WO2022240218A1 - Composition pharmaceutique de régulation de la tension artérielle chez un sujet souffrant d'accident ischémique cérébral ou d'attaque ischémique transitoire - Google Patents

Composition pharmaceutique de régulation de la tension artérielle chez un sujet souffrant d'accident ischémique cérébral ou d'attaque ischémique transitoire Download PDF

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WO2022240218A1
WO2022240218A1 PCT/KR2022/006838 KR2022006838W WO2022240218A1 WO 2022240218 A1 WO2022240218 A1 WO 2022240218A1 KR 2022006838 W KR2022006838 W KR 2022006838W WO 2022240218 A1 WO2022240218 A1 WO 2022240218A1
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blood pressure
mmhg
pharmaceutical composition
fimasartan
stroke
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PCT/KR2022/006838
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English (en)
Korean (ko)
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김봉석
홍명숙
정승희
조아영
김종연
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주식회사 보령
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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
    • A61K31/495—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • the present invention relates to a pharmaceutical composition for controlling blood pressure in a subject having ischemic stroke or transient ischemic attack, comprising fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof. will be.
  • Stroke is one of the health threats to the world's population and is the third leading cause of death after heart disease and cancer.
  • the annual death rate (per 100,000 population) due to stroke in Korea is 50.3 (2013), which has decreased considerably compared to the past (75.3 in 2003), the total stroke incidence rate is rather increasing.
  • the annual stroke incidence rate per 100,000 people in Korea is 216, which is the highest among Asian countries, following Taiwan (329/100,000), Pakistan (250/100,000), and China (219/100,000). shows this high
  • Korea is a country with a very rapid aging rate along with Japan among OECD countries, and considering that one of the major risk factors for stroke is old age, the burden of disease due to this is expected to increase considerably.
  • Stroke is divided into ischemic stroke and hemorrhagic stroke. While the rate of hemorrhagic stroke is on the decline, the rate of ischemic stroke, which has a high incidence rate, gradually increases as age increases. ), the rate of stroke due to large-vessel atherosclerosis (36%) was higher.
  • TIA transient ischemic attack
  • the most common risk factor was hypertension (64%), followed by smoking (33%) and diabetes (30%).
  • previous history of stroke (20%) were identified as major risk factors.
  • the risk of stroke increases as the blood pressure increases.
  • hypertension is a disease that can be managed with a variety of effective medications, and standard clinical guidelines recommend maintaining blood pressure at a level of 140/90 mmHg (135/80 mmHg for diabetics) and checking blood pressure at least once every two years. have.
  • a 10 mmHg decrease in systolic blood pressure reduced the risk of stroke by about one-third in patients aged 60 to 79 years.
  • hypertension treatment is important not only for the primary prevention of stroke but also for reducing the recurrence of stroke and major vascular disease after the acute phase, and appropriate blood pressure control is indicated for all patients with ischemic stroke regardless of their history of hypertension.
  • Patent Document 1 Korean Patent Registration No. 0354654
  • Patent Document 2 Korean Patent Application No. 10-2013-0118792
  • An object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof for controlling blood pressure in subjects with post-acute ischemic stroke or transient ischemic attack. is to provide
  • An object of the present invention is to provide a use of fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof for controlling blood pressure in subjects with post-acute ischemic stroke or transient ischemic attack.
  • An object of the present invention is to provide a blood pressure control method for subjects with ischemic stroke or transient ischemic attack after the acute phase of fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof.
  • An object of the present invention is to provide a use of fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a hydrate or solvate thereof for the treatment of hypertension in subjects with post-acute ischemic stroke or transient ischemic attack.
  • An object of the present invention is to provide a method for treating hypertension in subjects with post-acute ischemic stroke or transient ischemic attack of fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof for controlling blood pressure in subjects with post-acute ischemic stroke or transient ischemic attack. is to do
  • the pharmaceutical composition according to the present invention comprising pimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof, is administered to subjects with post-acute ischemic stroke or transient ischemic attack
  • a pharmaceutical composition for blood pressure control in, administered to a subject having a systolic blood pressure of 140 mmHg or more or a diastolic blood pressure of 90 mmHg or more within 5 days to 93 days from the date of symptom onset of ischemic stroke or transient ischemic attack.
  • fimasartan a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof has a systolic blood pressure of 140 mmHg or more within 93 days from the 5th day from the onset of ischemic stroke or transient ischemic attack symptoms.
  • administration may be started to a subject having a diastolic blood pressure of 90 mmHg or higher, and may be administered for a certain period of time after the start of administration.
