To formulate into parenteral formulations, ibudilast and triflusal can be prepared in solution or suspension by mixing in water with stabilizers or buffers.
본 발명의 의약 조성물은 스텐트 설치 후의 재협착 방지를 위해서 시클로덱스트린 포접체로서 이용될 수 있다. 또한, 본 발명의 의약조성물은 스텐트 재료인 생체 분해성 수지에 도포하거나, 또는 스텐트 자체에 매립함으로써 사용될 수 있다.The pharmaceutical composition of the present invention can be used as a cyclodextrin clathrate for preventing restenosis after stent placement. In addition, the pharmaceutical composition of the present invention can be used by applying to a biodegradable resin that is a stent material, or embedded in the stent itself.
본 발명의 조성물을 포함하는 혈소판 응집억제 또는 혈전용해를 위한 키트에는 이부틸라스트 및 트리플루살 이외에 이 약물이 작용할 수 있는데 필요한 시약들이 함께 포함될 수 있다.The kit for platelet aggregation inhibition or thrombolysis comprising the composition of the present invention may include reagents necessary for the drug to function in addition to ibutylast and triflusal.
본 발명에 따른 조성물의 1일 투여용량은 투여하고자 하는 대상의 증상 정도, 발병시기, 연령, 건강상태, 합병증 등 다양한 요인에 따라 달라질 수 있으며, 성인을 기준으로 할 때 일반적으로는 이부딜라스트 1-50mg, 바람직하게는 5-30mg, 더욱 바람직하게는 10-30mg, 트리플루살은 25-1200mg, 바람직하게는 100-900mg, 더욱 바람직하게는 300-900mg을 투여할 수 있다. 그러나, 증상의 정도가 심한 환자에게는 본 발명의 조성물을 상기 범위를 벗어난 대용량까지 증량하여 투여할 수 있다. 따라서 상기 투여용량의 함량으로 본 발명의 조성물을 제조할 수 있다. 본 발명의 조성물은 1일 1~3회로 나누어 투여 가능하다. 본 발명의 조성물로 제조된 단위 제제는 투여 횟수를 고려하여 성분의 함유량을 조절할 수 있다. 예를 들어, 본 발명에 따른 조성물을 함유하는 단위 제제는 예를 들어 이부딜라스트 10mg 및 트리플루살 300 mg을 함유하도록 하고 이를 1일 1~3회, 1회 1단위 제제(예를 들어, 1정 또는 1캅셀 등)을 투여할 수 있다. 본 발명에 따른 조성물은 이부딜라스트: 트리플루살을 몰비로 1:0.01~90, 바람직하게는 1:0.1~30, 더욱 바람직하게는 1:10~30의 비율로 포함한다. 본 발명의 바람직한 발명의 일 형태로 상기 조성비를 가지며, 이부딜라스트 1-50mg, 바람직하게는 5-30mg, 더욱 바람직하게는 10-30mg, 트리플로살은 25-1200mg, 바람직하게는 100-900mg, 더욱 바람직하게는 300-900mg을 함유하는 조성물을 포함한다. The daily dosage of the composition according to the present invention may vary depending on various factors, such as the degree of symptoms, the onset, age, health condition, complications, etc. of the subject to be administered, generally based on adult ibudilast 1 -50 mg, preferably 5-30 mg, more preferably 10-30 mg, triflusal may be administered 25-1200 mg, preferably 100-900 mg, more preferably 300-900 mg. However, patients with severe symptoms may be administered by increasing the composition of the present invention to a large amount out of the above range. Therefore, the composition of the present invention can be prepared in the above dosage amount. The composition of the present invention can be administered divided into 1 to 3 times a day. The unit preparation prepared from the composition of the present invention may adjust the content of the component in consideration of the frequency of administration. For example, a unit formulation containing a composition according to the present invention may contain, for example, 10 mg of ibudilast and 300 mg of triflusal, which may be 1 to 3 times a day, 1 unit once (e.g., 1 Tablets or 1 capsule, etc.) may be administered. The composition according to the invention comprises ibudilast: triflusal in a ratio of 1: 0.01 to 90, preferably 1: 0.1 to 30, more preferably 1:10 to 30 in molar ratio. One embodiment of the present invention has the above composition ratio, 1-50 mg of ibudilast, preferably 5-30 mg, more preferably 10-30 mg, trilosal is 25-1200 mg, preferably 100-900 mg More preferably 300-900 mg.
이하, 실험예 및 제제 실시예로써 본 발명을 설명한다. 그러나, 하기 실험예 및 실시예는 본 발명을 구체적으로 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 제조예로 한정되는 것은 아니다. Hereinafter, the present invention will be described as experimental examples and formulation examples. However, the following Experimental Examples and Examples are only illustrative of the present invention in detail, and the content of the present invention is not limited to the following Examples and Preparation Examples.
실시예EXAMPLE
실험동물과 혈장Laboratory Animals and Plasma
실험에 사용된 동물은 180-250 g의 Sprague-Dawley 웅성 흰쥐를 사용하였다. 혈장은 서울대학교병원 혈액은행에서 사람의 신선 동결혈장을 공급받아 사용하였다.Animals used in the experiment were 180-250 g of Sprague-Dawley male rats. Plasma was supplied from human fresh frozen plasma from Seoul National University Blood Bank.
시험물질의 조제Preparation of Test Substance
이부딜라스트는 Wuxi Fortune사(중국)에서, 트리플루살은 Zhejiang Apeloa 사(중국) 에서 구입하였으며, 기타 시약은 일급시약을 사용하였다. Ibudillast was purchased from Wuxi Fortune (China), Triflusal from Zhejiang Apeloa (China), and other reagents were used as first-class reagents.
활성을 측정하고자 하는 시료를 0.5% EtOH(최종농도)에 녹여 사용하였다. 시험약물들은 용해가 가능한 최고농도로서 트리플루살은 최종농도 1400uM, 이부딜라스트는 최종농도 1000uM까지 실험하였다.The sample to be measured for activity was dissolved in 0.5% EtOH (final concentration). The test drugs were the highest solubilities. Triflusal was tested to a final concentration of 1400 uM and ibudilast to a final concentration of 1000 uM.
통계처리Statistical processing
모든 실험결과는 평균±표준오차 (Mean±S.E.)로 계산하였으며, 각 군 간의 유의성 검정은 Student's t-test를 사용하였다.All experimental results were calculated as mean ± standard error (Mean ± SE), and the significance test between each group was Student's t- test.
