WO2021251644A1 - Complex pharmaceutical preparation, for preventing or treating cardiovascular disease, comprising amlodipine, losartan and chlorthalidone in single-layer tablet - Google Patents

Complex pharmaceutical preparation, for preventing or treating cardiovascular disease, comprising amlodipine, losartan and chlorthalidone in single-layer tablet Download PDF

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WO2021251644A1
WO2021251644A1 PCT/KR2021/006285 KR2021006285W WO2021251644A1 WO 2021251644 A1 WO2021251644 A1 WO 2021251644A1 KR 2021006285 W KR2021006285 W KR 2021006285W WO 2021251644 A1 WO2021251644 A1 WO 2021251644A1
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Prior art keywords
amlodipine
pharmaceutically acceptable
losartan
chlorthalidone
combination formulation
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PCT/KR2021/006285
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French (fr)
Korean (ko)
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정진아
손한길
정민숙
임이랑
조혁준
최민종
임호택
김용일
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한미약품 주식회사
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Priority to MX2022015607A priority Critical patent/MX2022015607A/en
Priority to CN202180041395.8A priority patent/CN115666564A/en
Priority to CR20220664A priority patent/CR20220664A/en
Priority claimed from KR1020210064538A external-priority patent/KR20210152943A/en
Publication of WO2021251644A1 publication Critical patent/WO2021251644A1/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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a single-layered tablet combination formulation for the prevention or treatment of cardiovascular diseases, comprising amlodipine, losartan and chlorthalidone as active ingredients in a single-layered tablet, and more specifically, amlodipine, losartan and chlorthalidone in a low dose. It relates to a pharmaceutical combination formulation with improved dissolution rate, stability and productivity contained in a single-layer tablet.
  • cardiovascular diseases have a high prevalence and many chronic diseases that develop over a long period of time and continue to recur, so proper treatment management from the beginning is important.
  • a stepped care approach starting with single drug treatment, was preferred.
  • An increase in the number of patient visits to the hospital for addition, a decrease in patient compliance, and a failure to control blood pressure accordingly, and treatment inertia due to repeated up-titration and drug addition Even if it is not, it will be accepted) was a problem. Therefore, there is a clinical need for an effective cardiovascular disease treatment method that can replace the existing complex step-by-step treatment approach.
  • Combination formulations of drugs with different mechanisms of action show a superior effect in the prevention or treatment of hypertension and cardiovascular disease than the conventional single formulation, and reduce the side effects of each used drug and reduce the patient It has the advantage of increasing compliance.
  • the combination formulation is disclosed in Korean Patent Registration Nos. 1160151 and 1232296, etc., and is currently sold under the trade name of Amosartan.
  • Korean Patent Registration Nos. 1914930 and 1910902 discloses amlodipine and chlorthalidone in order to prevent a decrease in the dissolution rate of the drug due to losartan gelation.
  • a method for preparing a complex formulation is provided by separating the first mixed part containing and the second mixed part containing losartan.
  • One aspect is to provide a low-dose pharmaceutical combination formulation with improved dissolution rate, stability and productivity that can be used for the prevention or treatment of early cardiovascular disease.
  • Another aspect is to provide a method for preparing the combination formulation.
  • Another aspect is to provide a method for treating cardiovascular disease using the combination formulation.
  • One aspect is prevention of cardiovascular disease comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in a low dose. It provides a pharmaceutical monolayer tablet combination formulation for treatment.
  • Another aspect is for the prevention or treatment of cardiovascular diseases comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in a low dose
  • cardiovascular diseases comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in a low dose
  • a method for manufacturing a pharmaceutical single-layer tablet combination formulation comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in a low dose
  • Another aspect is the administration of a pharmaceutical single-layer tablet combination formulation comprising, as an active ingredient, amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof in a low dose. It provides a method of treating early cardiovascular disease according to the present invention.
  • the pharmaceutical single-layer tablet combination formulation according to an aspect can be used for the prevention or treatment of early cardiovascular disease, and the dissolution rate of the active ingredient is improved, and the stability and productivity of the combination formulation are improved.
  • a pharmaceutical combination preparation comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and chlorthalidone or a pharmaceutically acceptable salt thereof in a low dose as an active ingredient according to an aspect is clinically Because it minimizes adverse reactions resulting from drug administration and exhibits improved blood pressure lowering effects, it can overcome the limitations of existing blood pressure treatment methods due to excessive blood pressure drop or adverse reactions, and has excellent benefits versus risks.
  • the combination formulation effectively prevents or treats cardiovascular diseases by co-administering drugs with different mechanisms, and maximizes the blood pressure lowering effect by suppressing all possible mechanisms of hypertension at once, and has a complementary effect It can reduce patient-specific variability and increase the blood pressure treatment rate for hypertension due to a multifactorial mechanism.
  • the combined formulation is excellent in safety as a treatment for hypertension because the dose-dependent adverse reactions can be reduced by lowering the dose of each single component as much as possible.
  • the low-dose pharmaceutical combination formulation rapidly and effectively initially treats the blood pressure of an individual suffering from mild hypertension to moderate hypertension, and by increasing the blood pressure control rate, therapeutic inertia or inertia (treatment of clinicians or patients) Failure of blood pressure control due to inertia) can be avoided, and target blood pressure can be reached quickly, ultimately improving patient compliance.
  • the low-dose pharmaceutical combination preparation can lower the expression of ankle edema, which is an amlodipine drug-specific adverse reaction.
  • the combination formulation can reduce the patient's pill burden and improve dosing convenience, reduce patient-specific variability, and improve patient compliance by applying a simple dosing regimen, and It is economical because the drug cost is reduced compared to stepped-care therapy.
  • the combination preparation includes amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof as an active ingredient in one and the same layer.
  • amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof as an active ingredient in one and the same layer.
  • the composite formulation is excellent in the tableting process yield and at the same time the formulation uniformity is excellent to improve the pharmaceutical quality.
  • the combination formulation can reduce the variability of each patient with respect to the effect of a complementary mechanism of action.
  • the combination formulation is effective for 24 hours to reduce nighttime hypertension and blood pressure variability after activity.
  • Figure 2 shows sitSBP change from baseline in FAS at week 8.
  • blood pressure responders refer to subjects with sitSBP decrease ⁇ 20 mmHg or sit DBP decrease ⁇ 10 mmHg compared to baseline.
  • One aspect is prevention of cardiovascular disease comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in a low dose. It provides a pharmaceutical monolayer tablet combination formulation for treatment.
  • cardiovascular disease includes not only direct diseases caused by various causes such as abnormalities, dysfunctions, and damage of the circulatory system in vivo, but also secondary diseases derived from such direct diseases.
  • the cardiovascular disease may include hypertension, dyslipidemia, angina pectoris, arteriospasticity, cardiac arrhythmias, cardiac hypertrophy, cerebral infarction, congestive heart failure, arteriosclerosis, coronary heart disease, or myocardial infarction.
  • blood pressure refers to the pressure that blood flowing along the blood vessel exerts on the wall of the blood vessel. Blood pressure can be summarized as two measures in pulse: systolic systolic blood pressure and diastolic diastolic blood pressure.
  • hypertension refers to a chronic disease in which blood pressure is higher than the normal range. Hypertension can be divided into essential hypertension (primary hypertension) and secondary hypertension.
  • criteria for hypertension can be defined as blood pressure, which increases mortality due to cardiovascular complications through various epidemiological investigations.
  • criteria for hypertension may be defined in consideration of the risk-to-risk effect, that is, a value that proves that the benefit is greater than the risk when the corresponding blood pressure is lowered. For example, according to the criteria for the diagnosis of hypertension of the European Society of Hypertension (ESH) guidelines in 2018, normal or hypertension can be classified as follows.
  • the ideal optimal blood pressure for humans is 120/80 mmHg or less, systolic blood pressure of 120 to 129 mmHg, and/or diastolic blood pressure of 80 to 84 mmHg can be referred to as normal.
  • the ESH guidelines subdivide the classification according to systolic blood pressure and diastolic blood pressure. 179/100 ⁇ 109mmHg), stage 3 hypertension (180/110mmHg or more), and systolic single hypertension (140mmHg or more/less than 90mmHg).
  • normal blood pressure at rest is 100 to 140 mmHg during contraction, 60 to 90 mmHg at relaxation, and hypertension can be said when the blood pressure is continuously 140/90 mmHg or higher.
  • DBP diastolic blood pressure
  • pulse pressure refers to the difference between systolic blood pressure and diastolic blood pressure (sitSBP - sitDBP). Pulse pressure is the difference in blood pressure when the heart contracts and relaxes. As the blood vessel wall thickens and loses elasticity with aging, the systolic pressure increases. can In a 1999 Framingham study, Franklin et al. reported that pulse pressure was a strong predictor of risk for coronary artery disease when age, sex, and other risk factors were adjusted.
  • systolic blood pressure and pulse pressure may have greater predictive power for cardiovascular complications than diastolic blood pressure (Summary of Evidence-Based Hypertension Recommendation for Primary Medical Use, Korean Medical Association, Korea Centers for Disease Control and Prevention).
  • the term “complication” refers to the presence of other symptoms in a certain disease.
  • High blood pressure can accompany symptoms such as dizziness, headache, heart disease, and breathing difficulties, and if the body is in a state of high blood pressure for a long time, it can cause a lot of complications such as stroke, coronary heart disease, and renal failure.
  • the combination formulation may be used for the prevention or treatment of cardiovascular diseases including hypertension or complications thereof.
  • drugs used for the treatment of hypertension are largely divided into diuretics, sympathetic nerve inhibitors, and vasodilators depending on the mechanism of action of the drug. It can be divided into blockers and calcium channel blockers.
  • Amlodipine is 3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5 -Common name of dicarboxylate, as a calcium channel blocker, it relaxes vascular smooth muscle by blocking calcium ion channels on the surface of myocardium and vascular smooth muscle, and relaxes renal afferent arterioles to increase glomerular filtration rate, thereby inducing diuresis and lowering blood pressure show the effect. Amlodipine blocks calcium channels and is used to treat cardiovascular diseases such as angina, hypertension and congestive heart attack.
  • amlodipine is slowly absorbed when administered orally, and due to its long half-life of about 35-40 hours, it has a mild blood pressure lowering effect for a long time, and side effects such as orthostatic hypotension are reduced, and it is effective in preventing systolic hypertension and stroke. It is useful for angina pectoris as it has a coronary artery dilation effect.
  • Chlorthalidone is the generic name for benzenesulfonamide-2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl), It is currently sold under the trade name Hygroton ® . Chlorthalidone is a thiazide diuretic that blocks the Na + /Cl - transporter in the renal distal tubule, inhibits the reabsorption of Na + and Cl - and increases the excretion of K + to retain water in the urine.
  • chlorthalidone is a thiazide-type diuretic by blocking the Na + /Cl - transporter in the distal renal tubule, inhibiting the reabsorption of Na + and Cl - and increasing the excretion of K + to increase the excretion of urine water. It acts as a stagnant. Since chlorthalidone has a half-life of 50 to 60 hours and an action time of 48 to 72 hours, the duration and action time are longer than that of hydrochlorothiazide, which has a half-life of 9 to 10 hours and an action time of 16 to 24 hours. It is more useful for regulating blood pressure.
  • Losartan means 2-butyl-4-chloro-1-[ ⁇ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- It is a generic name for 1H-imidazole-5-methanol, and was developed for the first time among angiotensin receptor antagonists.
  • Losartan is used to treat hypertension and heart failure by blocking the binding of angiotensin II, a vasoconstrictor, to receptors. It is also used to treat ischemic peripheral circulation disorder, myocardial ischemia (angina pectoris), prevent the progression of heart failure after myocardial infarction, and treat diabetic neuropathy and glaucoma.
  • angiotensin II a powerful vasoconstrictor
  • hypertension heart failure
  • ischemic peripheral circulation disorder myocardial ischemia (angina pectoris), etc.
  • myocardial ischemia angina pectoris
  • the combination preparation comprises amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in a low dose.
  • DDD Dynamic Defined Dose
  • the daily doses of amlodipine, losartan potassium, and chlorthalidone may be about 5 to 10 mg, 50 to 100 mg, and 12.5 to 25 mg, respectively.
  • the lowest usual daily dose of amlodipine, losartan potassium, and chlorthalidone may be about 5 mg, 50 mg, and 12.5 mg, respectively.
  • low dose refers to a dose that is lower than the usual daily dose of a drug.
  • the low dose may be about 1/6 to about 1/2 dose, about 1/5 to about 1/2 dose, or about 1/4 to about 1/2 dose compared to the usual daily dose.
  • amlodipine or a pharmaceutically acceptable salt thereof may be included in an amount of 0.5 to 5 mg when converted into amlodipine free base form. In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof may be included in an amount of 0.8 to 3 mg when converted into amlodipine free base form.
  • chlorthalidone or a pharmaceutically acceptable salt thereof may be included in an amount of 1 to 7 mg when converted to chlorthalidone free base form. In one embodiment, it may be included in an amount of 2 to 7 mg when converted to chlorthalidone free base form.
  • the losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 7 to 30 mg when converted into losartan free acid form.