  • the pharmaceutically acceptable salt may be fimasartan potassium salt.
  • the hydrate may be fimasartan potassium salt trihydrate.
  • the fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof according to any one of (1) to (5) above can be administered orally.
  • the daily dose of the fimasartan, pharmaceutically acceptable salt thereof, stereoisomer thereof, or hydrate or solvate thereof according to any one of (1) to (6) above is about 15 mg to about 120 mg.
  • the fimasartan, pharmaceutically acceptable salt thereof, stereoisomer thereof, or hydrate or solvate thereof according to any one of (1) to (7) above may be administered once a day. .
  • the fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof according to any one of (1) to (11) above can reduce the stroke recurrence rate.
  • the fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof according to any one of (1) to (12) above can reduce the incidence of cardiovascular accidents. .
  • the cardiovascular accident according to (13) above may be selected from the group consisting of acute myocardial infarction, hospitalization due to heart failure and unstable angina, coronary and peripheral artery revascularization, and death.
  • the ischemic stroke may be caused by causes such as large-vessel atherosclerosis, small-vessel occlusion, cardiogenic embolism, arterial dissection, cerebrovascular vasculitis, moyamoya disease, and polycythemia vera.
  • Ischemic stroke or transient ischemic attack after the acute phase means from the 5th day after the onset of symptoms of ischemic stroke or transient ischemic attack, preferably from the 8th day after the onset of symptoms.
  • the symptom onset time point may be based on the last normal time. For example, if the person was normal before going to bed but had symptoms after waking up in the morning, the bedtime may be recorded as the symptom onset time.
  • the blood pressure control means that the systolic blood pressure of the subject having a systolic blood pressure of 140 mmHg or more or a diastolic blood pressure of 90 mmHg or more is lowered to less than 140 mmHg or less than 90 mmHg.
  • the pharmaceutical composition may be administered to a subject having an ischemic stroke within 87 days from the 5th day from the onset of symptoms. Preferably, it can be administered within 87 days from day 8.
  • the pharmaceutical composition may be administered to a subject having a transient ischemic attack within 93 days from the 5th day from the onset of symptoms. Preferably, it can be administered within 93 days from day 8.
  • the subject may not be administered another antihypertensive agent for blood pressure control purposes prior to the administration.
  • the pharmaceutical composition is administered to a subject having an ischemic stroke or transient ischemic attack after an acute phase having a systolic blood pressure of 140 mmHg or more or a diastolic blood pressure of 90 mmHg or more, thereby controlling the subject's systolic blood pressure to less than 140 mmHg and diastolic blood pressure to less than 90 mmHg.
  • the pharmaceutical composition is administered to a subject having an ischemic stroke or transient ischemic attack after an acute phase having a systolic blood pressure of 140 mmHg or more or a diastolic blood pressure of 90 mmHg or more, thereby reducing the subject's systolic blood pressure to less than 140 mmHg and diastolic blood pressure at 24 weeks of administration. It can be adjusted to less than 90 mmHg.
  • the systolic and diastolic blood pressure reduction rates may be higher over the course of the administration period, compared to the case where the blood pressure is not controlled as described above.
  • the pharmaceutical composition is administered to a subject having an ischemic stroke or transient ischemic attack after an acute phase in which the systolic blood pressure is 140 mmHg or more or the diastolic blood pressure is 90 mmHg or more, thereby improving the degree of disability or dependence (modified Rankin Scale; mRS, Modified Rankine Scale).
  • modified Rankin Scale modified Rankin Scale
  • mRS Modified Rankine Scale
  • the mRS score is a commonly used scale to evaluate the degree of disability or dependence in daily activities of stroke patients.
  • the pharmaceutical composition may be administered to a subject having an ischemic stroke or a transient ischemic attack after an acute phase having a systolic blood pressure of 140 mmHg or more or a diastolic blood pressure of 90 mmHg or more, thereby reducing the stroke recurrence rate.
  • the pharmaceutical composition can reduce the incidence of cardiovascular accidents by being administered to subjects having ischemic stroke or transient ischemic attack after the acute phase with systolic blood pressure of 140 mmHg or more or diastolic blood pressure of 90 mmHg or more. It may include hospitalization, coronary artery, peripheral artery revascularization and death due to the acute myocardial infarction, heart failure and unstable angina.
  • the subject refers to animals including humans, and includes, for example, mice, rats, other rodents, rabbits, dogs, pigs, cats, cows, sheep, horses, primates and humans. It may be a mammal, preferably a primate or a human, more preferably a human.
  • the fimasartan may be a compound represented by Formula 1 below.