<실시예 1> ADP 유도 혈소판응집에 대한 억제 활성 Example 1 Inhibitory Activity on ADP Induced Platelet Aggregation
혈소판풍부혈장(Platelet rich plasma; PRP) 및 혈소판 빈약혈장(platelet poor plasma; PPP)의 조제 Preparation of Platelet Rich Plasma (PRP) and Platelet Poor Plasma (PPP)
흰쥐를 디에틸에테르(diethyl ether)로 흡입 마취하였으며, 모든 혈소판을 이용한 실험에는 폴리스티렌 (polystylene) 또는 폴리에틸렌 (polyethylene) 용기를 사용하였다. 항응고제로서 2.2% trisodium citrate 0.1 volume를 플라스틱 주사기에 넣고, 이를 이용하여 심장으로부터 0.9 volume의 혈액을 채취하였다. 혈액을 조심스럽게 섞은 후, 상온에서 200 × g로 10분간 원심분리하여 상층액 PRP(혈소판 풍부혈장Platelet rich plasma)를 얻었다. PRP를 취하고 남은 층을 1500 × g에서 20분간 원심 분리하여 PPP(Platelet poor plasma)를 얻고, PRP을 PPP로 희석하여 혈소판 수를 350 - 450 x 106/mL로 맞추어 실험에 사용하였다. Rats were inhaled anesthesia with diethyl ether, and all the platelets were used in a polystyrene (polystylene) or polyethylene container. As an anticoagulant, 2.2% trisodium citrate 0.1 volume was placed in a plastic syringe, and 0.9 volume of blood was collected from the heart. After carefully mixing the blood, centrifuged for 10 minutes at 200 × g at room temperature to obtain a supernatant PRP (platelet rich plasma). PRP was taken and the remaining layer was centrifuged at 1500 × g for 20 minutes to obtain PPP (Platelet poor plasma), and PRP was diluted with PPP to adjust platelet count to 350-450 × 10 6 / mL and used in the experiment.
혈소판응집 억제 작용의 측정 (Turbidimetric method)Measurement of platelet aggregation inhibitory activity (Turbidimetric method)
문헌(Transfus Apher Sci 2003, 28, 307-17 및 Thromb Res 2000, 100, 511-8)에 기재된 방법을 참고하여 혈소판 응집 억제 활성을 측정하였다.The platelet aggregation inhibitory activity was measured with reference to the methods described in Transfus Apher Sci 2003, 28, 307-17 and Thromb Res 2000, 100, 511-8.
혈소판 응집기(platelet aggregometer, 490X, Chrono-Log Corp., Havertown, PA, USA)를 사용하였으며, McNicol(Platelets-A Practical approach: Oirl Press at Oxford University Press, pp1-26, 1996) 또는 Yun-Choi HS등(Thromb Res, vol.100, p511-518, 2000)의 방법을 참조하였다. 혈소판 수를 일정하게 맞춘 PRP 500 ul를 37oC aggregometer에서 2분간 배양시키고 1200 rpm으로 교반하면서 각 5 ul 의 시료용액 (또는 vehicle:0.5% EtOH)을 가하였다. 1분 30초 후 응집유도물질로서 ADP 5 uL를 첨가하여 혈소판응집을 유도하였다. 응집유도 물질인 ADP의 최종농도는 2 - 3 uM이었다. 혈소판 응집 억제율(%)은 다음의 식에 의하여 구하였다.Platelet aggregometer (490X, Chrono-Log Corp., Havertown, PA, USA) was used and McNicol (Platelets-A Practical approach: Oirl Press at Oxford University Press, pp1-26, 1996) or Yun-Choi Reference was made to the method of HS et al. (Thromb Res, vol. 100, p511-518, 2000). Pul 500 Pul with a constant platelet count was incubated for 2 minutes in a 37 ° C. aggregometer and 5 ul of sample solution (or vehicle: 0.5% EtOH) was added while stirring at 1200 rpm. After 1 minute and 30 seconds, platelet aggregation was induced by adding 5 uL of ADP as a coagulant-inducing substance. The final concentration of ADP, a coagulant-inducing substance, was 2-3 uM. Platelet aggregation inhibition rate (%) was calculated | required by the following formula.
혈소판응집억제(%)= (A-B )/A x 100Platelet aggregation inhibition (%) = (A-B) / A x 100
A:PRP에 vehicle (최종농도0.5% EtOH)을 가한 후 응집유도물질을 가하였을 때의 혈소판 응집도A: Platelet aggregation degree when agglomerate-inducing substance was added after vehicle (final concentration 0.5% EtOH) was added to A: PRP
B: PRP에 최종농도0.5% EtOH에 녹인 실험시료를 가한 후 응집유도물질을 가하였을 때의 혈소판 응집도B: Platelet coagulation when PRP was added to the test sample dissolved in 0.5% EtOH at the final concentration
우선 응집유도 물질인 ADP에 대하여 이부딜라스트 및 트리플루살이 각각 10 ~ 80 %의 응집억제도를 보이는 농도를 확인하고, 그 농도 범위에서 2종의 약물을 함께 사용하였을 때의 억제도를 %로 구하였다. 양성대조군으로 아스피린을 사용하여 복합시료의 작용강도를 비교함으로써 실제 사용 시의 결과를 예측하였다. 시험은 5회 반복하여 실시하였다.First, the concentrations of ibudilast and triflusal were 10 to 80%, respectively, against the coagulation-inducing substance ADP, and the inhibition rate when the two drugs were used together in the concentration range was%. Obtained. Aspirin was used as a positive control to predict the results of actual use by comparing the strength of complex samples. The test was repeated five times.
ADP 유도 혈소판응집에 대한 억제 활성 시험결과 Inhibitory activity test results for ADP-induced platelet aggregation
표 1 및 도 1에서 보는 바와 같이, ADP에 의하여 유도되는 혈소판응집에 대하여 이부딜라스트를 단독으로 첨가한 경우 600 uM 농도까지 억제작용을 보이지 않았으며 1000 uM에서 10%의 억제 효과를 나타내었고, 트리플루살은 1000 uM까지 전혀 억제작용을 보이지 않았으며 1400 uM 에서 약34 %의 억제효과를 보여, 양성대조군(positive control)인 아스피린과 비교하여 억제효과가 훨씬 낮았다. As shown in Table 1 and FIG. 1, when ibudilast alone was added to platelet aggregation induced by ADP, it did not show an inhibitory effect up to 600 uM concentration and showed an inhibitory effect of 10% at 1000 uM. Triflusal showed no inhibitory activity up to 1000 uM and showed an inhibitory effect of about 34% at 1400 uM, which was much lower than that of the positive control aspirin.