  • amlodipine or a pharmaceutically acceptable salt thereof is included in an amount of 0.5 to 5 mg when converted into amlodipine free base form, and chlorthalidone or a pharmaceutically acceptable salt thereof is converted into chlorthalidone free base form It may be included in an amount of 1 to 7 mg, and losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 7 to 30 mg when converted to the form of losartan free acid.
  • amlodipine or a pharmaceutically acceptable salt thereof is included in an amount of 0.8 to 3 mg when converted into amlodipine free base form, and chlorthalidone or a pharmaceutically acceptable salt thereof is chlorthalidone free base form. It may be included in an amount of 2 to 7 mg in terms of conversion, and losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 7 to 30 mg in terms of losartan free acid form.
  • amlodipine or a pharmaceutically acceptable salt thereof may be included in an amount of 1.25 to 3.5 mg or 1.25 to 2.5 mg when converted to amlodipine free base form.
  • it may be included in an amount of 3 to 6.25 mg when converted to chlorthalidone free base form.
  • losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 11 to 22 mg in terms of losartan free acid form. In one embodiment, losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 11.5 to 25 mg or 11.5 to 23 mg in terms of losartan free acid form.
  • amlodipine or a pharmaceutically acceptable salt thereof is included in an amount of 1.25 to 2.5 mg when converted to amlodipine free base form, and chlorthalidone or a pharmaceutically acceptable salt thereof is converted to chlorthalidone free base form. It may be included in an amount of 3 to 6.25 mg, and losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 11 to 22 mg when converted to losartan free acid form.
  • amlodipine or a pharmaceutically acceptable salt thereof is included in an amount of 1.25 to 2.5 mg when converted to amlodipine free base form, and chlorthalidone or a pharmaceutically acceptable salt thereof is converted to chlorthalidone free base form. It may be included in an amount of 3 to 6.25 mg, and losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 11.5 to 23 mg in terms of losartan free acid form.
  • amlodipine or a pharmaceutically acceptable salt thereof is 0.5 to 4 mg, 0.5 to 3 mg, 0.8 to 3 mg, 0.8 to 2.5 mg, 0.83 to 2.5 mg, 1.25 when converted to amlodipine free base form. to 2.5 mg, 1 to 3 mg, 1.5 to 3.5 mg, 1.5 to 2.5 mg, or 1.25 to 2.5 mg.
  • the amlodipine free base or pharmaceutically acceptable salt of amlodipine may be in an amount of 0.83 mg, 1 mg, 1.25 mg, 1.5 mg, 1.67 mg, 2.5 mg, 3 mg, or 3.5 mg, or It may be included in a range set as an upper limit or a lower limit.
  • the amlodipine may be included in the form of a pharmaceutically acceptable salt such as amlodipine camsylate or amlodipine besylate in an amount of 1 to 4 mg, 1.3 to 3.9 mg, 1.5 to 4 mg, 1.8 to 4 mg, or 1.96 to 3.9 mg.
  • the pharmaceutically acceptable salt of amlodipine such as amlodipine camsylate or amlodipine besylate is in an amount of 1.3 mg, 1.57 mg, 1.74 mg, 1.96 mg, 2.32 mg, 2.62 mg, 3.47 mg, or 3.92 mg, Or it may be included in a range having the numerical value as an upper limit or a lower limit.
  • 1 to 7 mg, 2 to 7 mg, 2 to 6.5 mg, 2.1 to 6.25 mg, 3 to 6.25 mg 3.13 to 6.25 mg, 3 to 6.5 mg when converted to chlorthalidone free base form in the low-dose pharmaceutical combination preparation may be included in an amount of 3 to 7 mg.
  • the chlorthalidone may be included in an amount of 2.08 mg, 2.5 mg, 3.13 mg, 4.17 mg, or 6.25 mg, or in a range having the above value as an upper limit or a lower limit.
  • losartan or a pharmaceutically acceptable salt thereof is 5 to 30 mg, 7 to 30 mg, 7 to 25 mg, 7.5 to 23 mg, 7.6 to 22.9 mg when converted to losartan free acid form. , 10 to 30 mg, 11 to 23 mg, 11 to 22 mg, 11.4 to 22.95 mg, 11.47 to 22.93 mg, 11.5 to 23 mg or 12 to 25 mg.
  • the losartan free acid may be included in an amount of about 7.64 mg, 9.17 mg, 11.47 mg, 12.5 mg, 15.29 mg, 16.67 mg, 22.93 mg, or 25 mg, or within a range having the upper or lower limit of the value.
  • the losartan may be in the form of a pharmaceutically acceptable salt, such as 8 to 30 mg, such as 8.3 to 25 mg, 10 to 25 mg, or 12.5 to 25 mg, as losartan potassium.
  • the pharmaceutically acceptable salt of losartan such as losartan potassium may be in an amount of about 8.33 mg, 10 mg, 12.5 mg, 16.67 mg, or 25 mg, or in a range having the upper or lower limit of the value. may be included.
  • the low-dose pharmaceutical combination preparation comprises amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and chlorthalidone or a pharmaceutically acceptable salt thereof, respectively, amlodipine free base, losartan free acid, and chlorin.
  • amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and chlorthalidone or a pharmaceutically acceptable salt thereof are respectively amlodipine free base and losartan free acid.
  • the dose may vary in consideration of the patient's age, sex, weight, degree of disease, age, race, and route of administration.
  • the effectiveness of antihypertensive drugs is generally evaluated by evaluating the amount of change in left systolic blood pressure before and after treatment as the primary evaluation item when evaluating the blood pressure lowering effect, and the amount of change in left diastolic blood pressure before and after treatment as the primary evaluation item. It can be evaluated as a secondary evaluation item.
  • the degree of response to treatment for hypertension refers to the normalization rate of blood pressure, that is, the blood pressure control rate (the proportion of subjects with systolic blood pressure less than 140 mmHg and diastolic blood pressure less than 90 mmHg after treatment) (ratio of subjects with sitSBP ⁇ 140 mmHg and sitDBP ⁇ 90 mmHg). ) can be evaluated.
  • the degree of response to treatment for hypertension is defined as the blood pressure response rate (responder rate) (the ratio of subjects with a decrease in systolic blood pressure of 20 mmHg or more or a decrease in diastolic blood pressure of 10 mmHg or more after treatment) (a decrease in sitSBP ⁇ 20 mmHg or a decrease in sitDBP compared to the baseline value ⁇ 10mmHg subject ratio).
  • responder rate the ratio of subjects with a decrease in systolic blood pressure of 20 mmHg or more or a decrease in diastolic blood pressure of 10 mmHg or more after treatment
  • the effectiveness of the antihypertensive agent may be evaluated based on a pulse pressure change amount, for example, a mean pulse pressure change amount (mean sitSBP - sitDBP).
  • the low-dose pharmaceutical combination preparation may reduce the amount of change in the left systolic blood pressure and/or the change in the left diastolic blood pressure, and simultaneously or selectively reduce the change in the pulse pressure.
  • the low-dose pharmaceutical combination formulation according to one embodiment can safely, quickly and sufficiently inhibit blood pressure rise and exhibit a blood pressure lowering effect in individuals with mild to moderate hypertension.
  • the low-dose pharmaceutical combination formulation according to one embodiment may be used as an initial therapy for the treatment of hypertension.
  • the low-dose pharmaceutical combination formulation according to one embodiment has a superior blood pressure improvement effect compared to placebo, and has a blood pressure improvement effect similar to that when amlodipine 5 mg or 10 mg is administered or losartan 100 mg is administered. .
  • the low-dose pharmaceutical combination formulation according to one embodiment can be effectively used for the treatment of mild to moderate hypertension.
  • mild hypertension refers to a case in which systolic blood pressure (mmHg) is 140 or more and less than 160 and/or diastolic blood pressure (mmHg) is 90 or more and less than 100.
  • moderate hypertension refers to a case in which the systolic blood pressure (mmHg) is 160 or more and less than 180 and/or the diastolic blood pressure (mmHg) is 100 or more and less than 110.
  • the low-dose pharmaceutical combination formulation can effectively improve the blood pressure of an individual having a systolic blood pressure (mmHg) of 140 or more and less than 180 and/or a diastolic blood pressure (mmHg) of 90 or more and less than 110, and the risk versus benefit is can be excellent
  • the combination formulation can effectively improve the blood pressure of an individual having a systolic blood pressure (mmHg) of 140 or more and 179 or less and/or a diastolic blood pressure (mmHg) of 90 or more and 109 or less.
  • mild hypertension to moderate hypertension may include stages 1 to 2 of hypertension according to the European Society for Hypertension (ESH) guidelines in 2018.
  • ESH European Society for Hypertension
  • the low-dose pharmaceutical combination formulation according to one embodiment can be effectively used for the treatment of hypertension stage 1 (Grade 1) or stage 2 (Grade 2) according to the ESH (2016) guidelines.
  • stage 1 hypertension refers to a case in which systolic blood pressure (mmHg) is 140 or more and 159 or less and/or diastolic blood pressure (mmHg) is 90 or more and 99 or less.
  • the second stage of hypertension refers to a case in which the systolic blood pressure (mmHg) is 160 or more and 179 or less and/or the diastolic blood pressure (mmHg) is 100 or more and 109 or less.
  • the low-dose pharmaceutical combination formulation according to one embodiment can effectively improve the blood pressure of an individual having a systolic blood pressure (mmHg) of 140 or more and 179 or less and/or a diastolic blood pressure (mmHg) of 90 or more and 109 or less.
  • the combination formulation can effectively improve the blood pressure of an individual having a systolic blood pressure (mmHg) of 140 or more and 159 or less and/or a diastolic blood pressure (mmHg) of 90 or more and 99 or less.
  • the low-dose pharmaceutical combination formulation according to one embodiment can effectively improve blood pressure in an individual having a sitting systolic blood pressure (sitSBP) of less than 160 mmHg.
  • the low-dose pharmaceutical combination formulation according to one embodiment can provide an effective initial therapeutic agent for patients with mild to moderate hypertension.
  • the low-dose pharmaceutical combination formulation may be effective for hypertension with a sitting systolic blood pressure (sitSBP) of less than 160 mmHg.
  • the combination formulation may exhibit a proportionally increased blood pressure decrease according to the dose in subjects with sitSBP of less than 160 mmHg.
  • the low-dose pharmaceutical combination formulation is a fixed-dose combination formulation comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and chlorthalidone or a pharmaceutically acceptable salt thereof in the above-mentioned content (fixed-dose combination formulation).
  • the combination formulation may be administered once to several times a day, for example, once or three times, depending on the dosage.
  • the low-dose pharmaceutical combination preparation may be for administration once a day.
  • the combination formulation can provide optimal pharmacological clinical effects in terms of blood pressure lowering effect while improving patient convenience and medication compliance by administering once a day.
  • the combination formulation may be administered for at least 4 weeks or 8 weeks, or more or less, in consideration of the pathological condition and severity of the subject to be administered.
  • the pharmaceutically acceptable salt of amlodipine, losartan, or chlorthalidone refers to a salt prepared according to a method conventional in the art, and the preparation method is known to those skilled in the art.
  • the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic acids and organic acids and bases.
  • suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methane sulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, carboxylic acid, besylic acid, camsylic acid, and the like.
  • Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium, or potassium, alkaline earth metals such as calcium, magnesium.
  • the pharmaceutically acceptable salt of amlodipine is formed from an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate. , fumarate, lactate, tartrate, citrate, gluconate, besylate and camsylate, but are not limited thereto.
  • a pharmaceutically acceptable anion for example, hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate. , fumarate, lactate, tartrate, citrate, gluconate, besylate and camsylate, but are not limited thereto.
  • amlodipine besylate salt or camsylate salt can be used.
  • the amlodipine includes amlodipine racemate and (S)-amlodipine.
  • the pharmaceutically acceptable salt of losartan may be, for example, losartan potassium salt, but is not
  • the combination preparation may include amlodipine camsylate, losartan potassium, and chlorthalidone.
  • the combination preparation may include amlodipine besylate, losartan potassium, and chlorthalidone.
  • the low-dose pharmaceutical combination preparation is sterile aqueous for oral use such as powders, tablets, capsules, aqueous or oily suspensions, emulsions or dispersible powders or granules, parenteral administration such as intravenous, subcutaneous, intramuscular or intravascular administration or as oily solutions or suspensions, forms suitable for topical use such as creams, gels or ointments, or suppositories for rectal administration.
  • the low-dose pharmaceutical combination preparation may be formulated in the form of a tablet, capsule, or caplet.
  • the combination formulation is a single-layer tablet.
  • tablette is intended to include compressed pharmaceutical dosage forms of all shapes and sizes.
  • double-layer tablet refers to a tablet in which two or more different components are independently present in two layers by separating the compartments.
  • single-layer tablet refers to a tablet in which two or more different components are mixed in one layer.
  • amlodipine, chlorthalidone, and losartan do not exist in separate compartments, but may be present in the same single layer.
  • the term single-layer tablet is used separately from multi-layered tablets such as double-layered tablets and three-layered tablets in which two or more components are independently present in different layers by separating compartments.
  • the pharmaceutical combination preparation according to one embodiment is a single-layer tablet, and does not cause problems such as gelation of the losartan or reduced dissolution or generation of related substances.
  • Gelation of losartan may be a problem when preparing a complex formulation containing amlodipine, chlorthalidone and losartan.
  • Losartan shows a very good dissolution pattern when eluted at a relatively high pH such as purified water, pH 4.0, and pH 6.8.