  • the pharmaceutically acceptable salt refers to inorganic acid salts, organic acid salts, and metal salts commonly used by pharmaceutical manufacturers to prepare pharmaceuticals, and examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid.
  • organic acids include citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholineethanesulfonic acid , Camphorsulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, calacturonic acid, emboic acid, glutamic acid, aspartic acid, adipic acid, or camsylic acid may be used, and the metal is sodium, Potassium, calcium or magnesium may be used.
  • the salt of fimasartan may preferably be a fimasartan potassium salt, hydrochloride salt, calcium salt, sulfate salt, adipate salt, camsylate salt or besylate salt, more preferably a potassium salt.
  • fimasartan potassium salt hydrochloride salt, calcium salt, sulfate salt, adipate salt, camsylate salt or besylate salt, more preferably a potassium salt.
  • these are commercially available and can be prepared by a known method (eg, Republic of Korea Patent Registration No. 0354654).
  • the hydrate may include a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • the solvate may include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • the solvent refers to a common organic solvent used in the production of organic compounds, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-acetate, acetone, acetic acid, no Sol, tetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, dimethyl sulfoxide, pentane, heptane, etc., but examples thereof are limited to the solvates of the present invention. It is not.
  • the hydrate and solvate may contain water or a solvent in a ratio of about 0.25 to about 10 moles per mole of fimasartan potassium, for example, about 0.5 mole, about 1 mole, It may be about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc., and more preferably about 1 mol or about 3 mol of water per 1 mol of fimasartan potassium.
  • the pharmaceutical composition may include fimasartan potassium salt monohydrate or fimasartan potassium salt trihydrate, preferably fimasartan potassium salt trihydrate.
  • the pharmaceutical composition may include about 5% by weight to about 60% by weight of fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof based on the total weight of the composition, preferably Preferably, it may include about 10% by weight to about 50% by weight.
  • the pharmaceutical composition may further include a pharmaceutically acceptable additive.
  • pharmaceutically acceptable means physiologically acceptable and, when administered to humans, usually does not cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions. As for commonly used, reference may be made to Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA.
  • the additives may be carriers, excipients, extenders, antioxidants, buffers, fillers, anti-agglomerating agents, lubricants, wetting agents, flavoring agents, emulsifiers, suspending agents, surfactants and preservatives.
  • the additives include lactose, dextrose, calcium silicate, corn starch, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl Cellulose, Polyvinylpyrrolidone, Water, Methylhydroxybenzoate, Propylhydroxybenzoate, Talc, Stearic Acid, Magnesium Stearate, Calcium Stearate, Mineral Oil, Saline, Glucose Solution, Pseudosugar Solution, Alcohol, Glycol , ether (eg polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, or a mixture thereof.
  • the additives that may be included in the composition according to the present invention are not limited to the materials listed above, and these are only examples.
  • the pharmaceutical composition of the present invention may be formulated according to a conventional method, and may be prepared as a preparation for oral administration or a preparation for parenteral administration.
  • the pharmaceutical composition of the present invention may be formulated for oral administration.
  • the preparation for oral administration may be a solid preparation such as tablets, pills, powders, granules, capsules, etc., or liquid preparations such as suspensions, solutions for internal use, emulsions, syrups, etc., preferably solid preparations. It can be one, more preferably it can be a tablet.
  • additives used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate , gelatin, talc, and the like.
  • compositions When the pharmaceutical composition is formulated as a liquid formulation for oral administration, various additives such as simple diluents such as water, liquid, and paraffin, wetting agents, sweeteners, fragrances, preservatives, preservatives, and coloring agents may be added to the pharmaceutical composition to be formulated.
  • the additives include water, saline, aqueous glucose solution, similar aqueous sugar solution, alcohol, glycol, ether (eg polyethylene glycol 400), oil, fatty acid, fatty acid ester, glycerine Ride etc. are mentioned.
  • the content of the additives included in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within the range of content used in conventional formulations.
  • the pharmaceutical composition comprises fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in an amount of about 15 mg to about 120 mg, or about 30 mg to about 120 mg of fimasartan. mg, about 30 mg, about 60 mg or about 120 mg.
  • the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied), and the dosage is the patient's weight, age, sex, health
  • the range may vary depending on the condition, diet, administration time, administration method, administration period or interval, excretion rate, constitutional specificity, nature of the preparation, severity of the disease, and the like.
  • the dosage of fimasartan per day may be about 1 mg to about 240 mg, preferably about 30 mg to about 180 mg, orally administered.
  • Application may be applied once a day or divided into several times.