그러나 위와 같이 단독으로 첨가하였을 때 ADP에 의해 유도된 혈소판 응집에 대한 억제효과를 보이지 않았던 농도인 이부딜라스트 300uM 및 트리플루살 300 uM을 동시에 첨가하면 16±9.2%, 이부딜라스트 600uM 및 트리플루살 300 uM을 동시에 첨가하면 15±6.8%, 이부딜라스트 300uM 및 트리플루살 500 uM을 동시에 첨가하면 24±7.0%의 억제효과를 나타내었다. 이와 같이 단독 사용에 의해서는 혈소판 응집 억제효과가 없었던 두 가지 약물을 병용함으로 인하여 억제효과를 보이는 것은 단독 약물로부터 전혀 예측할 수 없는 효과이다.However, the addition of ibudilast 300 uM and triflusal 300 uM, the concentrations of which did not show an inhibitory effect on ADP-induced platelet aggregation when added alone, was 16 ± 9.2%, ibudilast 600uM and triflusal 300 Simultaneous addition of uM showed an inhibitory effect of 15 ± 6.8%, ibudilast 300uM and triflusal 500uM at the same time. As such, showing the inhibitory effect by using two drugs that did not have the effect of inhibiting platelet aggregation by single use is an unpredictable effect from the single drug.
또한, 단독으로 사용할 때 10±0%의 억제효과를 보였던 이부딜라스트 1000uM과 34±0.7%의 억제효과를 보였던 트리플루살 1400uM을 동시에 첨가할 경우 49±9.1%의 억제효과가 나타나 두 약물의 각각의 억제효과를 더한 값보다 더 높은 억제율을 보여 두 약물을 병용 사용하면 억제효과가 상승적으로 나타난다는 것이 확인되었다.In addition, when added alone, 1000uM of ibudilast and 10400% of Triflusal, which showed 34 ± 0.7% of inhibitory effect, showed 49 ± 9.1% of inhibitory effect. It was confirmed that the inhibitory effect was synergistic when the two drugs were used in combination because the inhibition rate was higher than the inhibitory effect of.
표 1 ADP 유도 혈소판 응집에 대한 억제 효과
Aspirin(uM) Ibudilast(uM) Triflusal(uM) Inhibition(%)
300 - - 9.0± 0.6
400 - - 18±7.2
450 - - 17±2.5
500 - - 32±0.0
1000 - - 35±4.2
2000 - - 62±8.1
- - 300 N*
- - 500 N
- - 1000 N
- - 1400 34±0.7
- 300 - N
- 600 - N
- 1000 - 10±0
- 300 300 16±9.2
- 600 300 15±6.8
- 300 500 24±7.0
- 1000 1400 49±9.1
Table 1 Inhibitory Effect on ADP-induced Platelet Aggregation
Aspirin (uM) Ibudilast (uM) Triflusal (uM) Inhibition (%)
300 - - 9.0 ± 0.6
400 - - 18 ± 7.2
450 - - 17 ± 2.5
500 - - 32 ± 0.0
1000 - - 35 ± 4.2
2000 - - 62 ± 8.1
- - 300 N *
- - 500 N
- - 1000 N
- - 1400 34 ± 0.7
- 300 - N
- 600 - N
- 1000 - 10 ± 0
- 300 300 16 ± 9.2
- 600 300 15 ± 6.8
- 300 500 24 ± 7.0
- 1000 1400 49 ± 9.1
N: No effectN: No effect
<실시예 2> 아라키돈산 유도 혈소판응집에 대한 억제 활성 Example 2 Inhibitory Activity on Arachidonic Acid-Induced Platelet Aggregation
실시예1에 기재된 바와 동일한 방법으로 PRP 및 PPP를 제조하여 혈소판 응집 억제작용을 측정하였다. PRP and PPP were prepared in the same manner as described in Example 1 to measure platelet aggregation inhibition.
다만, 아라키돈산(AA; Arachidonic acid))에 의하여 유도되는 혈소판응집은 역치농도(threshold concentration)의 콜라겐 존재 하에서 실시되었다. 즉 역치농도의 콜라겐(1 - 1.8 ug/mL)을 가하고 30초 후 AA 5 uL를 가하여 혈소판응집을 유도하였다. 응집유도 물질인 AA의 최종농도는 50 - 150 uM 이었다.　However, platelet aggregation induced by Arachidonic acid (AA) was performed in the presence of collagen at a threshold concentration. In other words, collagen (1-1.8 ug / mL) of threshold concentration was added, and after 30 seconds, AA 5 uL was added to induce platelet aggregation. The final concentration of the coagulant induced AA was 50-150 uM.
우선 응집유도 물질인 AA에 대하여 이부딜라스트 및 트리플루살이 각각 10 ~ 80 %의 응집억제도를 보이는 농도를 확인하고, 그 농도범위에서2종의 물질을 함께 가하였을 때의 억제도를 %로 구하였다. 양성 대조군으로 아스피린을 사용하여 복합시료의 작용강도를 비교함으로써 실제 사용 시 결과를 예측하였다. 시험은 5회 반복하여 실시하였다. First, the concentrations of ibudilast and triflusal were 10-80% of aggregation inhibitory concentration to AA, which is a coagulant-inducing substance, and the inhibition rate when two substances were added together in the concentration range was%. Obtained. Aspirin was used as a positive control to predict the results of actual use by comparing the strength of the composite samples. The test was repeated five times.
아라키돈산 유도 혈소판응집에 대한 억제 활성 시험결과 Inhibitory activity test results for arachidonic acid-induced platelet aggregation
표 2및 도 2에서 나타난 바와 같이, 아라키돈산에 의하여 유도되는 혈소판응집에 대하여 이부딜라스트의 경우 300 ~ 700 uM에서 13 ~ 58 %의 농도의존적인 응집억제도를 보였으며, 트리플루살은 300 ~ 600 uM에서 23 ~ 65 %의 응집억제도를 나타내었다. As shown in Table 2 and Figure 2, for the platelet aggregation induced by arachidonic acid showed a concentration-dependent coagulation inhibitory concentration of 13 ~ 58% at 300 ~ 700 uM for ibudilast, the triple lusal At 600 uM, it showed a 23 to 65% cohesion inhibitor.