  • a relatively high pH such as purified water, pH 4.0, and pH 6.8.
  • losartan gels and elutes slowly. This phenomenon greatly affects the dissolution rate of the formulation in that the first place where disintegration and dissolution occurs when oral formulations are taken is the stomach where the digestive juice of low pH is secreted, and furthermore, it can affect the absorption of the drug in vivo.
  • losartan gels as described above amlodipine and chlorthalidone mixed with losartan are also trapped in the gel, resulting in a problem of reduced dissolution.
  • a decrease in dissolution due to gelation of the losartan may not occur.
  • the single-layer tablet combination formulation containing amlodipine, chlorthalidone and losartan in a low dose exhibits improved dissolution rate, stability and productivity without causing such gelation problems.
  • the low-dose single-layered pharmaceutical combination formulation according to one embodiment can improve the dissolution rate, content uniformity, storage safety, tableting speed, and productivity of the drug components contained therein.
  • a low-dose single-layer pharmaceutical combination formulation comprises amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof into a mixed granule part.
  • the single-layered pharmaceutical combination formulation contains the active ingredient in the mixed granulation part, and the dissolution rate of the active ingredient is reduced or the increase in related substances is reduced compared to the case where the active ingredient is included in the separate granular part to form a double-layered tablet or a single-layered tablet.
  • the dissolution rate of amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof and the stability of the combination formulation are excellent.
  • the total weight of the pharmaceutical monolayer tablet combination formulation for the prevention or treatment of cardiovascular disease may be 350 mg or less. In one embodiment, the total weight of the combination formulation may be 330 mg or less, 300 mg or less, 200 mg or less, 170 mg or less, or 165 mg or less. As the total weight of the combined formulation is 330 mg or less, 300 mg or less, 200 mg or less, 170 mg or less, or 165 mg or less, more improved dissolution rates of amlodipine, chlorthalidone and losartan may be exhibited.
  • the total weight of the combined formulation may be 42 mg or more, 40 mg or more, 50 mg or more, 60 mg or more, 70 mg or more, or 80 mg.
  • the total weight of the pharmaceutical monolayer tablet combination formulation for the prevention or treatment of cardiovascular disease may be 70 mg or more and 350 mg or less.
  • the dissolution rate of the active ingredient may be improved, and at the same time, uniformity of the preparation may be secured, and the combination preparation may be manufactured with excellent quality.
  • the total weight of amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in the combination preparation is 15 mg or more can
  • the dissolution rate of the active ingredient can be improved, and at the same time, uniformity of the formulation can be secured, and the composite formulation can be manufactured with excellent quality.
  • the active ingredient may be included in an amount of 10% or more.
  • the active ingredient may be included in an amount of 20% or more.
  • the dissolution rate can be improved, and the composite formulation can be prepared with excellent quality.
  • it further comprises a disintegrant, in which case the content of the disintegrant may be 1 to 15% based on the total weight of the combined formulation.
  • it further comprises a disintegrant, wherein the content of the disintegrant may be 2% or more, 3% or more, 4% or more, or 5% or more based on the total weight of the combination formulation.
  • it further comprises a disintegrant, wherein the content of the disintegrant may be 4 to 15% based on the total weight of the combined formulation.
  • it further comprises a disintegrant, wherein the content of the disintegrant may be 4.5 to 10% based on the total weight of the combined formulation.
  • it further comprises a disintegrant, wherein the content of the disintegrant may be 9 to 15% based on the total weight of the combined formulation.
  • the dissolution rate can be improved, and the composite formulation can be prepared with excellent quality.
  • the combination preparation may further include a pharmaceutical additive selected from a diluent, a disintegrant, a lubricant, and combinations thereof.
  • the diluent may be any one selected from microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate, lactose, low-substituted hydroxypropyl cellulose, and combinations thereof.
  • the disintegrant may be any one selected from crospovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch, or a combination thereof.
  • the lubricant may be any one selected from magnesium stearate, palmitic acid, talc (talc), magnesium stearate, zinc stearate, calcium stearate, or a combination thereof.
  • the combination preparation may further include a binder.
  • the binder may be any one selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, acacia gum, and combinations thereof.
  • amlodipine or a pharmaceutically acceptable salt thereof in the combination preparation may be included in an amount of 0.1 to 7% by weight.
  • amlodipine or a pharmaceutically acceptable salt thereof in the combination preparation may be included in an amount of 0.5 to 3% by weight.
  • chlorthalidone or a pharmaceutically acceptable salt thereof may be included in an amount of 0.3 to 9% by weight. For example, it may be included in an amount of 1 to 5% by weight.
  • losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 1 to 40% by weight. For example, it may be included in an amount of 5 to 20% by weight.
  • the diluent may be included in an amount of 40 to 95% by weight.
  • it may be included in an amount of 50 to 90% by weight.
  • the disintegrant may be included in an amount of 1 to 20% by weight. For example, it may be included in an amount of 1.5 to 15% by weight.
  • the lubricant may be included in an amount of 0.1 to 2% by weight.
  • it may be included in an amount of 0.5 to 1.5% by weight.
  • the binder may be included in an amount of 0 to 10% by weight. For example, it may be included in an amount of 0.1 to 10% by weight. For example, it may be included in an amount of 0.5 to 5% by weight.
  • the complex formulation may further include a pH adjuster, a suspending agent, a preservative, a flavoring agent, a colorant, a sweetener, an adsorbent, a solubilizer, and the like, if necessary.
  • a pH adjuster a suspending agent, a preservative, a flavoring agent, a colorant, a sweetener, an adsorbent, a solubilizer, and the like, if necessary.
  • the content of the additive is not particularly limited in the present invention and may be appropriately adjusted as necessary.
  • the diluent may be included so that the weight ratio of the diluent to the low-substituted hydroxypropyl cellulose is 6:1 to 1:1 except for the low-substituted hydroxypropyl cellulose.
  • the diluent further comprises microcrystalline cellulose and low-substituted hydroxypropyl cellulose, wherein the weight ratio of microcrystalline cellulose to low-substituted hydroxypropyl cellulose may be 2:1 to 1:1.
  • the weight ratio may be 6:1 to 1:1, 5:1 to 1:1, 4:1 to 1:1, or 2:1 to 1.5:1.
  • a diluent other than low-substituted hydroxypropyl cellulose to low-substituted hydroxypropyl cellulose for example, microcrystalline cellulose to low-substituted hydroxypropyl cellulose in the above-mentioned content range, it is possible to manufacture tablets with improved quality. it becomes possible
  • the total weight of amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof to the diluent is 1:2 to 1:9 may be further included.
  • the dissolution rate of the active ingredient can be improved, and the complex preparation can be manufactured with excellent quality.
  • the single-layer tablet combination formulation may have a dissolution rate of 80% or more of the active ingredient within 30 minutes during a dissolution test according to the oral drug dissolution standard setting guidelines.
  • the combination formulation may have a dissolution rate of 80% or more of amlodipine within 30 minutes during a dissolution test according to the guidelines for setting dissolution standards for oral pharmaceuticals.
  • the combination formulation may have a dissolution rate of 80% or more of chlorthalidone within 30 minutes during a dissolution test according to the guidelines for setting dissolution standards for oral pharmaceuticals.
  • the combination formulation may have a dissolution rate of 80% or more of losartan within 30 minutes during a dissolution test according to the guidelines for setting dissolution standards for oral drugs
  • the monolayer tablet combination formulation has a dissolution rate of amlodipine within 30 minutes at 100 ⁇ 5 rpm, 37 ⁇ 0.5 ° C, 0.01 M hydrochloric acid, 900 mL according to the US Pharmacopoeia dissolution test item paddle method. % or more.
  • the single-layer tablet combination formulation is a dissolution test at 75 rpm ⁇ 2 rpm, 37 ⁇ 0.5 ° C, 900 mL of purified water by the paddle method according to the dissolution test item of the US Pharmacopoeia chlorthalidone tablet section, chlorthalidone within 30 minutes
  • the dissolution rate of money may be 80% or more.
  • the single-layer tablet combination formulation is a dissolution test at 75 rpm ⁇ 2 rpm, 37 ⁇ 0.5 ° C, 900 mL of purified water by the paddle method according to the dissolution test item of the US Pharmacopoeia Losartan potassium tablet dissolution test, 30 minutes Within that time, the dissolution rate of losartan may be 80% or more.
  • the combined formulation may have a dissolution rate of 85% or more within 30 minutes of each active ingredient during a dissolution test according to the paddle method of the US Pharmacopoeia dissolution test item, and in one embodiment, a dissolution rate of 85% or more within 15 minutes.
  • amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof are combined in one mixed part or a granular part may exist in
  • amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof are included in one mixing part or a granulation part in the combination formulation,
  • the maximum tableting speed, the tableting process yield are higher, and the content uniformity is better than when the drug is included in the separate mixing part or the granulation part.
  • the combination preparation is prepared by mixing amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutical additive such as a diluent and a disintegrant. It can be done as a mixing part.
  • the mixing part may be tableted after granulation by a conventional granulation method, for example, a compression granulation method.
  • the mixing unit may be in the form of granules subjected to a roller compaction process.
  • the compressed granulated mixing part may be mixed with a lubricant to obtain a final granulated part.
  • the dissolution rate of amlodipine, chlorthalidone and losartan is excellent, the desired dissolution pattern without gelation of losartan is exhibited, and the stability of the composite formulation is excellent.
  • the composite formulation when the composite formulation is compressed into a single-layer tablet, the maximum tableting speed, the tableting process yield are higher, and the content uniformity is excellent compared to that of the double-layer tablet.
  • the particle size (D90) of chlorthalidone or a pharmaceutically acceptable salt thereof in the combination formulation may be about 0.5 to 50 ⁇ m, for example 0.5 to 25 ⁇ m, or, for example, 0.5 to 10 ⁇ m.
  • the particle size can be performed using a commercially available apparatus based on a laser diffraction/scattering method based on the Mie theory. For example, it can measure using commercially available apparatuses, such as a HELOS (Helium-neon Laser for Optical Spectrometry, Sympatec) laser diffraction apparatus. In this device, when a helium-neon laser beam is irradiated to particles, scattering occurs and a light scattering pattern appears on the detector, and the particle size distribution can be obtained by analyzing the light scattering pattern according to the Mie theory.
  • HELOS Helium-neon Laser for Optical Spectrometry, Sympatec
  • the method for controlling the particle size in the preparation of the combination preparation is not particularly limited and a method known in the art may be appropriately selected.
  • the chlorthalidone is a jet mill, a hammer mill, a ball mill, a fluid energy mill, etc. using a conventional mill capable of pulverizing particles. can be crushed
  • a sieve method performed using a sieve or a size classification method such as air current classification may be used to subdivide the particle size of the drug.
  • Another aspect is for the prevention or treatment of cardiovascular diseases comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof in a monolayer tablet at a low dose
  • cardiovascular diseases comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof in a monolayer tablet at a low dose
  • a method for preparing a pharmaceutical combination preparation comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof in a monolayer tablet at a low dose
  • the manufacturing method includes mixing a pharmaceutically acceptable additive.
  • a pharmaceutically acceptable additive when converted into amlodipine free base form, amlodipine or a pharmaceutically acceptable salt thereof, in an amount of 0.5 to 5 mg when converted into amlodipine free base form, when converted into chlorthalidone free base form, chlorin corresponding to an amount of 1 to 7 mg
  • Mixing thalidone or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof in an amount of 7 to 30 mg when converted to losartan free acid form, and a pharmaceutically acceptable additive may include
  • amlodipine or a pharmaceutically acceptable salt thereof corresponding to an amount of 0.8 to 3 mg when converted into amlodipine free base form, when converted into chlorthalidone free base form, chlorin corresponding to an amount of 2 to 7 mg
  • Mixing thalidone or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof in an amount of 7 to 30 mg when converted to losartan free acid form, and a pharmaceutically acceptable additive may include
  • amlodipine in an amount of 1 to 3 mg when converted into amlodipine free base form, or a pharmaceutically acceptable salt thereof, when converted to chlorthalidone free base form, chlorin corresponding to an amount of 3 to 7 mg
  • Mixing thalidone or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof in an amount of 10 to 30 mg when converted to losartan free acid form, and a pharmaceutically acceptable additive may include
  • the preparation method comprises the steps of mixing amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to form a mixture ( One),
  • the pharmaceutically acceptable additive mixed in step (1) may include a diluent, a disintegrant, and a combination thereof.
  • the pharmaceutically acceptable additive mixed in step (2) may include a lubricant.
  • Another aspect is the administration of a combination formulation comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof in a monolayer tablet at a low dose.
  • a method of treating early cardiovascular disease is provided.
  • the treatment method according to one embodiment may be effective as an initial therapy for the treatment of mild to moderate hypertension.
  • Amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, included in the combination preparation or composition may be used in an amount effective for treatment or prevention of an individual or patient. , it can be administered by various administration methods, either oral or parenteral, depending on the intended purpose. As for the administration method, the administration dose for a specific individual or patient should be determined in light of several related factors such as the patient's weight, age, race, sex, health status, diet, administration time, administration method, and the severity of the disease. It should be understood that it can be appropriately increased or decreased by the above dosage, and the above dosage is not intended to limit the scope of the present invention in any way.