  • the daily dosage of the fimasartan, its pharmaceutically acceptable salt, its stereoisomer or its hydrate or solvate in the pharmaceutical composition is about 15 mg to about 120 mg, about 30 mg to about 120 mg, about 30 mg to about 60 mg, about 30 mg, about 60 mg or about 120 mg.
  • Fimasartan of the pharmaceutical composition, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof may be administered in an increased amount within the above dosage range during the administration period.
  • the fimasartan, its pharmaceutically acceptable salt, its stereoisomer or its hydrate or solvate is about 15 mg to about 120 mg, about 30 mg to about 30 mg to the subject. It may be administered once a day at a dose of about 120 mg, about 30 mg to about 60 mg, about 30 mg, about 60 mg or about 120 mg.
  • the fimasartan, its pharmaceutically acceptable salt, its stereoisomer or its hydrate or solvate is about 15 mg to about 120 mg, about 30 mg to about 30 mg to the subject. It may be administered once a day for about 24 weeks at a dose of about 120 mg, about 30 mg to about 60 mg, about 30 mg, about 60 mg or about 120 mg.
  • the pharmaceutical composition may further contain an active ingredient having other pharmacological activity in addition to the fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • composition of the present invention may further include an antihypertensive agent, a diuretic agent, a hyperlipidemia agent, an antiobesity agent, or a diabetes agent in addition to the fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • the composition of the present invention contains amlodipine, nifedipine, verapamil, diltiazem, nicardipine, lercardipine, Atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, simvastatin, rosuvastatin, nicotinic acid, theophylline, caffeine, theobromine, aminophylline, hydrochlorothiazide, bendroflumethiazide, alogliptin, saxagl liptin, sitagliptin, metformin, exenatide, rosiglitazone, pioglitazone, tolbutamide, troglitazone, leptin, ephedrine, fenfluramine, fluoxetine, and the like.
  • composition of the present invention may be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response modifiers for blood pressure control in subjects with post-acute ischemic stroke or transient ischemic attack (TIA).
  • TIA transient ischemic attack
  • the pharmaceutical composition of the present invention is administered alone and may not be administered in combination with other antihypertensive agents for blood pressure control in subjects with post-acute ischemic stroke or transient ischemic attack (TIA).
  • TIA transient ischemic attack
  • the present invention is directed to administering a pharmaceutical composition containing fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to a subject suffering from ischemic stroke or transient ischemic attack (TIA) after the acute phase, to treat the subject
  • TIA ischemic stroke or transient ischemic attack
  • Provides a method for regulating blood pressure in The subject has a systolic blood pressure of 140 mmHg or more or a diastolic blood pressure of 90 mmHg or more, within 93 days from the 5th day to the onset of symptoms of an ischemic stroke or transient ischemic attack.
  • the present invention provides use of fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for controlling blood pressure in a subject having ischemic stroke or transient ischemic attack (TIA) after the acute phase.
  • the subject has a systolic blood pressure of 140 mmHg or more or a diastolic blood pressure of 90 mmHg or more, within 93 days from the 5th day to the onset of symptoms of an ischemic stroke or transient ischemic attack.
  • the present invention has an ischemic stroke or transient ischemic attack (TIA) after the acute phase and has a systolic blood pressure of 140 mmHg or more or a diastolic blood pressure of 90 mmHg within 93 days from the 5th day after the onset of symptoms of the ischemic stroke or transient ischemic attack.
  • TIA ischemic stroke or transient ischemic attack
  • fimasartan a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof for the manufacture of a medicament for controlling blood pressure in a subject with abnormalities.
  • the present invention has an ischemic stroke or transient ischemic attack (TIA) after the acute phase and has a systolic blood pressure of 140 mmHg or more or a diastolic blood pressure of 90 mmHg within 93 days from the 5th day after the onset of symptoms of the ischemic stroke or transient ischemic attack.
  • TIA ischemic stroke or transient ischemic attack
  • fimasartan a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof in treating hypertension in a subject with abnormalities.
  • the present invention has an ischemic stroke or transient ischemic attack (TIA) after the acute phase, and within 93 days from the 5th day after the onset of symptoms of the ischemic stroke or transient ischemic attack, and the systolic blood pressure is 140 mmHg or more or the diastolic blood pressure is 90 mmHg
  • TIA ischemic stroke or transient ischemic attack
  • the systolic blood pressure is 140 mmHg or more or the diastolic blood pressure is 90 mmHg
  • fimasartan a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof for the preparation of a drug for treating hypertension in a subject with abnormalities.