이부딜라스트와 트리플루살을 동시에 투여하면, 각각의 약물을 단독으로 투여하였을 때와 비교하여 상승적으로 억제효과가 증가하였다. 예를 들어, 이부딜라스트 600 uM및 트리플루살 300 uM을 단독으로 투여할 경우 각각 30±8.0% 및 23±9.0%의 억제율을 보였으나, 두 약물을 동시 투여하면, 86+8.0 %의 억제작용을 보였다. Simultaneous administration of ibudilast and triflusal resulted in a synergistically increased inhibitory effect compared to the administration of each drug alone. For example, ibudilast 600 uM and Triflusal when administered to 300 uM alone or showed respectively 30 ± inhibition rate of 8.0% and 23 ± 9.0%, when co-administered with the two drugs, 86 + inhibition of 8.0% action Showed.
표 2 아리키돈산 유도 혈소판응집에 대한 억제 효과
Aspirin(uM) Ibudilast(uM) Triflusal(uM) Inhibition(%)
30 - - 8.0±7.1
50 - - 28±12
100 - - 98±0.0
200 - - 97±0.6
- - 300 23±9.0
- 500 48±12.0
- - 600 65±7.8
- 300 - 13±9.0
- 600 - 30±8.0
- 700 - 58±19.0
- 300 300 54±4.7
- 600 300 86±8.0
- 700 300 98±1.7
- 300 500 86±12.0
- 600 500 86±7.8
- 300 600 97±1.2
TABLE 2 Inhibitory Effect on Arikidonic Acid-Induced Platelet Aggregation
Aspirin (uM) Ibudilast (uM) Triflusal (uM) Inhibition (%)
30 - - 8.0 ± 7.1
50 - - 28 ± 12
100 - - 98 ± 0.0
200 - - 97 ± 0.6
- - 300 23 ± 9.0
- 500 48 ± 12.0
- - 600 65 ± 7.8
- 300 - 13 ± 9.0
- 600 - 30 ± 8.0
- 700 - 58 ± 19.0
- 300 300 54 ± 4.7
- 600 300 86 ± 8.0
- 700 300 98 ± 1.7
- 300 500 86 ± 12.0
- 600 500 86 ± 7.8
- 300 600 97 ± 1.2
<실시예3> 혈액 항응고 작용 Example 3 Blood Anticoagulant Action
이부딜라스트 및 트리플루살 복합제의 혈액 항응고작용을 알아보기 위하여 aPPT, PT 및 TT 에세이를 하였다.APPT, PT and TT assays were performed to investigate the anticoagulant activity of ibudilast and triflusal.
aPTT (Activated Partial Thromboplastin Time) assayaPTT (Activated Partial Thromboplastin Time) assay
J. Ethnopharmacol. (2003, vol.89, p101-5)에 기재된 방법을 참조하여 aPTT를 측정하였다. 약물시료 3 ul (또는 vehicle)를 혈장 100 ul에 넣고 37 oC에서 2분간 배양시킨 후, aPTT 시약(STA PTT A⑤, Stago) 100 ul 를 넣고 계속해서 37 oC에서 3분간 배양시켰다. 0.025 M CaCl2 100 ul를 첨가한 후 혈장이 응고되기까지의 시간을 fibrometer로 측정하였으며 모든 데이터는 초 단위로 표시하였다.J. Ethnopharmacol. APTT was measured with reference to the method described in (2003, vol. 89, p101-5). After 3 ul of drug sample (or vehicle) was put in 100 ul of plasma and incubated for 2 minutes at 37 o C, 100 ul of aPTT reagent (STA PTT A ⑤, Stago) was added and then incubated for 3 minutes at 37 o C. After adding 100 μl of 0.025 M CaCl 2 , the time to plasma coagulation was measured by a fibrometer. All data were expressed in seconds.
PT (Prothrombin Time) assayPT (Prothrombin Time) assay
　J. Ethnopharmacol. (2003, vol.89, p101-5)에 기재된 방법을 참조하여 PT를 측정하였다. 약물시료 3 ul (또는 vehicle)를 혈장 100 ul 에 넣고 37 oC 에서 3분간 배양시킨 후, 미리 37 oC 로 가열시켜 놓은 PT 시약(Neoplastine® CI Plus②,Stago) 200 ul를 첨가하고 혈장이 응고되기까지의 시간을 fibrometer로 측정하였으며 모든 데이터는 초단위로 표시하였다.J. Ethnopharmacol. PT was measured with reference to the method described in (2003, vol. 89, p101-5). 3 ul sample drug (or vehicle) in the plasma was placed in a 100 ul incubated for 3 minutes at 37 o C, PT reagents placed in advance by heating to 37 o C (Neoplastine® CI Plus②, Stago) was added to 200 ul and plasma clot The time to completion was measured with a fibrometer and all data were expressed in seconds.
TT (Thrombin Time) assayTT (Thrombin Time) assay
　Thromb. Res. 2000, 100, 511-8에 기재된 방법을 참고하여 TT를 측정하였다. 약물시료 3 ul (또는 vehicle)를 혈장 100 ul 에 넣고 37 oC 에서 3 분간 배양시킨 후, 미리 37 oC 로 가열시켜 놓은 TT 시약(STA®Thrombin②,Stago) 200 ul 를 첨가하고 혈장이 응고되기까지의 시간을 fibrometer로 측정하였으며 모든 데이터는 초 단위로 표시하였다.Thromb. Res. TT was measured with reference to the methods described in 2000, 100, 511-8. Is added to the sample 3 ul drug (or vehicle) in the plasma was placed in a 100 ul incubated for 3 minutes at 37 o C, 37 o pre-TT reagent (STA®Thrombin②, Stago) was placed and heated to 200 C and ul plasma clot The time until was measured with a fibrometer and all data were expressed in seconds.