  • a physician having ordinary skill in the related art can easily determine and prescribe the dosage of the compound to be used as needed. For example, a physician may start a dose of a compound of the present invention used in a pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.
  • treatment is used as a concept including all treatment, improvement, amelioration, or management of a disease.
  • treating refers to inhibiting a disease, e.g., inhibiting a disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptom of a disease, condition or disorder, pathology. and/or preventing further occurrence of symptoms, ameliorating the disease, or reversing the pathology and/or symptoms, such as reducing disease severity.
  • preventing refers to preventing a disease, e.g., in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or exhibit the pathology or signs of the disease. To prevent a disease, condition or disorder.
  • the term “subject” or “patient” refers to any animal, including mammals, eg, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates and humans. say, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates and humans. say, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates and humans. say
  • the amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof are administered as a single dosage form, or It may be administered in multiple dosage forms comprising each individually.
  • the components may be present in one single dosage form, or each may be present in separate dosage forms and administered in combination.
  • the single dosage form or individual dosage form may be in the form of a tablet or capsule.
  • sequential administration may also include (but not limited to), for example, alternating administration of the active ingredients.
  • the dosage of the drug in the treatment method may vary depending on the age, sex, weight, pathological condition and severity of the subject to be administered, the route of administration, or the judgment of the prescriber. Determination of the amount to be applied based on these factors is within the level of one of ordinary skill in the art. In addition, if necessary, it may be administered in combination with one or more other pharmaceuticals for preventing or treating cardiovascular diseases.
  • Test subjects were selected based on the following selection criteria and exclusion criteria.
  • test drug As a test drug to be administered to the selected target group, a test drug containing the following content was prepared.
  • the present inventors have developed a low-dose combination formulation with an appropriate dose in consideration of both safety and effectiveness, based on 5/50/12.5 mg of amlodipine, losartan, and chlorthalidone, which are the lowest doses of Amosartan Plus TM, respectively, between major components.
  • the dose was searched for by reducing the dose at a constant ratio while maintaining the same ratio.
  • the present inventors came to present the test drug in the following ratio.
  • HCP1803-2.5/25/6.25 amlodipine 2.5mg, losartan potassium 25mg, chlorthalidone 6.25mg
  • HCP1803-1.67/16.67/4.17 amlodipine 1.67 mg, losartan potassium 16.67 mg, chlorthalidone 4.17 mg
  • HCP1803-1.25/12.5/3.13 Amlodipine 1.25mg, Losartan Potassium 12.5mg, Chlorthalidone 3.13mg
  • HGP0904 Novasc TM tablets 5 mg
  • Amlodipine 5 mg Pfizer Korea Co., Ltd.
  • Koza TM tablets 100 mg Lisartan potassium 100 mg
  • the tablets prepared in (1) to (3) were packaged in DB capsules (DB caps ® size A; Capsugel, USA) and a clinical test was conducted.
  • the test drug or control drug and a placebo of HGP0904 or a placebo of HCP1803-1.25/12.5/3.13 were filled together in the DB capsule.
  • the group receiving 10 mg of amlodipine 2 tablets of HGP0904 were filled into the DB capsule in consideration of the size of the DB capsule.
  • This clinical trial was designed as a multicenter, joint, randomized, double-blind, parallel design trial.
  • test subject visits the laboratory at week 0 (Visit 2), week 4 (Visit 3), and week 8 (Visit 4) to evaluate efficacy and safety, and during the trial period,
  • week 0 Visit 2
  • week 4 Visit 3
  • week 8 Visit 4
  • the same treatment method was maintained without adjusting the dose of the drug.
  • all subjects were asked to maintain constant lifestyle habits that could affect blood pressure measurement results, such as diet (salt intake), smoking, alcohol intake, weight and exercise during the entire clinical trial period.
  • the appropriate dose for the phase 3 confirmation study was selected by comprehensively evaluating the efficacy and safety of each administration group.
  • the result values obtained based on the clinical trial evaluation items were statistically analyzed in the following way. Efficacy evaluation analysis was conducted for all analysis subjects (Full analysis set: FA set or FAS) (from among the subjects who took the investigational drug at least once after being randomly assigned, sitSBP was administered at least once until the end of the clinical trial after administration of the investigational drug. The measured test subject) was used as the main analysis target, and the protocol-compliant clinical test group (Per protocol set: PP set or PPS) was used as the secondary analysis target.
  • ANCOVA Analysis of covariance
  • ANCOVA Analysis of covariance
  • ANCOVA Analysis of covariance
  • ANCOVA covariance
  • the safety analysis was conducted on subjects who had taken the investigational drug at least once after being randomized, and the investigator checked safety-related data at least once until the end of the clinical trial after taking the investigational drug.
  • Adverse reaction refers to all harmful and unintended signs (abnormalities in laboratory test values), symptoms, or diseases that occur in subjects who have administered the investigational drug, and must have a causal relationship with the investigational drug. no. The investigator recorded and evaluated any adverse events that occurred during the trial.
  • TEAEs Treatment Emergent Adverse Events
  • NCS clinically non-significant abnormality
  • CS clinically significant abnormality
  • Clinical Trial Example 1 Observation of serious adverse reactions and adverse drug reactions following administration of a low-dose antihypertensive agent in the test subject group
  • Adverse drug reaction refers to any adverse and unintended reaction that occurs at any dose of an investigational drug, and a causal relationship with the investigational drug cannot be excluded. In this clinical trial, adverse reactions evaluated as having a causal relationship were classified as adverse drug reactions.
  • Serious AE refers to a case that falls under any of the following among the adverse reactions or drug reactions occurring at any dose of the investigational drug.
  • Low-dose antihypertensive drugs (amlodipine 2.5mg, losartan potassium 25mg, chlorthalidone 6.25mg; amlodipine 1.67mg, losartan potassium 16.67mg, chlorthalidone 4.17mg ; or amlodipine 1.25mg, rosa Administration of rutan potassium 12.5 mg, chlorthalidone 3.13 mg) did not show any clinically significant serious adverse reactions or adverse drug reactions.
  • the systolic and diastolic blood pressures of the test subjects were measured before administration of the test drug.
  • Systolic blood pressure and diastolic blood pressure according to the administration of the test drug in the target group were measured, and compared with the results of administration of the control drug or placebo.
  • low-dose antihypertensive drugs HCP1803-2.5/25/6.25, HCP1803-1.67/16.67/4.17, HCP1803-1.25/12.5/3.13 prepared as an investigational drug showed superior blood pressure improvement compared to placebo, and amlodipine 5 mg Alternatively, when 10 mg was administered, or when losartan 100 mg was administered, blood pressure improvement effects were similar.
  • test drug did not show an excessive decrease in blood pressure in patients with mild to moderate hypertension, and at the same time showed an average blood pressure lowering effect sufficient to control blood pressure, confirming that it was excellent in safety and tolerability.
  • test drug in the target group was superior to the risk versus benefit in mild or moderate hypertension, such as stage 1 to 2 hypertension according to the ESH (2018) guidelines, than the reference drug or placebo.
  • low-dose antihypertensive drugs (amlodipine 2.5 mg, losartan potassium 25 mg, chlorthalidone 6.25 mg; amlodipine 1.67 mg, losartan potassium 16.67 mg, chlorthalidone 4.17 mg; or amlodipine 1.25 mg, losartan potassium 12.5 mg; Chlorthalidone 3.13 mg) showed superior blood pressure improvement compared to placebo in patients with mild or moderate hypertension, including stage 1 or 2 hypertension, according to the ESH (2018) guidelines. The effect was similar to that of the usual dose of amlodipine or losartan.
  • a low-dose antihypertensive agent (HCP1803-2.5/25/6.25, HCP1803-1.67/16.67/4.17, HCP1803-1.25/12.5/3.13) showed an improved blood pressure normalization rate in mild to moderate hypertension including stage 1 or 2 hypertension according to the ESH (2016) guidelines.
  • ANCOVA covariance
  • the least squares mean ⁇ standard error (LS Mean ⁇ SE) of the change in sitSBP after 8 weeks from baseline, the primary efficacy evaluation variable of this clinical trial, was amlodipine/losartan potassium/chlorthalidone 1.25/12.5/3.13 mg (hereinafter, A/ L/C-1.25/12.5/3.13), amlodipine/losartan potassium/chlorthalidone 1.67/16.67/4.17 mg (hereinafter, A/L/C-1.67/16.67/4.17), amlodipine/losartan potassium/chlorthali Don 2.5/25/6.25 mg (hereafter, A/L/C-2.5/25/6.25) group was -14.91 ⁇ 3.89 mmHg, -19.49 ⁇ 4.36 mmHg, and -17.21 ⁇ 3.60 mmHg greater than the placebo group, respectively, This showed a statistically significant difference (p 0.0003, p ⁇ 0.0001, p ⁇ 0.0001). Through this, for all doses of the test drug
  • Table 2 and Figure 2 show the results of comparing each test group with the active control group based on the FAS for the least squares mean ⁇ standard error (LS Mean ⁇ SE) of the change in sitSBP after 8 weeks compared to the baseline estimated as a result of the covariance analysis. It was
  • Figure 2 shows the sitSBP change from baseline in all analyzed subjects (FAS) at week 8.
  • the amount of sitSBP change after 8 weeks compared to the baseline in the A/L/C-1.25/12.5/3.13 group was compared with the group administered with amlodipine 5 mg (hereinafter, A5), the group administered with amlodipine 10 mg (hereinafter, referred to as A10), and the group administered with losartan potassium 100 mg (hereinafter, L100).
  • the difference in the change between the administration groups was -5.68, respectively.
  • ANCOVA analysis of covariance
  • Figure 3 shows the results of comparing each test group and the control group based on the FAS with respect to the least squares mean ⁇ standard error (LS Mean ⁇ SE) of the change in sitDBP after 8 weeks compared to the baseline estimated as a result of the covariance analysis.
  • LS Mean ⁇ SE least squares mean ⁇ standard error
  • the proportion of subjects adjusted to sitSBP less than 140 mmHg and sitDBP less than 90 mmHg was 57.14% (20 / 35 patients) in the A/L/C-1.25/12.5/3.13 group, A/L/ C-1.67/16.67/4.17 administration group 69.70% (23 / 33 patients), A/L/C-2.5/25/6.25 administration group 63.89% (23 / 36 patients), A5 administration group 44.12% (15 / 34 patients) ), 66.67% (22 / 33 patients) in the A10 administration group, 41.18% (14 / 34 patients) in the L100 administration group, and 18.18% (6 / 33 patients) in the Placebo administration group.
  • blood pressure responders refer to subjects with sitSBP decrease ⁇ 20 mmHg or sit DBP decrease ⁇ 10 mmHg compared to baseline.
  • the proportion of subjects with sitSBP decrease ⁇ 20 mmHg or sitDBP decrease ⁇ 10 mmHg compared to baseline was 51.43% (18 / 35 patients) in the A/L/C-1.25/12.5/3.13 group, A/ L/C-1.67/16.67/4.17 administration group 60.61% (20 / 33 patients), A/L/C-2.5/25/6.25 administration group 58.33% (21 / 36 patients), A5 administration group 47.06% (16 / 34), 63.64% (21 / 33 patients) in the A10 administration group, 32.35% (11 / 34 patients) in the L100 administration group, and 21.21% (7 / 33 patients) in the Placebo administration group.
  • Clinical Trial Example 10 Subgroup analysis: Mean change in sitSBP after 8 weeks from baseline (basal blood pressure sitSBP ⁇ 160 mmHg)
  • Table 3 and Figure 7 show the results of comparing each test group with the control group based on the FAS with respect to the least squares mean ⁇ standard error (LS Mean ⁇ SE) of the change in sitSBP after 8 weeks compared to the baseline estimated as a result of the covariance analysis. .
  • the edema test was performed by measuring the ankle circumference for each clinical trial drug administration group.
  • the Wilcoxon rank sum test was performed to compare the changes in ankle circumference after 8 weeks compared to the baseline between the test drug administration group and the amlodipine single drug administration group.
  • the ankle with the largest absolute value of the change in ankle circumference after 8 weeks compared to the baseline value was selected among both ankles of each subject. 8 shows.
  • the mean ⁇ standard deviation (Mean ⁇ SD) of the change in ankle circumference after 8 weeks compared to the baseline was -0.76 ⁇ 6.33 mm in the test drug administration group and 2.48 ⁇ 8.79 mm in the amlodipine single agent administration group.
  • DBP diastolic blood pressure
  • sitDBP sitting diastolic blood pressure
  • sitSBP sitting systolic blood pressure
  • HbA1c glycated hemoglobin (Hemoglobin A 1c )
  • amlodipine, chlorthalidone, losartan microcrystalline cellulose and low-substituted hydroxypropyl cellulose (Low-Substituted Hydroxypropyl Cellulose) and crospovidone were taken and mixed for 10 minutes.
  • the mixture is compacted to make slugs, and then sieved through a 1.0 mm sieve to prepare granules.
  • Magnesium stearate is added to this granular part and mixed for 5 minutes to make the final granular part.
  • a single-layer tablet composite was produced using the final granular part.
  • compositions of the pharmaceutical combination formulations according to Examples 1 to 6 are shown in Table 4 below.