  • the present invention is directed to administering a pharmaceutical composition containing fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to a subject suffering from ischemic stroke or transient ischemic attack (TIA) after the acute phase to treat the subject
  • TIA ischemic stroke or transient ischemic attack
  • a method for treating hypertension in The subject has a systolic blood pressure of 140 mmHg or more or a diastolic blood pressure of 90 mmHg or more, within 93 days from the 5th day to the onset of symptoms of an ischemic stroke or transient ischemic attack.
  • the pharmaceutical composition according to the present invention comprises fimasartan, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a hydrate or solvate thereof, for those suffering from ischemic stroke or transient ischemic attack (TIA) after the acute phase. Blood pressure in a subject can be effectively controlled.
  • the pharmaceutical composition according to the present invention can reduce the degree of disability or dependence and the recurrence rate of stroke in the subject, and reduce the incidence of cardiovascular accidents.
  • 1 is a graph showing the rate of blood pressure control by fimasartan alone or combined administration therapy, and is a graph presented according to LOCF (Last Observation Carried Forward) treatment.
  • 3 is an analysis graph according to raw data and LOCF treatment of diastolic blood pressure at 24 weeks compared to the baseline time point (baseline).
  • Figure 4 is a graph showing the distribution of systolic blood pressure at baseline, 4 weeks of enrollment, 12 weeks of enrollment, and 24 weeks of enrollment.
  • Figure 5 is a graph showing the distribution of diastolic blood pressure at baseline, 4 weeks of enrollment, 12 weeks of enrollment, and 24 weeks of enrollment.
  • Figure 6 is a graph of change in mean mRS during the 24-week study period.
  • the main purpose of this study was to evaluate the rate of blood pressure control by tracking patients receiving pimasartan-based antihypertensive therapy among patients with post-acute ischemic stroke or transient ischemic attack (TIA). This is a multicenter, longitudinal observational study.
  • the main purpose of this study was to administer fimasartan-based antihypertensive treatment to subjects who had not started antihypertensive treatment before the time of enrollment in this study among patients who had a stroke/TIA for at least 5 days to 3 months. If so, it is to check whether blood pressure is controlled at 24 weeks.
  • Voluntary consent for this study was obtained from patients who visited or were hospitalized at the clinical research institute, and patients who provided written consent were given a subject number and the inclusion/exclusion criteria were confirmed. 1,035 subjects who met the inclusion/exclusion criteria were sequentially enrolled, and the following study-related information, including information on pimasartan prescription, was collected when the subjects who met the conditions visited the institution during the study period.
  • the observation period for each subject was about 6 months (24 weeks ⁇ 4 weeks), and the entire study period (registration of the first subject to end of observation of the last subject) was planned to be about 1 year and 6 months.
  • This study is an observational study, and in principle, the number of visits and intervals of subjects are determined under the clinical judgment of the researcher. 4 weeks), if the above study-related data were available, they were collected in the case report.
  • an angiotensin receptor blocker (ARB)
  • beta blocker and CCB for heart rate control in patients with atrial fibrillation
  • hemorrhagic stroke e.g., intracerebral hemorrhage, subarachnoid hemorrhage
  • antihypertensive drugs are administered to patients after the acute phase after a stroke/TIA event when they recover neurological function or when they are neurologically stable and do not have additional cerebral infarction.
  • antihypertensive drugs are administered to patients after the acute phase after a stroke/TIA event when they recover neurological function or when they are neurologically stable and do not have additional cerebral infarction.
  • the daily dose of fimasartan administered to each subject during the entire study period ranged from 15 mg to 120 mg, and the average (standard deviation) dose was 52.64 (25.03) mg (Table 4).
  • the number of subjects with daily doses of 30 mg, 60 mg, and 120 mg was 630, 626, and 134, respectively. In most cases, 30 mg or 60 mg was administered. received. Based on the median total administration period for each dose of fimasartan, the duration of administration of 30 mg/day was relatively short at 91 days, and the median duration of administration of 60 mg/day or 120 mg/day was 140 days and 133 days, respectively. It was (Table 5).
  • the median daily dose of fimasartan administered on the base visit day was 30 mg, and the median daily dose on subsequent visit days was maintained at 60 mg, and the daily dose range of fimasartan across all visits was 15 mg to 120 mg.
  • the mean (standard deviation) of the daily dose of fimasartan administered on the day of the baseline visit was 43.63 (17.92) mg, and from 4 weeks thereafter, the mean daily dose exceeded 50 mg, showing a tendency to increase little by little.
  • the mean (standard deviation) of daily doses of fimasartan administered on the 24-week visit and final visit were 56.09 (27.89) mg and 54.40 (28.03) mg, respectively.