혈액 항응고 효과에 대한 실험 결과Experimental Results on Blood Anticoagulant Effects
실시예 1 및 2에서 이부딜라스트와 트리플루살의 두 종의 약물을 병용처리하여 혈소판 응집억제 작용의 상승효과를 보인 농도인 이부딜라스트 또는 트리플루살 각각 300 ~ 500 uM 농도에서 정상응고시간에 비하여 aPTT, PT　또는 TT 시간을 연장시키는가 관찰하였다. 또한 2종의 약물을 동시 처리하여 혈소판응집 억제작용의 상승작용을 보인 농도에서 혈액응고시간 연장효과가 있는가를 관찰하였다. 양성 대조군으로 헤파린을 사용하여 복합시료의 작용강도를 비교함으로써 실제 사용 시 결과를 예측하였다. 　　 　　　　　　　　　 In Examples 1 and 2, two drugs, ibudilast and triflusal, were used in combination to show the synergistic effect of platelet aggregation. prolonging the aPTT, PTVIII or TT time was observed. In addition, the simultaneous treatment of two drugs was used to observe the effect of prolonging the blood coagulation time at the concentration showing the synergistic effect of platelet aggregation inhibition. Heparin was used as a positive control and the results were predicted in actual use by comparing the strength of complex samples.
이부딜라스트 및 트리플루살을 포함하는 조성물이 혈액 항응고작용을 갖는가를 내인계, 외인계 및 공통 응고계에 대하여 응고시간을 연장시키는지 여부로 검토하였다. 표3에서 정리된 바와 같이 헤파린의 경우 0.05~2 U/ml의 농도에서 대조군과 비교하여 aPTT, PT, TT시간(sec)이 각각 80.2%, 106.6%, 171.7% 연장되어 강력한 항혈액응고 효과를 나타냄을 알 수 있었으며 이는 출혈 위험성이 상당히 크다는 것을 나타내며 따라서 사용에 상당한 주의를 필요로 한다. Whether the composition comprising ibudilast and triflusal had blood anticoagulant action was examined by prolonging the coagulation time for the endogenous, exogenous and common coagulation systems. As summarized in Table 3, in the case of heparin, aPTT, PT, and TT time (sec) were extended by 80.2%, 106.6%, and 171.7%, respectively, at concentrations of 0.05 ~ 2 U / ml, resulting in a strong anticoagulant effect. This indicates that the risk of bleeding is quite high and therefore requires great care in use.
이부딜라스트 또는 트리플루살을 단독처리할 때 PT와 aPTT시간에는 영향이 없거나 10 % 이하의 약한 연장을 보인 반면, TT시간을 12 ~ 18 % 연장시켜 공통계에 의한 혈액 응고시간 연장효과를 가져 항응고 효과를 보이나, 대조군과 비교하여 그 정도가 그리 크리 않았다. Treatment with ibudilast or triflusal alone did not affect PT and aPTT time or showed a weak extension of less than 10%, while extending the TT time by 12 to 18%, resulting in an extended blood clotting time by the common system. It showed a coagulation effect, but not so much compared to the control.
또한 이부딜라스트와 트리플루살을 동시 투여하였을 때 역시 PT와 aPTT시간은 10 % 이하의 연장을 보인 반면, TT시간을 19 ~ 23 % 연장시켜 단독 투여하였을 때보다 약간 증가되었다. 이로부터, 이부딜라스트 및 트리플루살 병용처리는 혈액응고 기전 중 공통계인 TT시간 만을 연장시켜 이들 물질들의 혈소판 응집억제 효과를 보완하면서, 출혈 위험성이 적을 것으로 추정된다(표 3).　 In addition, PT and aPTT time showed an extension of 10% or less when ibudilast and triflusal were co-administered, while the TT time was 19-23% longer than that of monotherapy. From this, the combination of ibudilast and triflusal is expected to reduce the risk of bleeding while prolonging the TT time, which is a common system in the coagulation mechanism, to compensate for the platelet aggregation inhibitory effect of these substances (Table 3).
표 3 혈액응고시간에 대한 효과
Triflusal(uM) Ibudilast(uM) aPT(sec)(대조군대비증가율) PT(sec)(대조군대비증가율) TT(sec)(대조군대비증가율)
대조군 - - 46.4 ± 1.3 16.6 ± 0.2 18.7 ± 0.7
헤파린a) - - 83.6 ± 1.1(80.2%) 34.3 ± 2.2(106.6%) 50.8 ± 3.7(171.7%)
- 100 - 47.9 ± 0.8(3.2%) 16.5 ± 0.3(0%) 19.1 ± 0.6(2.1%)
- 200 - 49.2 ± 0.5*(6%) 16.6 ± 0.2(0%) 19.9 ± 0.2(6.4%)
- 300 - 49.6 ± 1.0*(6.9%) 16.7 ± 0.2(0.6%) 21.1 ± 0.9**(12.8%)
- 500 - 50.7 ± 1.6*(9.3%) 17.1 ± 0.4(3.0%) 21.8 ± 0.4**(16.6%)
- - 100 48.1 ± 0.8(3.7%) 16.5 ± 0.3(0%) 19.4 ± 0.4(3.7%)
- - 200 49.0 ± 0.3*(5.6%) 17.2 ± 0.2*((3.6%) 20.0 ± 0.4(7.0%)
- - 300 49.6 ± 1.7(6.9%) 17.7 ± 0.4**(6.6%) 21.0 ± 0.6**(12.3%)
- - 500 50.8 ± 2.4*(9.4%) 17.9 ± 0.2**(7.8%) 22.0 ± 0.6**(17%)
- 300 300 50.3 ± 1.9*(8.4%) 17.2 ± 0.4(3.6%) 22.3 ± 0.4**(19.3%)
- 300 500 50.8 ± 0.7**(9.4%) 17.8 ± 0.4**(7.2%) 22.4 ± 0.4**(19.8%)
- 500 500 51.0 ± 1.4**(9.9%) 17.9 ± 0.4**(7.8%) 23.0 ± 0.2**(23%)
TABLE 3 Effect on Blood Coagulation Time
Triflusal (uM) Ibudilast (uM) aPT (sec) (growth of control) PT (sec) (growth of control) TT (sec) (growth of control)
Control - - 46.4 ± 1.3 16.6 ± 0.2 18.7 ± 0.7
Heparin a) - - 83.6 ± 1.1 (80.2%) 34.3 ± 2.2 (106.6%) 50.8 ± 3.7 (171.7%)
- 100 - 47.9 ± 0.8 (3.2%) 16.5 ± 0.3 (0%) 19.1 ± 0.6 (2.1%)