  • Comparative Examples 1 to 4 Preparation of a double-layered or single-layered tablet comprising a granular part I containing amlodipine and chlorthalidone and a granular part II containing losartan
  • amlodipine, chlorthalidone, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose and crospovidone were taken and mixed for 10 minutes.
  • the mixture is compacted to make a slug, and then sieved through a 1.0 mm sieve size.
  • Magnesium stearate was added to this granular part and mixed for 5 minutes to prepare granular part I.
  • Comparative Examples 1 and 3 A two-layer tablet was produced by using the granular part I as the upper granular part and the granular part II as the lower granular part.
  • Comparative Examples 2 and 4 The granular part I and the granular part II were finally mixed to produce a single-layer tablet.
  • Comparative Examples 5 to 8 Preparation of a single-layer tablet comprising a granular part I containing amlodipine and chlorthalidone and a granular part II containing losartan
  • amlodipine, chlorthalidone, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose and crospovidone were taken and mixed for 10 minutes.
  • the mixture is compacted to make a slug, and then sieved through a 1.0 mm sieve size.
  • Magnesium stearate was added to this granular part and mixed for 5 minutes to prepare granular part I.
  • compositions of the pharmaceutical combination formulations according to Comparative Examples 5 to 8 are shown in Table 5 below.
  • Test Example 1 Dissolution test of amlodipine and chlorthalidone according to gelling by losartan content
  • Test solution 0.01 M hydrochloric acid solution, 900 mL
  • UV absorption spectrophotometer (measurement wavelength: 240 mm)
  • Comparative Example 1 a double-layered tablet containing a high dose (50 mg) of losartan in the granular portion separated from amlodipine or chlorthalidone, compared with Comparative Example 2, a single-layered tablet, amlodipine and chlorin under the same conditions.
  • the dissolution rate of thalidon was high.
  • Comparative Example 3 a double-layered tablet, containing losartan in a low dose (25 mg) in a granular portion separated from amlodipine and chlorthalidone
  • Comparative Example 4 a single-layered tablet, under the same conditions were amlodipine and chlorthalidone. There was no significant difference in the dissolution rate of thalidon.
  • Comparative Example 4 a single-layer tablet containing a low dose (25 mg) of losartan in a granular portion separated from amlodipine and chlorthalidone, and a low dose (25 mg) of losartan were mixed with amlodipine and chlorthalidone.
  • Example 1 which was included in the granular part mixed with thalidone and was a single-layer tablet, showed a similar dissolution rate.
  • Comparative Examples 5 and 6 which contain a high dose (50 mg or 33.33 mg, respectively) of losartan in the granule part mixed with amlodipine and chlorthalidone, and are single-layer tablets, have a low dose (25 mg ) containing losartan in the granule part mixed with amlodipine and chlorthalidone, and showed a lower dissolution rate compared to Example 4, which is a single-layer tablet.
  • the dissolution rate of amlodipine and chlorthalidone may be affected due to the degree of gelation according to the dose of losartan in the combination formulation, and in particular, when the dose of losartan is high, the dissolution rate of amlodipine and chlorthalidone is lowered due to gelation. was confirmed.
  • the shape of the tablet affects the dissolution rate of amlodipine and chlorthalidone (FIG. 9), but when losartan is included in a low dose, the combination It was confirmed that the tablet form (single-layer tablet, double-layer tablet) or granular form (mixed granular part, separated granular part) did not have a significant effect on the dissolution rate of amlodipine and chlorthalidone ( FIGS. 10 and 11 ).
  • Test Example 2 Stability test according to the form of tablets and granules
  • the content changes of amlodipine, chlorthalidone and losartan related substances were measured for the separated granular bilayer tablet of Comparative Example 3, the separated granular monolayer tablet of Comparative Example 4, and the mixed granular monolayer tablet of Example 1 under the following severe storage conditions. The stability of the tablets was evaluated.
  • Test conditions Initial, 1 week, 2 weeks
  • UV absorption spectrophotometer (measured wavelength: 239 mm)
  • FIG. 12 is a diagram showing the content (%) of related substances (%) of (a) impurity B (Imp B) and (b) unknown related substances (Unknown max) of chlorthalidone in Comparative Examples 3, 4, and 1 Shows the result of checking whether related substances are generated.
  • Test Example 3 Dissolution test of amlodipine, losartan, and chlorthalidone
  • Test solution 0.01 M hydrochloric acid solution, 900 mL
  • Judgment condition 80% or more dissolution rate after 30 minutes
  • Test solution purified water, 900 mL
  • Judgment condition 80% or more dissolution rate after 30 minutes
  • UV absorption spectrophotometer (measurement wavelength: 240 mm)
  • Example 2 As shown in FIG. 13 , as a result of measuring the dissolution rates of Examples 1 and 2, the dissolution rates of amlodipine, chlorthalidone and losartan were higher in Example 2, in which the total tablet weight was reduced by 50%, than in Example 1. .
  • Example 5 in which the total weight of the tablet and the content of each component of Example 4 were reduced by 1/2, and the tablet total weight and the content of each component were reduced by 2/3 Example 6 showed a dissolution rate similar to that of Example 4, respectively (Tablet hardness of Examples 5 to 6 16 kp).
  • all of the tablets of Examples 4 to 6 satisfied the conditions for determining the uniformity of the formulation (Test Example 4).
  • Test Example 4 Preparation uniformity test of amlodipine, chlorthalidone and losartan
  • UV absorption spectrophotometer (measurement wavelength: 240 mm)
  • Table 8 shows the uniformity results of amlodipine, chlorthalidone and losartan formulations.
  • Test Example 5 Productivity (compression speed) and quality (content uniformity) test
  • Example 3 it exhibits higher productivity than when the mixed granule portion is compressed into a single-layer tablet (Example 1) and produced compared to a two-layer tablet (Comparative Example 3) obtained by tableting the separated granules into upper and lower layers. In addition, it exhibits higher productivity when tableting the mixed granular portion into a single-layered tablet than a single-layered tablet including a separate granular portion.

Abstract

The present invention relates to a complex pharmaceutical single-layer tablet preparation, for preventing or treating a cardiovascular disease, comprising as active ingredients amlodipine or pharmaceutically acceptable salts thereof, chlorthalidone or pharmaceutically acceptable salts thereof, and losartan or pharmaceutically acceptable salts thereof in small amounts.

Description

암로디핀, 로사르탄 및 클로르탈리돈을 단층정에 포함하는 심혈관계 질환의 예방 또는 치료용 약제학적 복합제제A pharmaceutical combination formulation for the prevention or treatment of cardiovascular diseases, comprising amlodipine, losartan and chlorthalidone in a single-layer tablet
본 발명은 유효성분으로서 암로디핀, 로사르탄 및 클로르탈리돈을 단층정에 포함하는 심혈관계 질환의 예방 또는 치료용 단층정 복합제제에 관한 것으로, 보다 구체적으로 암로디핀, 로사르탄 및 클로르탈리돈을 저용량으로 단층정에 포함하는 용출률, 안정성 및 생산성이 향상된 약제학적 복합제제에 관한 것이다. The present invention relates to a single-layered tablet combination formulation for the prevention or treatment of cardiovascular diseases, comprising amlodipine, losartan and chlorthalidone as active ingredients in a single-layered tablet, and more specifically, amlodipine, losartan and chlorthalidone in a low dose. It relates to a pharmaceutical combination formulation with improved dissolution rate, stability and productivity contained in a single-layer tablet.
전 세계적으로 심혈관계 질환은 유병률이 높고 오랜 기간을 통해 발병해 계속 재발하는 만성 질환이 많으므로 초기부터 적절한 치료 관리가 중요하다. 기존에는 고혈압을 비롯한 심혈관계 치료를 위해 단일제 치료부터 시작하는 단계적 치료 접근방식(stepped care approach)이 선호되었으나 이러한 치료법에서는 단일제 약물의 용량 증량에 따른 용량-의존적 이상반응이 증가, 약물 용량 증량 및 약물 추가를 위한 환자의 병원 방문횟수가 증가, 이에 따른 환자 복용 순응도 저하 및 이에 따른 혈압 조절의 실패, 그리고 반복된 상향 적정(up-titration) 및 약물 추가에 따른 치료적 타성(treatment inertia; 혈압이 조절되지 않아도 수용하게 됨)이 문제되었다. 따라서, 기존의 복잡한 단계적 치료 접근방식을 대체할 수 있는 효과적인 심혈관계 질환 치료 방법이 임상적으로 필요하다.Globally, cardiovascular diseases have a high prevalence and many chronic diseases that develop over a long period of time and continue to recur, so proper treatment management from the beginning is important. Conventionally, for the treatment of cardiovascular diseases including hypertension, a stepped care approach, starting with single drug treatment, was preferred. An increase in the number of patient visits to the hospital for addition, a decrease in patient compliance, and a failure to control blood pressure accordingly, and treatment inertia due to repeated up-titration and drug addition Even if it is not, it will be accepted) was a problem. Therefore, there is a clinical need for an effective cardiovascular disease treatment method that can replace the existing complex step-by-step treatment approach.
서로 다른 작용 메커니즘을 가진 약물의 복합제제 예컨대 암로디핀 및 로사르탄의 복합제제는 기존의 단일제제보다 고혈압 및 심혈관계질환의 예방 또는 치료에 더욱 뛰어난 효과를 나타내고, 각각 사용되는 약물의 부작용을 감소시키며 환자의 순응도를 높이는 장점이 있다. 상기 복합제제는 대한민국 특허등록 제1160151호 및 제1232296호 등에 개시되어 있으며, 현재 아모잘탄이라는 상품명으로 판매된고 있다. 또한, 암로디핀, 로사르탄 및 클로르탈리돈의 복합제제에 관한 연구가 이루어지고 있으며, 대한민국 특허등록 제1914930호 및 제1910902호는 로사르탄 겔화로 인한 약물의 용출률 저하를 방지하기 위해 암로디핀 및 클로르탈리돈을 포함하는 제1혼합부와 로사르탄을 포함하는 제2혼합부를 분리하여 복합제제를 제조하는 방법을 제시한다. Combination formulations of drugs with different mechanisms of action, such as amlodipine and losartan, show a superior effect in the prevention or treatment of hypertension and cardiovascular disease than the conventional single formulation, and reduce the side effects of each used drug and reduce the patient It has the advantage of increasing compliance. The combination formulation is disclosed in Korean Patent Registration Nos. 1160151 and 1232296, etc., and is currently sold under the trade name of Amosartan. In addition, research on a combination formulation of amlodipine, losartan, and chlorthalidone is being conducted, and Korean Patent Registration Nos. 1914930 and 1910902 discloses amlodipine and chlorthalidone in order to prevent a decrease in the dissolution rate of the drug due to losartan gelation. A method for preparing a complex formulation is provided by separating the first mixed part containing and the second mixed part containing losartan.
그런데, 기존에 알려진 단일제제의 상용량을 포함하는 복합제제를 초기 심혈관계 질환, 예를 들어 경증 고혈압 내지는 중등증 고혈압으로 분류되는 환자에게 투여하면, 과도한 혈압강하와 이에 따른 부작용을 나타날 수 있는 문제점이 있다. 또한, 심혈관계 질환 치료제의 이상사례 보고 건수는 매년 증가하고 있으며, 예를 들어 암로디핀을 비롯한 칼슘채널길항제에는 말초부종, 전신부종, 얼굴부종 등 부종과 관련한 이상반응이 다른 계열 보다 많은 것으로 알려져 있다. 또한, 기존에 연구된 복합제제와 이의 제조방법은 저용량 복합제제를 제공하는 방법으로는 용출률, 안정성 또는 생산성 면에서 바람직하지 못하다. 따라서, 따라서, 초기 심혈관계 질환의 예방 또는 치료에 사용될 수 있는 용출률, 안정성 및 생산성이 개선된 저용량 복합제제를 개발할 필요가 있다.However, when a previously known combination formulation containing the usual dose of a single agent is administered to a patient classified as an early cardiovascular disease, for example, mild hypertension or moderate hypertension, there is a problem that excessive blood pressure lowering and side effects may occur. have. In addition, the number of reports of adverse events for cardiovascular disease treatment is increasing every year. For example, it is known that calcium channel blockers including amlodipine have more adverse reactions related to edema, such as peripheral edema, systemic edema, and facial edema, than other types. In addition, the previously studied combination formulation and its manufacturing method are not preferable in terms of dissolution rate, stability or productivity as a method of providing a low-dose combination formulation. Therefore, there is a need to develop a low-dose combination formulation with improved dissolution rate, stability and productivity that can be used for the prevention or treatment of early cardiovascular disease.
일 양상은 초기 심혈관계 질환의 예방 또는 치료에 사용될 수 있는 용출률, 안정성 및 생산성이 개선된 저용량 약제학적 복합제제를 제공하는 것이다. One aspect is to provide a low-dose pharmaceutical combination formulation with improved dissolution rate, stability and productivity that can be used for the prevention or treatment of early cardiovascular disease.
다른 일 양상은 상기 복합제제의 제조방법을 제공하는 것이다. Another aspect is to provide a method for preparing the combination formulation.
다른 일 양상은 상기 복합제제를 이용한 심혈관계 질환의 치료 방법을 제공하는 것이다.Another aspect is to provide a method for treating cardiovascular disease using the combination formulation.