  • Safety evaluation target group All subjects who received pimasartan administration after enrollment in this study and were followed up for safety were included.
  • the safety evaluation target group was used when analyzing efficacy endpoints related to demographic information, medical history, prior/concomitant medications, baseline characteristics, antihypertensive drug administration information, adverse events, and prognosis evaluation.
  • Efficacy evaluation target group Subjects who satisfied the inclusion/exclusion criteria among the safety evaluation study subjects and whose blood pressure information was collected at least one of the 4, 12, and 24-week time points in addition to the baseline blood pressure information were included. Among the efficacy evaluation variables, the efficacy evaluation target group was used for blood pressure control rate, blood pressure descriptive statistics at each time point, and mRS descriptive statistics.
  • the frequency and percentage and 95% confidence interval were obtained for deaths due to cardiovascular diseases, including stroke.
  • the average, standard deviation, median, minimum, and maximum values of the period from the onset of the first stroke symptom to death due to cardiovascular disease were obtained.
  • the median survival time and 95% confidence interval of the survival curve and survival time were presented using the Kaplan-Meier estimation method.
  • the number of subjects included in the analysis was 1,026, and 951 subjects were included in the analysis related to blood pressure change and mRS.
  • 65.98% (677/1,026) of the subjects were male, and male subjects were enrolled about twice as many as female subjects.
  • the mean (standard deviation) age was 64.48 (12.22) years old, and about two-thirds were over 60 (676 out of 1,026).
  • 92.30% (947/1,026) of the subjects had ischemic stroke, and large-vessel atherosclerosis (36.65%) and small-vessel occlusion (38.89%) were the most common.
  • the proportions of subjects with confirmed cardiogenic embolism and ischemic stroke due to unknown cause were 5.75% and 7.99%, respectively.
  • TIA patients accounted for 7.41% (76/1,026).
  • the duration of hospitalization for ischemic stroke/TIA ranged from 1 to 157 days (median: 7 days).
  • the National Institutes of Health Stroke Scale (NIHSS) score ranged from 0 to 28 (median: 2 points), and 76.80% (788/1,026) of the subjects had an NIHSS score of 4 or less.
  • the proportion of subjects with an NIHSS score of 16 or higher was 1.36% (14/1,026).
  • the mean (standard deviation) of systolic and diastolic blood pressure at baseline was 162.57 (16.11) mmHg and 92.13 (12.32) mmHg, respectively.
  • the systolic blood pressure ranged from 121 to 222 mmHg, and at least 75% of the subjects had a systolic blood pressure of 150 mmHg or more.
  • the diastolic blood pressure ranged from 60 to 148 mmHg, and more than 50% of the subjects had a diastolic blood pressure of 91 mmHg or higher (Table 9).
  • Subjects diagnosed with ischemic stroke started receiving fimasartan between 5 and 87 days (median: 10 days) from the onset of symptoms, and those diagnosed with TIA between 5 and 93 days (median: 10 days) after symptom onset. 15 days), administration of fimasartan was started. Excluding 100 subjects (about 10%), the remaining 90.25% of the subjects received concomitant medications other than fimasartan during the study period, and the tendency of concomitant drug administration was similar to that of the previous drug administration.
  • lipid-lowering drugs and antithrombotic drugs were the most common concomitant drugs, and the rates of users of these drugs were 91.62% (940/1,026) (double counting of single and combination drug users) and 81.29% (834/1,026), respectively.
  • the proportions of subjects who were prescribed insulin (/analog) or hypoglycemic drugs other than insulin as concomitant drugs were 2.05% (21/1,026) and 23.49% (241/1,026), respectively.
  • the 24-week blood pressure control rate (primary endpoint), including the 24-week blood pressure control rate (primary endpoint), which was considered for the calculation of the number of subjects, the blood pressure control rate, measured blood pressure values and changes included in the secondary endpoints, and the evaluation variables for mRS and change were analyzed by the efficacy evaluation target group. , and all other secondary endpoints were analyzed by the safety evaluation target group.
  • Table 10 shows the percentage of subjects with blood pressure (systolic/diastolic) less than 140/90 mmHg at 24 weeks after fimasartan-based antihypertensive treatment in patients with ischemic stroke/TIA.
  • the blood pressure control rate at 24 weeks after enrollment was 67.31% (558/829), and the 95% confidence interval was 64.00% to 70.50%.
  • the 24-week blood pressure control rate was 65.93% (627/951), and the 95% confidence interval was 62.82. % ⁇ 68.94%, which was similar to the results of analyzing the data as they were without LOCF treatment.