- 200 - 49.2 ± 0.5 * (6%) 16.6 ± 0.2 (0%) 19.9 ± 0.2 (6.4%)
- 300 - 49.6 ± 1.0 * (6.9%) 16.7 ± 0.2 (0.6%) 21.1 ± 0.9 ** (12.8%)
- 500 - 50.7 ± 1.6 * (9.3%) 17.1 ± 0.4 (3.0%) 21.8 ± 0.4 ** (16.6%)
- - 100 48.1 ± 0.8 (3.7%) 16.5 ± 0.3 (0%) 19.4 ± 0.4 (3.7%)
- - 200 49.0 ± 0.3 * (5.6%) 17.2 ± 0.2 * ((3.6%) 20.0 ± 0.4 (7.0%)
- - 300 49.6 ± 1.7 (6.9%) 17.7 ± 0.4 ** (6.6%) 21.0 ± 0.6 ** (12.3%)
- - 500 50.8 ± 2.4 * (9.4%) 17.9 ± 0.2 ** (7.8%) 22.0 ± 0.6 ** (17%)
- 300 300 50.3 ± 1.9 * (8.4%) 17.2 ± 0.4 (3.6%) 22.3 ± 0.4 ** (19.3%)
- 300 500 50.8 ± 0.7 ** (9.4%) 17.8 ± 0.4 ** (7.2%) 22.4 ± 0.4 ** (19.8%)
- 500 500 51.0 ± 1.4 ** (9.9%) 17.9 ± 0.4 ** (7.8%) 23.0 ± 0.2 ** (23%)
a) 헤파린 사용농도 PT: 2.0 U/mL, TT: 0.1 U/mL, aPTT: 0.05 U/mLa) Heparin concentration PT: 2.0 U / mL, TT: 0.1 U / mL, aPTT: 0.05 U / mL
* P〈 0.01, ** P〈 0.001* P <0.01, ** P <0.001
제제 실시예Formulation Example
이부딜라스트 및 트리플루살을 유효성분으로 함유하는 다양한 형태의 제제를 하기와 같이 제조하였다.Various forms of preparations containing ibudilast and triflusal as active ingredients were prepared as follows.
<실시예1> 정제Example 1 Tablet
이부딜라스트 10.0mgIbudillast 10.0mg
트리플루살 300.0mgTriflusal 300.0mg
유당 10.0mgLactose 10.0 mg
미결정셀룰로오스 5.5mg5.5mg of microcrystalline cellulose
포비돈 7.5mgPovidone 7.5mg
저치환도히드록시프로필셀룰로오스 10.0mgLow Substituted Hydroxypropyl Cellulose 10.0mg
스테아린산마그네슘 3.0mgMagnesium Stearate 3.0mg
이부딜라스트, 트리플루살, 유당, 미결정셀룰로오스, 저치환도히드록시프로필셀룰로오스를 혼합하고, 포비돈을 물에 녹인액을 가하여 연합하고 통상의 방법으로 과립하였다. 이를 건조한 후 정립하고 스테아린산마그네슘과 혼합하고 이를 정제화하였다.Ibudillast, triflusal, lactose, microcrystalline cellulose and low-substituted hydroxypropyl cellulose were mixed, the povidone was dissolved in water, added, and granulated in a conventional manner. After drying, it was established, mixed with magnesium stearate and purified.
이 제제는 1일 3회, 1회 1정씩 복용한다.This preparation is taken 3 times a day, 1 tablet once.
<실시예 2> 필름코팅정Example 2 Film Coated Tablet
이부딜라스트 10.0mgIbudillast 10.0mg
트리플루살 300.0mgTriflusal 300.0mg
유당 10.0mgLactose 10.0 mg
미결정셀룰로오스 5.5mg5.5mg of microcrystalline cellulose
포비돈 7.5mgPovidone 7.5mg
저치환도히드록시프로필셀룰로오스 10.0mgLow Substituted Hydroxypropyl Cellulose 10.0mg
스테아린산마그네슘 3.0mgMagnesium Stearate 3.0mg
오파드라이85G68914화이트 20.0mgOpadry 85G68914 White 20.0mg
산화티탄 3.0mgTitanium Oxide 3.0mg
이부딜라스트, 트리플루살, 유당, 미결정셀룰로오스, 저치환도히드록시프로필셀룰로오스를 혼합하고, 포비돈을 물에 녹인액을 가하여 연합하고 통상의 방법으로 과립하였다. 이를 건조한 후 정립하고 스테아린산마그네슘과 혼합하고 이를 정제화하였다. 이 정제를 오파드라이85G68914화이트와 산화티탄을 유기용매에 분산시킨 필름코팅액으로 통상의 방법에 따라 필름코팅하였다.Ibudillast, triflusal, lactose, microcrystalline cellulose and low-substituted hydroxypropyl cellulose were mixed, the povidone was dissolved in water, added, and granulated in a conventional manner. After drying, it was established, mixed with magnesium stearate and purified. This tablet was film-coated in accordance with a conventional method with a film coating liquid in which Opadry 85G68914 white and titanium oxide were dispersed in an organic solvent.
이 제제는 1일 3회, 1회 1정씩 복용한다.This preparation is taken 3 times a day, 1 tablet once.
<실시예 3> 당의정Example 3 Dragee
이부딜라스트 10.0mgIbudillast 10.0mg
트리플루살 300.0mgTriflusal 300.0mg
유당 10.0mgLactose 10.0 mg
미결정셀룰로오스 5.5mg5.5mg of microcrystalline cellulose
포비돈 7.5mgPovidone 7.5mg
저치환도히드록시프로필셀룰로오스 10.0mgLow Substituted Hydroxypropyl Cellulose 10.0mg
스테아린산마그네슘 3.0mgMagnesium Stearate 3.0mg
젤라틴 0.73mgGelatin 0.73mg
백당 22.2mg22.2mg per bag
참강탄산칼슘 51.8mgChamgang Calcium Carbonate 51.8mg
히드록시프로필메칠셀룰로오스2906 3.0mgHydroxypropylmethylcellulose 2906 3.0mg
이부딜라스트, 트리플루살, 유당, 미결정셀룰로오스, 저치환도히드록시프로필셀룰로오스를 혼합하고, 포비돈을 물에 녹인액을 가하여 연합하고 통상의 방법으로 과립하였다. 이를 건조한 후 정립하고 스테아린산마그네슘과 혼합하고 이를 정제화하였다. 이 정제를 젤라틴, 백당, 침강탄산칼슘, 히드록시프로필메칠셀룰로오스2906를 가지고 통상의 방법으로 당의정으로 하였다.Ibudillast, triflusal, lactose, microcrystalline cellulose and low-substituted hydroxypropyl cellulose were mixed, the povidone was dissolved in water, added, and granulated in a conventional manner. After drying, it was established, mixed with magnesium stearate and purified. This tablet was dragged with gelatin, white sugar, precipitated calcium carbonate and hydroxypropylmethylcellulose 2906 in a conventional manner.