일 양상은 유효성분으로서 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 및 로사르탄 또는 이의 약제학적으로 허용가능한 염을 저용량으로 포함하는 심혈관계 질환의 예방 또는 치료용 약제학적 단층정 복합제제를 제공한다.One aspect is prevention of cardiovascular disease comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in a low dose. It provides a pharmaceutical monolayer tablet combination formulation for treatment.
다른 일 양상은 유효성분으로서 암로디핀 또는 이의 약제학적 허용가능한 염, 클로르탈리돈 또는 이의 약제학적 허용가능한 염, 및 로사르탄 또는 이의 약제학적 허용가능한 염을 저용량으로 포함하는 심혈관계 질환의 예방 또는 치료용 약제학적 단층정 복합제제의 제조방법을 제공한다.Another aspect is for the prevention or treatment of cardiovascular diseases comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in a low dose Provided is a method for manufacturing a pharmaceutical single-layer tablet combination formulation.
다른 일 양상은 유효성분으로서 암로디핀 또는 이의 약제학적 허용가능한 염, 클로르탈리돈 또는 이의 약제학적 허용가능한 염, 및 로사르탄 또는 이의 약제학적 허용가능한 염을 저용량으로 포함하는 약제학적 단층정 복합제제를 투여함에 따른 초기 심혈관계 질환의 치료 방법을 제공한다.Another aspect is the administration of a pharmaceutical single-layer tablet combination formulation comprising, as an active ingredient, amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof in a low dose. It provides a method of treating early cardiovascular disease according to the present invention.
일 양상에 따른 약제학적 단층정 복합제제는 초기 심혈관계 질환의 예방 또는 치료에 사용될 수 있고, 유효성분의 용출률이 개선되고, 복합제제의 안정성 및 생산성이 개선된다. The pharmaceutical single-layer tablet combination formulation according to an aspect can be used for the prevention or treatment of early cardiovascular disease, and the dissolution rate of the active ingredient is improved, and the stability and productivity of the combination formulation are improved.
일 양상에 따른 유효성분으로서 암로디핀 또는 이의 약제학적 허용가능한 염, 로사르탄 또는 이의 약제학적 허용가능한 염, 및 클로르탈리돈 또는 이의 약제학적 허용가능한 염을 저용량으로 포함하는 약제학적 복합제제는, 임상적으로 약물 투여에 따른 이상반응을 최소화하면서도 개선된 혈압강하 효과를 나타내므로 과도한 혈압강하 또는 이상반응에 따른 기존 혈압치료법의 한계를 극복할 수 있으며, 위험성 대비 유익성이 우수하다. 또한, 상기 복합제제는 서로 다른 메커니즘을 가진 약물을 병용 투여함에 따라 심혈관계 질환을 효과적으로 예방 또는 치료하며, 가능한 모든 고혈압 발생기전을 한번에 억제하여 혈압 강하 효과를 최대화하고, 상호 보완적인 작용기전으로 효과에 대한 환자별 변동성을 감소시킬 수 있고, 다인성(multifactorial) 기전에 의한 고혈압에 대한 혈압 치료율을 높일 수 있다. 이와 동시에 상기 복합제제는 각 단일 성분의 투여 용량을 최대한 낮추어 용량-의존적인 이상반응을 줄일 수 있으므로 고혈압 치료제로서 안전성이 우수하다. A pharmaceutical combination preparation comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and chlorthalidone or a pharmaceutically acceptable salt thereof in a low dose as an active ingredient according to an aspect is clinically Because it minimizes adverse reactions resulting from drug administration and exhibits improved blood pressure lowering effects, it can overcome the limitations of existing blood pressure treatment methods due to excessive blood pressure drop or adverse reactions, and has excellent benefits versus risks. In addition, the combination formulation effectively prevents or treats cardiovascular diseases by co-administering drugs with different mechanisms, and maximizes the blood pressure lowering effect by suppressing all possible mechanisms of hypertension at once, and has a complementary effect It can reduce patient-specific variability and increase the blood pressure treatment rate for hypertension due to a multifactorial mechanism. At the same time, the combined formulation is excellent in safety as a treatment for hypertension because the dose-dependent adverse reactions can be reduced by lowering the dose of each single component as much as possible.
이에 따라, 상기 저용량 약제학적 복합제제는 경미한 고혈압 내지 중등증의 고혈압을 앓고 있는 개체의 혈압을 초기에 신속하고 효과적으로 치료하고, 혈압 조절률을 높임으로써 임상의 또는 환자들의 치료적 관성 또는 타성(treatment inertia)에 따른 혈압 조절의 실패를 피할 수 있으며, 빠르게 목표 혈압에 도달하여 궁극적으로 환자 순응도를 개선할 수 있다. Accordingly, the low-dose pharmaceutical combination formulation rapidly and effectively initially treats the blood pressure of an individual suffering from mild hypertension to moderate hypertension, and by increasing the blood pressure control rate, therapeutic inertia or inertia (treatment of clinicians or patients) Failure of blood pressure control due to inertia) can be avoided, and target blood pressure can be reached quickly, ultimately improving patient compliance.
또한, 일 구체예에서 상기 저용량 약제학적 복합제제는 암로디핀 약제 특이적 이상반응인 발목부종의 발현을 낮출 수 있다. In addition, in one embodiment, the low-dose pharmaceutical combination preparation can lower the expression of ankle edema, which is an amlodipine drug-specific adverse reaction.
또한, 상기 복합제제는 환자의 복용 부담(Pill burden)을 감소시키고 복용 편의성을 향상시킬 수 있으며, 환자별 변동성을 감소시키고, 단순한 투여용법의 적용이 가능하여 환자 순응도를 개선할 수 있으며, 기존의 stepped-care 치료법보다 약제 비용이 감소되므로 경제적이다. In addition, the combination formulation can reduce the patient's pill burden and improve dosing convenience, reduce patient-specific variability, and improve patient compliance by applying a simple dosing regimen, and It is economical because the drug cost is reduced compared to stepped-care therapy.
또한, 일 구체예에서 상기 복합제제는 유효성분으로서 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 로사르탄 또는 이의 약제학적으로 허용가능한 염을 하나의 동일한 층 즉, 단층정에 포함하여 이층정 등 다층정 보다 제조 시 타정속도를 높일 수 있으므로 복합제제 제조의 생산성을 향상시킨다. 또한, 상기 복합제제는 타정공정 수율이 우수하고 동시에 제제 균일성이 우수하여 의약품 품질을 향상시킨다.In addition, in one embodiment, the combination preparation includes amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof as an active ingredient in one and the same layer. In other words, it is possible to increase the tableting speed when manufacturing a multi-layer tablet such as a double-layer tablet by including it in a single-layer tablet, thereby improving the productivity of the composite preparation. In addition, the composite formulation is excellent in the tableting process yield and at the same time the formulation uniformity is excellent to improve the pharmaceutical quality.
또한, 상기 복합제제 중에 유효성분으로 포함된 암로디핀, 로사르탄 및 클로르탈리돈의 용출률, 함량 균일성 및 열 안정성이 우수하고, 유연물질 발생이 감소되며, 보관 안정성이 우수하므로 제약 분야에 유용하게 사용될 수 있다. 또한, 상기 복합제제는 상호 보완적인 작용기전으로 효과에 대한 환자별 변동성을 감소시킬 수 있다. 상기 복합제제는 24시간 동안 약효가 유지되어 야간 고혈압 및 활동 후 혈압 변동성을 감소시킬 수 있다. In addition, the dissolution rate, content uniformity and thermal stability of amlodipine, losartan and chlorthalidone included as active ingredients in the combined formulation are excellent, the generation of related substances is reduced, and the storage stability is excellent, so it can be usefully used in the pharmaceutical field. can In addition, the combination formulation can reduce the variability of each patient with respect to the effect of a complementary mechanism of action. The combination formulation is effective for 24 hours to reduce nighttime hypertension and blood pressure variability after activity.
도 1은 일 구체예에서 임상시험 대상자에게 도입기(Run-in period)를 거쳐서 처리 기간(Treatment period) 동안 암로디핀 2.5mg, 로사르탄 칼륨 25mg, 클로르탈리돈 6.25mg; 암로디핀 1.67mg, 로사르탄 칼륨 16.67mg, 클로르탈리돈 4.17mg; 또는 암로디핀 1.25mg, 로사르탄 칼륨 12.5mg, 클로르탈리돈 3.13mg을 각각 포함하는 시험용 의약품, 또는 암로디핀 5 mg 또는 10 mg, 또는 로사르탄 칼륨 100mg 을 각각 포함하는 대조용 의약품, 또는 위약(placebo)을 투여하는 방법을 도시한다. 1 shows amlodipine 2.5 mg, losartan potassium 25 mg, chlorthalidone 6.25 mg; amlodipine 1.67 mg, losartan potassium 16.67 mg, chlorthalidone 4.17 mg; or an investigational drug containing amlodipine 1.25 mg, losartan potassium 12.5 mg, and chlorthalidone 3.13 mg, respectively, or a control drug containing amlodipine 5 mg or 10 mg, or losartan potassium 100 mg, respectively, or a placebo; The method of administration is shown.
도 2는 8주차에 FAS에서 기저치(baseline)로부터의 sitSBP 변화를 나타낸다. Figure 2 shows sitSBP change from baseline in FAS at week 8.
도 3은 8주차에 FAS에서 기저치로부터의 sitDBP 변화를 나타낸다. 3 shows sitDBP change from baseline in FAS at week 8.
도 4는 8주차에 FAS에서 혈압 조절을 달성한 대상체 비율을 나타낸다. 이 때, 혈압 조절의 달성은 sitSBP < 140mmHg 및 sitDBP < 90mmHg 로 정의한다. 4 shows the proportion of subjects who achieved blood pressure control in FAS at Week 8. Here, achievement of blood pressure control is defined as sitSBP < 140 mmHg and sitDBP < 90 mmHg.
도 5는 8주차에 FAS에서 혈압 반응자의 비율을 나타낸다. 이 때, 혈압 반응자는 기저치 대비 sitSBP 감소량 ≥ 20 mmHg 또는 sit DBP 감소량 ≥ 10 mmHg 시험대상자를 지칭한다.5 shows the proportion of blood pressure responders in FAS at week 8. In this case, blood pressure responders refer to subjects with sitSBP decrease ≥ 20 mmHg or sit DBP decrease ≥ 10 mmHg compared to baseline.
도 6은 8주차에 FAS에서 기저치로부터의 맥압 변화를 나타낸다. 6 shows the change in pulse pressure from baseline in FAS at week 8.
도 7은 8주차에 FAS (sitSBP < 160 mmHg)에서 기저치로부터의 sitSBP 변화를 나타낸다.7 shows sitSBP change from baseline in FAS (sitSBP < 160 mmHg) at 8 weeks.
도 8은 암로디핀 2.5mg, 로사르탄 칼륨 25mg, 클로르탈리돈 6.25mg; 암로디핀 1.67mg, 로사르탄 칼륨 16.67mg, 클로르탈리돈 4.17mg; 또는 암로디핀 1.25mg, 로사르탄 칼륨 12.5mg, 클로르탈리돈 3.13mg을 각각 포함하는 시험용 의약품, 또는 암로디핀 5 mg 및 10 mg을 각각 포함하는 대조용 의약품 투여에 따른 8주차 FAS에서 발목 둘레의 기저치로부터의 변화(양쪽 발목 중 기저치로부터 8주차 발목 둘레 변화의 절대값이 큰 발목을 기준으로 함)를 나타낸다.8 is amlodipine 2.5 mg, losartan potassium 25 mg, chlorthalidone 6.25 mg; amlodipine 1.67 mg, losartan potassium 16.67 mg, chlorthalidone 4.17 mg; or an investigational drug containing amlodipine 1.25 mg, losartan potassium 12.5 mg, and chlorthalidone 3.13 mg, respectively, or a control drug containing amlodipine 5 mg and 10 mg, respectively, from baseline around the ankle in FAS at Week 8. Changes (based on the ankle with the largest absolute value of the change in ankle circumference at week 8 from baseline among both ankles) are shown.
도 9는 비교예 1 및 2의 시간에 따른 (a)암로디핀 베실레이트, (b)클로르탈리돈의 용출률(%)을 나타낸다. 9 shows the dissolution rates (%) of (a) amlodipine besylate and (b) chlorthalidone according to time in Comparative Examples 1 and 2.
도 10은 실시예 1과 비교예 3 및 4의 시간에 따른 (a)암로디핀 베실레이트, (b)클로르탈리돈의 용출률(%)을 나타낸다. 10 shows the dissolution rates (%) of (a) amlodipine besylate and (b) chlorthalidone according to time in Example 1 and Comparative Examples 3 and 4.
도 11은 실시예 4와 비교예 5 및 6의 시간에 따른 (a)암로디핀 베실레이트, (b)클로르탈리돈의 용출률(%)을 나타낸다. 11 shows the dissolution rates (%) of (a) amlodipine besylate and (b) chlorthalidone according to time in Example 4 and Comparative Examples 5 and 6.