  • the 24-week blood pressure control rate of subjects who were taking other antihypertensive drugs was 64.29% (18/28), and the 95% confidence interval was 44.07% to 81.36%, showing a rather wide distribution, which was only in 28 subjects. should be considered not
  • Blood pressure control rates at 4, 12, and 24 weeks for subjects treated with fimasartan alone were 55.23%, 67.25%, and 68.58%, respectively (no LOCF applied).
  • the rate of blood pressure control at 4 weeks, 12 weeks, and 24 weeks of subjects who took other antihypertensive drugs for blood pressure control was 35.46%, 50.33%, and 64.93%, respectively, compared to subjects who received only fimasartan at all time points. showed a somewhat lower blood pressure control rate (Table 12, Figure 1).
  • “subject reaching target blood pressure (%)” on the y-axis means blood pressure control rate (%).
  • the upper limit of the 95% confidence interval for the blood pressure control rate of the other antihypertensive drug combination group was smaller than the lower limit of the 95% confidence interval of the pimasartan monotherapy group, showing a smaller value than the lower limit of the 95% confidence interval of the pimasartan monotherapy group. It was confirmed that the blood pressure control rate of the group was significantly lower than that of the fimasartan monotherapy group.
  • the 95% confidence interval of the blood pressure control rate of the fimasartan monotherapy group was 64.48% to 72.47%, and the other antihypertensive drug combination group was 59.11% to 70.44%, which is still the blood pressure control rate of the other antihypertensive drug combination group. rate was estimated to be relatively low.
  • the upper limit of the 95% confidence interval for the blood pressure control rate of the other antihypertensive drug combination group was smaller than the lower limit of the 95% confidence interval of the pimasartan monotherapy group, showing a smaller value than the lower limit of the 95% confidence interval of the pimasartan monotherapy group. It was confirmed that the blood pressure control rate of the group was significantly lower than that of the fimasartan monotherapy group.
  • the 95% confidence interval for the blood pressure control rate of the fimasartan monotherapy group was 64.35% to 71.77%, and the other antihypertensive drug combination group was 55.99% to 66.92%, which is still the blood pressure control rate of the other antihypertensive drug combination group. rate was estimated to be relatively low.
  • the blood pressure control rates at 4 and 12 weeks after enrollment were 48.61% (95% confidence interval: 45.36% to 51.87%) and 61.37% (95% confidence interval: 58.05% to 64.61%), respectively, at 4 weeks after enrollment. Compared to , the blood pressure control rate increased significantly at 12 weeks (LOCF was not applied).
  • Tables 14 and 15 show the results of analyzing the raw data without LOCF treatment for descriptive statistics and change from baseline in blood pressure at 24 weeks from baseline.
  • the results analyzed by applying LOCF are presented in Tables 16 and 17.
  • systolic and diastolic blood pressure data at each time point were presented in a box-plot graph (FIGS. 2 and 3).
  • the analysis results of the raw data without LOCF treatment and the analysis result of applying LOCF were almost the same.
  • the baseline systolic blood pressure of the efficacy evaluation subjects ranged from 121 to 222 mmHg, and the average (standard deviation) was 162.34 (16.04) mmHg.
  • systolic blood pressure at 24 weeks ranged from 88 to 192 mmHg, and the mean (standard deviation) was 132.77 (15.64) mmHg.
  • systolic blood pressure at 24 weeks ranged from 79 to 192 mmHg, and the mean (standard deviation) was 132.88 (16.18) mmHg.
  • Diastolic blood pressure analysis The baseline diastolic blood pressure of the efficacy evaluation subjects ranged from 60 to 148 mmHg, and the average (standard deviation) was 92.21 (12.44) mmHg. In the case of raw data analysis, the diastolic blood pressure at 24 weeks ranged from 47 to 122 mmHg, and the mean (standard deviation) was 78.50 (10.94) mmHg. In the case of the LOCF application analysis, the diastolic blood pressure at 24 weeks ranged from 47 to 122 mmHg, and the mean (standard deviation) was 78.51 (11.00) mmHg.
  • the baseline mean (standard deviation) systolic blood pressures of subjects whose blood pressure was controlled at 24 weeks (control group) and subjects whose blood pressure was not controlled at 24 weeks (non-control group) were 161.14 (15.01) mmHg and 165.20 (17.45), respectively. ) mmHg, the average of the non-control group was about 4 mmHg higher than that of the control group. However, the average difference in systolic blood pressure between the control group and the non-control group increased over time, reaching about 8 mmHg (136.73 mmHg vs. 144.74 mmHg) at 4 weeks and about 10 mmHg (130.66 mmHg vs. 140.60 at 12 weeks).