이 제제는 1일 3회, 1회 1정씩 복용한다.This preparation is taken 3 times a day, 1 tablet once.
<실시예 4> 캅셀제Example 4 Capsule
이부딜라스트 10.0mgIbudillast 10.0mg
트리플루살 300.0mgTriflusal 300.0mg
스테아린산마그네슘 4.0mgMagnesium Stearate 4.0mg
이부딜라스트, 트리플루살, 옥수수전분, 유당, 스테아린산 마그네슘을 혼합한 후 캅셀에 통상의 방법으로 충전하였다.Ibudilast, triflusal, corn starch, lactose and magnesium stearate were mixed and then filled into capsules in the usual manner.
이 제제는 1일 3회, 1회 1정씩 복용한다.This preparation is taken 3 times a day, 1 tablet once.
<실시예 5> 장용정Example 5 Jang Yong-Jung
이부딜라스트 10.0mgIbudillast 10.0mg
트리플루살 300.0mgTriflusal 300.0mg
유당 10.0mgLactose 10.0 mg
미결정셀룰로오스 5.5mg5.5mg of microcrystalline cellulose
포비돈 7.5mgPovidone 7.5mg
저치환도히드록시프로필셀룰로오스 10.0mgLow Substituted Hydroxypropyl Cellulose 10.0mg
스테아린산 ·마그네슘 3.0mgStearic acid, magnesium 3.0mg
메타아크릴산아크릴산에틸코폴리머 18.0mgEthyl methacrylate copolymer 18.0 mg
프로필렌글리콜 2.0mgPropylene Glycol 2.0mg
산화티탄 1.0mgTitanium oxide 1.0mg
탈크 4.0mgTalc 4.0mg
이부딜라스트, 트리플루살, 유당, 미결정셀룰로오스, 저치환도히드록시프로필셀룰로오스를 혼합하고, 포비돈을 물에 녹인액을 가하여 연합하고 통상의 방법으로 과립하였다. 이를 건조한 후 정립하고 스테아린산마그네슘과 혼합하고 이를 정제화하였다. 이 정제를 메타아크릴산·아크릴산에틸코폴리머, 프로필렌글리콜, 산화티탄, 탈크를 사용하여 통상의 방법으로 장용성 정제로 제조하였다.Ibudillast, triflusal, lactose, microcrystalline cellulose and low-substituted hydroxypropyl cellulose were mixed, the povidone was dissolved in water, added, and granulated in a conventional manner. After drying, it was established, mixed with magnesium stearate and purified. This tablet was prepared as an enteric tablet by a conventional method using methacrylic acid, an ethyl acrylate copolymer, propylene glycol, titanium oxide, and talc.
이 제제는 1일 3회, 1회 1정씩 복용한다.This preparation is taken 3 times a day, 1 tablet once.
본 발명의 이부딜라스트 및 트리플루살을 유효성분으로 포함하는 의약 조성물, 상기 조성물을 포함하는 의약, 키트 그리고 상기 조성물을 투여하는 방법은 혈소판의 응집을 억제 또는 혈전을 용해하기 위하여 사용될 수 있다. 본 발명의 상기 조성물 또는 방법에 의하여 예방 또는 치료가 가능한 질병 또는 증상으로는 예를 들어, 심근경색, 협심증, 혈전성 정맥염, 동맥색전증, 관상 및 뇌동맥혈전증, 말초혈관 또는 심부정맥혈전증, 임의 혈관의 동맥 혈전증, 정맥혈전증,허혈성 뇌경색, 동맥경화, 고혈압, 폐고혈압, 뇌경색, 뇌졸증, 만성동맥폐색증, 폐경색, 뇌색전증, 신장색전증, 혈전색전증 및 지주막하 출혈 후의 병적 증상, 경피적 관상동맥 성형술(PTCA) 및 스텐트(stent) 삽입 시의 혈전 생성, 스텐트 설치 후의 재협착, 카테터 혈전성 폐색 또는 재폐색, 급성 관상동맥증후군, TIA(일과성 뇌허혈 발작 또는 급성 뇌혈관 증후군), 심부전증, 허혈성 병인에 의한 가슴통증, X 증후군, 진성당뇨병 등을 들 수 있다.A pharmaceutical composition comprising ibudilast and triflusal of the present invention as an active ingredient, a medicament comprising the composition, a kit and a method of administering the composition may be used to inhibit platelet aggregation or to dissolve blood clots. Diseases or symptoms that can be prevented or treated by the composition or method of the present invention include, for example, myocardial infarction, angina pectoris, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, peripheral vascular or deep vein thrombosis, and any blood vessels. Arterial thrombosis, venous thrombosis, ischemic cerebral infarction, arteriosclerosis, hypertension, pulmonary hypertension, cerebral infarction, stroke, chronic arterial obstruction, pulmonary infarction, cerebral embolism, renal embolism, pathological symptoms after thromboembolism and subarachnoid hemorrhage, percutaneous coronary angioplasty (PTCA) And thrombus formation at stent insertion, restenosis after stent placement, catheter thrombotic occlusion or redo occlusion, acute coronary syndrome, TIA (transient cerebral ischemic attack or acute cerebrovascular syndrome), heart failure, chest pain due to ischemic etiology , Syndrome X, diabetes mellitus and the like.

Claims (9)

  1. 유효성분으로 이부딜라스트 및 트리플루살을 포함하고 약제학적으로 허용되는 담체를 포함하는 것을 특징으로 하는 혈소판 응집 억제용 또는 혈전용해용 의약 조성물.A pharmaceutical composition for inhibiting platelet aggregation or thrombolysis, comprising ibudilast and triflusal as an active ingredient, and comprising a pharmaceutically acceptable carrier.