도 12는 비교예 3, 비교예 4, 및 실시예 1에서 클로르탈리돈의 (a)Imp B와 (b)Unknown max 유연물질 함량(%)을 나타낸다. 12 shows (a) Imp B and (b) Unknown max related substance content (%) of chlorthalidone in Comparative Examples 3, 4, and 1;
도 13은 실시예 1 및 2의 시간에 따른 (a)암로디핀 베실레이트, (b)로사르탄 칼륨, (c)클로르탈리돈의 용출률(%)을 나타낸다. 13 shows the dissolution rates (%) of (a) amlodipine besylate, (b) losartan potassium, and (c) chlorthalidone over time in Examples 1 and 2.
도 14은 실시예 2 내지 6의 시간에 따른 (a)암로디핀 베실레이트, (b)로사르탄 칼륨, (c)클로르탈리돈의 용출률(%)을 나타낸다. 14 shows the dissolution rates (%) of (a) amlodipine besylate, (b) losartan potassium, and (c) chlorthalidone over time in Examples 2 to 6.
도 15는 (a) 비교예 3 및 (b) 실시예 3 각각에서 타정 속도에 따른 함량판정치(%)를 나타낸다. 15 shows the content determination value (%) according to the tableting speed in each of (a) Comparative Example 3 and (b) Example 3.
이하, 본 발명을 보다 상세하게 설명한다. Hereinafter, the present invention will be described in more detail.
일 양상은 유효성분으로서 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 및 로사르탄 또는 이의 약제학적으로 허용가능한 염을 저용량으로 포함하는 심혈관계 질환의 예방 또는 치료용 약제학적 단층정 복합제제를 제공한다. One aspect is prevention of cardiovascular disease comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in a low dose. It provides a pharmaceutical monolayer tablet combination formulation for treatment.
본 명세서에서 사용된 용어 "심혈관계 질환"은, 생체 내 순환계 시스템의 이상, 기능장애, 손상 등의 다양한 원인으로 인하여 발생되는 직접적인 질환뿐만 아니라, 이러한 직접적인 질환에 의해 파생되는 2차적 질환을 포함한다. 예를 들어, 상기 심혈관계 질환은 고혈압, 이상지질혈증, 협심증, 동맥연축, 심부정맥, 심비대, 뇌경색, 울혈심부전, 동맥경화증, 관상동맥심장병, 또는 심근경색을 포함할 수 있다. As used herein, the term "cardiovascular disease" includes not only direct diseases caused by various causes such as abnormalities, dysfunctions, and damage of the circulatory system in vivo, but also secondary diseases derived from such direct diseases. . For example, the cardiovascular disease may include hypertension, dyslipidemia, angina pectoris, arteriospasticity, cardiac arrhythmias, cardiac hypertrophy, cerebral infarction, congestive heart failure, arteriosclerosis, coronary heart disease, or myocardial infarction.
본 명세서에서 사용된 용어 “혈압”은 혈관을 따라 흐르는 혈액이 혈관의 벽에 주는 압력을 말한다. 혈압은 맥박에서 수축기의 최고 혈압과 이완기의 최저 혈압의 두 측정치로 요약될 수 있다. As used herein, the term “blood pressure” refers to the pressure that blood flowing along the blood vessel exerts on the wall of the blood vessel. Blood pressure can be summarized as two measures in pulse: systolic systolic blood pressure and diastolic diastolic blood pressure.
본 명세서에서 사용된 용어“고혈압(hypertension)”은 혈압이 정상 범위보다 높은 만성 질환을 말한다. 고혈압은 본태성 고혈압(원발성 고혈압)과 이차성 고혈압으로 구분할 수 있다. 또한, 고혈압의 기준은 여러 가지 역학 조사를 통하여 심혈관계 합병증에 의한 사망률이 증가하는 혈압으로 정의될 수 있다. 또한, 고혈압의 기준은 위험대비 효과 즉, 해당 혈압을 낮추었을 때 이로 인한 위험보다 이득이 큰 것이 증명된 수치를 고려하여 정의될 수 있다. 예컨대 2018년 유럽고혈압학회(ESH) 가이드라인의 고혈압 진단기준에 따를 때 다음과 같이 정상 또는 고혈압을 구분할 수 있다.As used herein, the term “hypertension” refers to a chronic disease in which blood pressure is higher than the normal range. Hypertension can be divided into essential hypertension (primary hypertension) and secondary hypertension. In addition, the criteria for hypertension can be defined as blood pressure, which increases mortality due to cardiovascular complications through various epidemiological investigations. In addition, the criteria for hypertension may be defined in consideration of the risk-to-risk effect, that is, a value that proves that the benefit is greater than the risk when the corresponding blood pressure is lowered. For example, according to the criteria for the diagnosis of hypertension of the European Society of Hypertension (ESH) guidelines in 2018, normal or hypertension can be classified as follows.
[표 1][Table 1]
Figure PCTKR2021006285-appb-I000001
Figure PCTKR2021006285-appb-I000001
ESH(2018) 가이드라인에 따를 때, 사람에게 가장 이상적인 적정 혈압은 120/80mmHg 이하이며, 수축기 혈압이 120~129mmHg, 및/또는 이완기 혈압이 80~84mmHg인 경우 정상이라고 지칭할 수 있다. 또한, ESH 가이드라인은 수축기 혈압과 이완기 혈압에 따라 분류를 세분화하여 정상보다 높은 혈압(130~139/85~89mmHg), 고혈압 1기(140~159/90~99mmHg), 고혈압 2기(160~179/100~109mmHg), 고혈압 3기(180/110mmHg 이상), 수축기 단독 고혈압(140mmHg 이상/90mmHg 미만) 등으로 구분한다. According to the ESH (2018) guidelines, the ideal optimal blood pressure for humans is 120/80 mmHg or less, systolic blood pressure of 120 to 129 mmHg, and/or diastolic blood pressure of 80 to 84 mmHg can be referred to as normal. In addition, the ESH guidelines subdivide the classification according to systolic blood pressure and diastolic blood pressure. 179/100~109mmHg), stage 3 hypertension (180/110mmHg or more), and systolic single hypertension (140mmHg or more/less than 90mmHg).
또한, 일반적으로 휴식 시 정상 혈압은 수축시 100~140mmHg에 이완시 60~90mmHg이고, 혈압이 지속적으로 140/90mmHg 이상일 때 고혈압이 있다고 말할 수 있다. Also, in general, normal blood pressure at rest is 100 to 140 mmHg during contraction, 60 to 90 mmHg at relaxation, and hypertension can be said when the blood pressure is continuously 140/90 mmHg or higher.
2018 대한고혈압학회 고혈압 진료지침에 따르면, 고혈압 전단계의 이완기혈압 (DBP) 기준을 80 mmHg까지 낮춤으로서 적극적인 고혈압 예방을 장려하고 있다. 또한 '주의혈압 (SBP 120~129 mmHg 및 DBP 80 mmHg 미만)'이라는 개념의 도입을 통해 정상혈압보다 혈압이 조금 높더라도 가급적 혈압을 정상범위로 유지하도록 개정하였고 140/90 mmHg 미만으로 혈압을 조절하더라도 130/80 mmHg까지 혈압을 최대한 낮출 것을 권고하고 있다. According to the 2018 Korean Society of Hypertension guidelines for hypertension treatment, active prevention of hypertension is encouraged by lowering the diastolic blood pressure (DBP) standard in the prehypertensive stage to 80 mmHg. In addition, by introducing the concept of 'attention blood pressure (SBP 120-129 mmHg and DBP less than 80 mmHg)', it was revised to keep the blood pressure in the normal range as much as possible even if the blood pressure is slightly higher than normal blood pressure. However, it is recommended to lower the blood pressure to 130/80 mmHg as much as possible.
본 명세서에서 사용된 용어 “맥압”은 수축기 혈압과 이완기 혈압의 차이(sitSBP - sitDBP)를 말한다. 맥압은 심장이 수축하고 이완할 때의 혈압 차이로, 노화에 따라 혈관 벽이 두꺼워져서 탄력을 잃으면 수축기 압력이 커지고, 이 때 팽창한 동맥이 원래 상태로 돌아가기 어려워 이완기 혈압은 내려가므로 맥압이 커질 수 있다. 1999년의 Framingham 연구에서 Franklin 등은 연령, 성별, 기타 위험인자들을 보정했을 경우 맥압이 관동맥 질환의 강력한 위험 예측인자라고 보고하였다. 또한, 50세 이상에서는 이완기 혈압보다 수축기혈압, 맥압이 심혈관 합병증에 대해 더 큰 예측력을 가질 수 있다(일차 의료용 근거기반 고혈압 권고 요약본, 대한의학회, 질병관리본부). As used herein, the term “pulse pressure” refers to the difference between systolic blood pressure and diastolic blood pressure (sitSBP - sitDBP). Pulse pressure is the difference in blood pressure when the heart contracts and relaxes. As the blood vessel wall thickens and loses elasticity with aging, the systolic pressure increases. can In a 1999 Framingham study, Franklin et al. reported that pulse pressure was a strong predictor of risk for coronary artery disease when age, sex, and other risk factors were adjusted. In addition, in patients over 50 years of age, systolic blood pressure and pulse pressure may have greater predictive power for cardiovascular complications than diastolic blood pressure (Summary of Evidence-Based Hypertension Recommendation for Primary Medical Use, Korean Medical Association, Korea Centers for Disease Control and Prevention).
본 명세서에서 사용된 용어“합병증(complication)”은 어떤 질병에 다른 증상이 같이 있는 것을 말한다. 고혈압은 어지러움, 두통, 심계, 호흡곤란 등을 증상을 동반할 수 있으며, 만약 인체가 장기적으로 고혈압 상태에 처해 있을 경우, 중풍, 관상동맥 심장병, 신기능 실조 등과 같은 매우 많은 합병증을 유발할 수 있다. As used herein, the term “complication” refers to the presence of other symptoms in a certain disease. High blood pressure can accompany symptoms such as dizziness, headache, heart disease, and breathing difficulties, and if the body is in a state of high blood pressure for a long time, it can cause a lot of complications such as stroke, coronary heart disease, and renal failure.
상기 복합제제는 고혈압을 비롯한 심혈관계 질환 또는 이에 따른 합병증의 예방 또는 치료에 사용될 수 있다. The combination formulation may be used for the prevention or treatment of cardiovascular diseases including hypertension or complications thereof.
심혈관계 치료의 예로 고혈압의 치료에 사용되는 약물은 약물의 작용 메커니즘에 따라 이뇨제, 교감신경 억제제, 혈관확장제로 크게 구분되며 혈관확장제는 다시 작용 메커니즘에 따라 ACE(Angiotension converting enzyme) 억제제, 안지오텐신 II 수용체 차단제 및 칼슘 채널 차단제로 구분될 수 있다. As an example of cardiovascular treatment, drugs used for the treatment of hypertension are largely divided into diuretics, sympathetic nerve inhibitors, and vasodilators depending on the mechanism of action of the drug. It can be divided into blockers and calcium channel blockers.
"암로디핀(amlodipine)"은 3-에틸 5-메틸 2-[(2-아미노에톡시)메틸]-4-(2-클로로페닐)-6-메틸-1,4-디하이드로피리딘-3,5-디카복실레이트의 일반명으로, 칼슘 채널 차단제로서 심근 및 혈관 평활근 표면에 있는 칼슘 이온 채널을 막아 혈관 평활근을 이완시키고, 신장의 수입 세동맥을 이완시켜 사구체 여과율을 증가시킴으로써 이뇨작용을 유발하여 혈압 강하 효과를 나타낸다. 암로디핀은 칼슘 채널을 차단하여 협심증, 고혈압 및 울혈성 심장마비와 같은 심혈관계 질환의 치료에 사용된다. 암로디핀은 제 3 세대 CCB로서 경구투여 시 천천히 흡수되면서 약 35~40시간의 긴 반감기로 인하여, 장시간 완만한 혈압 강하효과를 나타내며 기립성 저혈압 등의 부작용이 경감되었으며, 수축기 고혈압 및 뇌졸중을 예방하는데 효과적이고, 관상동맥 확장작용이 있어 협심증에 유용하다. "Amlodipine" is 3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5 -Common name of dicarboxylate, as a calcium channel blocker, it relaxes vascular smooth muscle by blocking calcium ion channels on the surface of myocardium and vascular smooth muscle, and relaxes renal afferent arterioles to increase glomerular filtration rate, thereby inducing diuresis and lowering blood pressure show the effect. Amlodipine blocks calcium channels and is used to treat cardiovascular diseases such as angina, hypertension and congestive heart attack. As a third-generation CCB, amlodipine is slowly absorbed when administered orally, and due to its long half-life of about 35-40 hours, it has a mild blood pressure lowering effect for a long time, and side effects such as orthostatic hypotension are reduced, and it is effective in preventing systolic hypertension and stroke. It is useful for angina pectoris as it has a coronary artery dilation effect.