  • the systolic blood pressure may tend to increase again to 140 mmHg or more mainly at the 12th and 24th weeks.
  • the analysis results for the distribution of diastolic blood pressure also showed a similar trend.
  • the proportion of subjects with a diastolic blood pressure of 100 mmHg or higher at baseline was higher in the non-control group than in the control group (21.86% vs. 32.84%).
  • the control group the subjects moved from the 90 mmHg or higher ranges to the lower blood pressure ranges over time, and at 24 weeks, all subjects were distributed in the lower 90 mmHg range.
  • the non-control group the proportion of subjects with less than 90 mmHg increased slightly until week 12 (66.17% [week 4], 73.03% [week 12]), but at week 24, this ratio decreased to 54.24% ( Table 19, Figure 5).
  • Modified-Rankin scale (mRS) analysis was performed only on 829 patients, excluding 122 patients who had no blood pressure results at 24 weeks.
  • Tables 20 and 21 show the results without applying LOCF for the descriptive statistics of mRS at each study time point and the change from baseline, and the results of analysis with LOCF applied are presented in Tables 22 and 23.
  • the average value of mRS at each time point of all subjects is shown in FIG. 6 .
  • the results of the LOCF analysis and the analysis of the original data without LOCF treatment were almost the same.
  • Table 23 mRS change (LOCF) at 4 weeks, 12 weeks and 24 weeks from baseline
  • mRS ranged from 0 to 5, with a median of 1. At least 75% of the subjects had a baseline mRS score of 2 or less. At all subsequent time points, the median value of mRS was 1 point, and the 75th percentile was 1 point, the same as the median value, indicating additional functional improvement compared to baseline in some subjects.
  • the daily dose of fimasartan administered to each subject ranged from 15 mg to 120 mg, and the average (standard deviation) dose was 52.64 (25.03) mg.
  • the number of subjects for which the daily dose of fimasartan was recorded as 30 mg, 60 mg, and 120 mg was 630, 626, and 134, respectively. In most cases, 30 mg or 60 mg was administered.
  • fimasartan was administered, and in all three cases, the median duration of fimasartan administration (169 days or 170 days) was within the range of the follow-up period (140 to 196 days) of this study. That is, in most cases (at least 50%), it was determined that the administration of fimasartan was stable during the study period regardless of the dosage form or combination of other antihypertensive drugs.
  • 32.16% (330/1,026) of the safety evaluation target group were prescribed other antihypertensive drugs for the purpose of blood pressure control.
  • the most commonly prescribed other antihypertensive drugs were calcium channel blockers (vasoactive CCB 236 patients, cardiac CCB 1 patient), and other diuretics (thiazide-type 57 patients, low-ceiling diuretics other than thiazide 14 patients, high-ceiling diuretics 5 patients). , potassium-sparing diuretics 5), other ARB drugs (ARB and CCB/diuretic combination 26 patients, ARB single drug 24 patients) and beta-blockers (39 patients), etc., and 1 subject received ACEI. .
  • the stroke recurrence rate during the study period was 2.73% (28/1,026) [95% confidence interval: 1.82% to 3.92%].
  • subjects with large artery atherosclerosis had the highest recurrence rate at 5.05%.
  • two strokes one hemorrhagic stroke and one ischemic stroke
  • the odds of other cardiovascular events in patients with controlled blood pressure were about 90% lower than those with uncontrolled blood pressure.
  • the number of subjects included in the analysis was 1,026, and 951 subjects were included in the analysis related to blood pressure change and mRS.
  • the rate of blood pressure control ( ⁇ 140/90 mmHg) was 67.31% [95% confidence interval: 64.00% to 70.50%].
  • Subjects whose blood pressure was not controlled showed a tendency for systolic blood pressure to increase again to 140 mmHg or more at 12 and 24 weeks.
  • the range of mRS at baseline was 0 to 5 points (median: 1 point, 75th percentile: 2 points), and at all subsequent time points, both the median and 75th percentile of mRS were 1 point, and compared to baseline, some subjects Additional functional improvements were identified.

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Abstract

La présente invention concerne une composition pharmaceutique pouvant être administrée à un sujet qui présente un accident ischémique cérébral ou une attaque ischémique transitoire après une phase aiguë pour réguler efficacement la tension artérielle.
PCT/KR2022/006838 2021-05-14 2022-05-12 Composition pharmaceutique de régulation de la tension artérielle chez un sujet souffrant d'accident ischémique cérébral ou d'attaque ischémique transitoire WO2022240218A1 (fr)

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