  2. 제1항에 있어서, 이부딜라스트 및 트리플루살이 몰비로 1: 0.01 ~ 90의 비율로 포함되는 것을 특징으로 하는 혈소판 응집 억제용 또는 혈전용해용 의약 조성물.The pharmaceutical composition for inhibiting platelet aggregation or thrombolysis according to claim 1, wherein ibudilast and triflusal are included in a molar ratio of 1: 0.01 to 90.
  3. 제1항에 있어서, 이부딜라스트 및 트리플루살이 몰비로 1: 0.1 ~ 30의 비율로 포함되는 것을 특징으로 하는 혈소판 응집 억제용 또는 혈전용해용 의약 조성물. The pharmaceutical composition for inhibiting platelet aggregation or thrombolytic activity according to claim 1, wherein ibudilast and triflusal are included in a molar ratio of 1: 0.1 to 30.
  4. 유효성분으로 이부딜라스트 5-30mg 및 트리플루살 300-900mg을 포함하고 약제학적으로 허용되는 담체를 포함하는 것을 특징으로 하는 혈소판 응집 억제용 또는 혈전용해용 의약 조성물. A pharmaceutical composition for inhibiting platelet aggregation or thrombolysis, comprising 5-30 mg of ibudilast and 300-900 mg of triflusal as an active ingredient and comprising a pharmaceutically acceptable carrier.
  5. 제4항에 있어서, 이부딜라스트 10mg, 트리플루살 300mg을 함유하는 것을 특징으로 하는 혈소판 응집 억제용 또는 혈전용해용 의약 조성물. The pharmaceutical composition for inhibiting platelet aggregation or thrombolysis according to claim 4, which contains 10 mg of ibudilast and 300 mg of triflusal.
  6. 제1항 내지 제5항 중 어느 한 항에 있어서, 심근경색, 협심증, 혈전성 정맥염, 동맥색전증, 관상 및 뇌동맥혈전증, 말초혈관 또는 심부정맥혈전증, 임의 혈관의 동맥 혈전증, 정맥혈전증,허혈성 뇌경색, 동맥경화, 고혈압, 폐고혈압, 뇌경색, 뇌졸증, 만성동맥폐색증, 폐경색, 뇌색전증, 신장색전증, 혈전색전증 및 지주막하 출혈 후의 병적 증상, 경피적 관상동맥 성형술(PTCA) 및 스텐트(stent) 삽입 시의 혈전 생성, 스텐트 설치 후의 재협착, 카테터 혈전성 폐색 또는 재폐색, 급성 관상동맥증후군, TIA(일과성 뇌허혈 발작 또는 급성 뇌혈관 증후군), 심부전증, 허혈성 병인에 의한 가슴통증, X 증후군 및 진성당뇨병으로 구성된 군으로부터 선택되는 것을 예방 또는 치료하기 위한 의약 조성물. The method of claim 1, wherein myocardial infarction, angina pectoris, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, peripheral vascular or deep vein thrombosis, arterial thrombosis of any blood vessel, venous thrombosis, ischemic cerebral infarction, Arteriosclerosis, hypertension, pulmonary hypertension, cerebral infarction, stroke, chronic arterial occlusion, pulmonary infarction, cerebral embolism, renal embolism, thromboembolism and pathological symptoms after subarachnoid hemorrhage, thrombus during percutaneous coronary angioplasty (PTCA) and stent insertion Group consisting of production, restenosis after stent placement, catheter thrombotic occlusion or redo occlusion, acute coronary syndrome, transient cerebral ischemic attack or acute cerebrovascular syndrome (TIA), heart failure, chest pain due to ischemic etiology, syndrome X and diabetes mellitus A pharmaceutical composition for the prophylaxis or treatment of being selected from.
  7. 제1항 내지 5항 중 어느 한 항의 조성물로 제조된, 경질 및 연질 캅셀제, 정제, 당의정, 필름코팅정, 나정, 장용정, 산제, 현탁제, 시럽제 및 주사제로 구성된 군으로부터 선택된 혈소판 응집 억제용 또는 혈전용해용 의약제제. For inhibiting platelet aggregation selected from the group consisting of hard and soft capsules, tablets, dragees, film-coated tablets, uncoated tablets, enteric tablets, powders, suspensions, syrups and injections prepared from the composition of any one of claims 1 to 5 or Thrombolytic drugs.
  8. 이부딜라스트 및 트리플루살을 포함하는 것을 특징으로 하는 혈소판 응집 억제용 또는 혈전용해용 키트.Platelet aggregation inhibition or thrombolysis kit comprising ibudilast and triflusal.
  9. 이부딜라스트 및 트리플루살을 포함하는 조성물을 사용하여 혈소판 응집의 억제 또는 혈전을 용해하는 방법.A method of inhibiting platelet aggregation or dissolving a thrombus using a composition comprising ibudilast and triflusal.
PCT/KR2011/002267 2010-04-01 2011-04-01 Pharmaceutical composition for inhibiting platelet aggregation or for thrombolysis WO2011122899A2 (en)

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WO2015030543A1 (en) * 2013-08-30 2015-03-05 한국한의학연구원 Composition containing mulberry leaf alcohol extract as active ingredient for preventing and treating thrombotic diseases
CN108703971A (en) * 2017-07-11 2018-10-26 南华大学 The comparable purposes taken charge of it and be used to prepare antithrombotic reagent of inverase
WO2021061554A1 (en) * 2019-09-23 2021-04-01 Medicinova, Inc. Ibudilast oral formulations and methods of using same

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Publication number Priority date Publication date Assignee Title
WO2015030543A1 (en) * 2013-08-30 2015-03-05 한국한의학연구원 Composition containing mulberry leaf alcohol extract as active ingredient for preventing and treating thrombotic diseases
CN108703971A (en) * 2017-07-11 2018-10-26 南华大学 The comparable purposes taken charge of it and be used to prepare antithrombotic reagent of inverase
CN108703971B (en) * 2017-07-11 2023-04-07 南华大学 Application of anti-HIV (human immunodeficiency virus) medicament, namely, cobicistat, in preparation of antithrombotic medicament
WO2021061554A1 (en) * 2019-09-23 2021-04-01 Medicinova, Inc. Ibudilast oral formulations and methods of using same
US11865214B2 (en) 2019-09-23 2024-01-09 Medicinova, Inc. Ibudilast oral formulations and methods of using same

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