"클로르탈리돈(chlorthalidone)"은 벤젠술폰아마이드-2-클로로-5-(2,3-다이히드로-1-히드록시-3-옥소-1H-아이소인돌-1-일)의 일반명으로, 하이그로톤(Hygroton®)이라는 상품명으로 현재 판매되고 있다. 클로르탈리돈은 티아지드 계열의 이뇨제로서 신장 원위세뇨관의 Na+/Cl- 동시 수송체를 차단하여, Na+와 Cl-의 재흡수를 억제하고 K+의 배설을 증가시켜 뇨에 수분을 저류하게 하는 작용을 한다. 구체적으로 클로르탈리돈은 티아지드 계열의 이뇨제로서 신장 원위세뇨관의 Na+/Cl- 동시 수송체를 차단하여, Na+와 Cl-의 재흡수를 억제하고 K+의 배설을 증가시켜 뇨의 수분을 저류하게 하는 작용을 한다. 클로르탈리돈은 반감기가 50 내지 60시간이고, 작용시간이 48 내지 72시간이므로, 반감기가 9 내지 10시간, 작용시간이 16 내지 24시간인 하이드로클로로티아지드에 비해 지속시간 및 작용시간이 길어 야간 혈압조절에 더 유용하다."chlorthalidone" is the generic name for benzenesulfonamide-2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl), It is currently sold under the trade name Hygroton ® . Chlorthalidone is a thiazide diuretic that blocks the Na + /Cl - transporter in the renal distal tubule, inhibits the reabsorption of Na + and Cl - and increases the excretion of K + to retain water in the urine. acts to Specifically, chlorthalidone is a thiazide-type diuretic by blocking the Na + /Cl - transporter in the distal renal tubule, inhibiting the reabsorption of Na + and Cl - and increasing the excretion of K + to increase the excretion of urine water. It acts as a stagnant. Since chlorthalidone has a half-life of 50 to 60 hours and an action time of 48 to 72 hours, the duration and action time are longer than that of hydrochlorothiazide, which has a half-life of 9 to 10 hours and an action time of 16 to 24 hours. It is more useful for regulating blood pressure.
"로사르탄(losartan)"은 2-부틸-4-클로로-1-[{2'-(1H-테트라졸-5-일)[1,1'-비페닐]-4-일]메틸]-1H-이미다졸-5-메탄올의 일반명으로, 안지오텐신 수용체 길항제 계열 성분 중 가장 처음으로 개발되었다. 로사르탄은 혈관수축 물질인 안지오텐신 Ⅱ가 수용체에 결합하는 것을 차단하여 고혈압 및 심부전을 치료하는데 사용된다. 또한 허혈성 말초 순환장애, 심근허혈(협심증)을 치료하고, 심근경색 후 심부전의 진행을 예방하며, 당뇨병성 신경병증, 녹내장 등을 치료하는데 사용된다. 또한, 강력한 혈관수축 물질인 안지오텐신 Ⅱ의 수용체를 선택적, 경쟁적으로 길항함으로써 혈압 강하효과를 나타내며, 고혈압, 심부전, 허혈성 말초 순환장애, 심근허혈(협심증) 등을 치료하거나, 심근경색후 심부전의 진행을 예방하고, 당뇨병성 신경병증, 녹내장 등에 유용하다. "Losartan" means 2-butyl-4-chloro-1-[{2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- It is a generic name for 1H-imidazole-5-methanol, and was developed for the first time among angiotensin receptor antagonists. Losartan is used to treat hypertension and heart failure by blocking the binding of angiotensin II, a vasoconstrictor, to receptors. It is also used to treat ischemic peripheral circulation disorder, myocardial ischemia (angina pectoris), prevent the progression of heart failure after myocardial infarction, and treat diabetic neuropathy and glaucoma. In addition, it exhibits a blood pressure lowering effect by selectively and competitively antagonizing the receptor of angiotensin II, a powerful vasoconstrictor, and treats hypertension, heart failure, ischemic peripheral circulation disorder, myocardial ischemia (angina pectoris), etc., or inhibits the progression of heart failure after myocardial infarction. It is useful for preventing, diabetic neuropathy, and glaucoma.
일 구체예에서 상기 복합제제는 유효성분으로서 암로디핀 또는 이의 약제학적 허용가능한 염, 클로르탈리돈 또는 이의 약제학적 허용가능한 염, 및 로사르탄 또는 이의 약제학적 허용가능한 염을 저용량으로 포함한다. In one embodiment, the combination preparation comprises amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in a low dose.
본 명세서에서 사용된 용어 “일일상용량(Daily Defined Dose; DDD)”은 해당 의약품의 주성분별로 주요 적응증에 대하여 70 kg의 성인 1인이 1일 동안 복용해야 하는 평균 유지용량)을 말한다. 예를 들어, 시판 중인 의약품의 경우 암로디핀, 로사르탄 칼륨, 및 클로르탈리돈의 일일 상용량은 각각 약 5 내지 10 mg, 50 내지 100 mg, 및 12.5 내지 25 mg일 수 있다. 예를 들어, 암로디핀, 로사르탄 칼륨, 및 클로르탈리돈의 일일 상용량 중 최저용량은 각각 약 5 mg, 50 mg, 및 12.5 mg일 수 있다. As used herein, the term “Daily Defined Dose (DDD)” refers to the average maintenance dose that an adult of 70 kg should take for one day for the main indications for each main component of the drug. For example, in the case of commercially available pharmaceuticals, the daily doses of amlodipine, losartan potassium, and chlorthalidone may be about 5 to 10 mg, 50 to 100 mg, and 12.5 to 25 mg, respectively. For example, the lowest usual daily dose of amlodipine, losartan potassium, and chlorthalidone may be about 5 mg, 50 mg, and 12.5 mg, respectively.
본 명세서에서 사용된 용어 “저용량”은 의약품의 일일 상용량 대비 더 적은 용량을 의미한다. 상기 저용량은 일일 상용량 대비 약 1/6 내지 약 1/2 용량, 약 1/5 내지 약 1/2 용량, 또는 약 1/4 내지 약 1/2 용량일 수 있다. As used herein, the term “low dose” refers to a dose that is lower than the usual daily dose of a drug. The low dose may be about 1/6 to about 1/2 dose, about 1/5 to about 1/2 dose, or about 1/4 to about 1/2 dose compared to the usual daily dose.
일 구체예에서, 암로디핀 또는 이의 약제학적 가능한 염은 암로디핀 자유 염기 형태로 환산했을 때 0.5 내지 5 mg의 양으로 포함할 수 있다. 일 구체예에서, 암로디핀 또는 이의 약제학적 허용가능한 염은 암로디핀 자유 염기 형태로 환산했을 때 0.8 내지 3 mg의 양으로 포함할 수 있다. In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof may be included in an amount of 0.5 to 5 mg when converted into amlodipine free base form. In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof may be included in an amount of 0.8 to 3 mg when converted into amlodipine free base form.
일 구체예에서, 클로르탈리돈 또는 이의 약제학적 허용 가능한 염은 클로르탈리돈 자유 염기 형태로 환산했을 때 1 내지 7 mg의 양으로 포함할 수 있다. 일 구체예에서, 클로르탈리돈 자유 염기 형태로 환산했을 때 2 내지 7 mg의 양으로 포함할 수 있다. In one embodiment, chlorthalidone or a pharmaceutically acceptable salt thereof may be included in an amount of 1 to 7 mg when converted to chlorthalidone free base form. In one embodiment, it may be included in an amount of 2 to 7 mg when converted to chlorthalidone free base form.
일 구체예에서, 상기 로사르탄 또는 이의 약제학적 허용 가능한 염은 로사르탄 자유 산 형태로 환산했을 때 7 내지 30 mg 양으로 포함할 수 있다.In one embodiment, the losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 7 to 30 mg when converted into losartan free acid form.
일 구체예에서, 암로디핀 또는 이의 약제학적 가능한 염은 암로디핀 자유 염기 형태로 환산했을 때 0.5 내지 5 mg의 양으로 포함하고, 클로르탈리돈 또는 이의 약제학적 허용 가능한 염은 클로르탈리돈 자유 염기 형태로 환산했을 때 1 내지 7 mg의 양으로 포함하고, 로사르탄 또는 이의 약제학적 허용 가능한 염은 로사르탄 자유 산 형태로 환산했을 때 7 내지 30 mg의 양으로 포함할 수 있다. In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof is included in an amount of 0.5 to 5 mg when converted into amlodipine free base form, and chlorthalidone or a pharmaceutically acceptable salt thereof is converted into chlorthalidone free base form It may be included in an amount of 1 to 7 mg, and losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 7 to 30 mg when converted to the form of losartan free acid.
일 구체예에서, 암로디핀 또는 이의 약제학적 허용가능한 염은 암로디핀 자유 염기 형태로 환산했을 때 0.8 내지 3 mg의 양으로 포함하고, 클로르탈리돈 또는 이의 약제학적 허용가능한 염은 클로르탈리돈 자유 염기 형태로 환산했을 때 2 내지 7 mg의 양으로 포함하고, 로사르탄 또는 이의 약제학적 허용가능한 염은 로사르탄 자유 산 형태로 환산했을 때 7 내지 30 mg의 양으로 포함할 수 있다. In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof is included in an amount of 0.8 to 3 mg when converted into amlodipine free base form, and chlorthalidone or a pharmaceutically acceptable salt thereof is chlorthalidone free base form. It may be included in an amount of 2 to 7 mg in terms of conversion, and losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 7 to 30 mg in terms of losartan free acid form.
일 구체예에서, 암로디핀 또는 이의 약제학적 허용가능한 염은 암로디핀 자유 염기 형태로 환산했을 때 1.25 내지 3.5 mg 또는 1.25 내지 2.5 mg의 양으로 포함할 수 있다. In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof may be included in an amount of 1.25 to 3.5 mg or 1.25 to 2.5 mg when converted to amlodipine free base form.
일 구체예에서, 클로르탈리돈 자유 염기 형태로 환산했을 때 3 내지 6.25 mg의 양으로 포함할 수 있다. In one embodiment, it may be included in an amount of 3 to 6.25 mg when converted to chlorthalidone free base form.
일 구체예에서, 로사르탄 또는 이의 약제학적 허용가능한 염은 로사르탄 자유 산 형태로 환산했을 때 11 내지 22 mg의 양으로 포함할 수 있다. 일 구체예에서, 로사르탄 또는 이의 약제학적 허용가능한 염은 로사르탄 자유 산 형태로 환산했을 때 11.5 내지 25 mg 또는 11.5 내지 23 mg의 양으로 포함할 수 있다.In one embodiment, losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 11 to 22 mg in terms of losartan free acid form. In one embodiment, losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 11.5 to 25 mg or 11.5 to 23 mg in terms of losartan free acid form.
일 구체예에서, 암로디핀 또는 이의 약제학적 허용가능한 염은 암로디핀 자유 염기 형태로 환산했을 때 1.25 내지 2.5 mg으로 포함하고, 클로르탈리돈 또는 이의 약제학적 허용가능한 염은 클로르탈리돈 자유 염기 형태로 환산했을 때 3 내지 6.25 mg으로 포함하고, 로사르탄 또는 이의 약제학적 허용가능한 염은 로사르탄 자유 산 형태로 환산했을 때 11 내지 22 mg으로 포함할 수 있다. In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof is included in an amount of 1.25 to 2.5 mg when converted to amlodipine free base form, and chlorthalidone or a pharmaceutically acceptable salt thereof is converted to chlorthalidone free base form. It may be included in an amount of 3 to 6.25 mg, and losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 11 to 22 mg when converted to losartan free acid form.
일 구체예에서, 암로디핀 또는 이의 약제학적 허용가능한 염은 암로디핀 자유 염기 형태로 환산했을 때 1.25 내지 2.5 mg으로 포하되고, 클로르탈리돈 또는 이의 약제학적 허용가능한 염은 클로르탈리돈 자유 염기 형태로 환산했을 때 3 내지 6.25 mg으로 포함하고, 로사르탄 또는 이의 약제학적 허용가능한 염은 로사르탄 자유 산 형태로 환산했을 때 11.5 내지 23 mg으로 포함할 수 있다. In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof is included in an amount of 1.25 to 2.5 mg when converted to amlodipine free base form, and chlorthalidone or a pharmaceutically acceptable salt thereof is converted to chlorthalidone free base form. It may be included in an amount of 3 to 6.25 mg, and losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 11.5 to 23 mg in terms of losartan free acid form.
상기 저용량 약제학적 복합제제에서 암로디핀 또는 이의 약제학적 허용가능한 염은 암로디핀 자유 염기 형태로 환산했을 때 0.5 내지 4 mg, 0.5 내지 3 mg, 0.8 내지 3 mg, 0.8 내지 2.5 mg, 0.83 내지 2.5 mg, 1.25 내지 2.5 mg, 1 내지 3 mg, 1.5 내지 3.5 mg, 1.5 내지 2.5 mg, 또는 1.25 내지 2.5 mg의 양으로 포함될 수 있다. 예를 들어, 상기 암로디핀 자유 염기 또는 암로디핀의 약제학적으로 허용가능한 염은 0.83 mg, 1 mg, 1.25 mg, 1.5 mg, 1.67 mg, 2.5 mg, 3 mg, 또는 3.5 mg의 양으로, 또는 상기 수치를 상한 또는 하한으로 하는 범위로 포함될 수 있다. In the low-dose pharmaceutical combination preparation, amlodipine or a pharmaceutically acceptable salt thereof is 0.5 to 4 mg, 0.5 to 3 mg, 0.8 to 3 mg, 0.8 to 2.5 mg, 0.83 to 2.5 mg, 1.25 when converted to amlodipine free base form. to 2.5 mg, 1 to 3 mg, 1.5 to 3.5 mg, 1.5 to 2.5 mg, or 1.25 to 2.5 mg. For example, the amlodipine free base or pharmaceutically acceptable salt of amlodipine may be in an amount of 0.83 mg, 1 mg, 1.25 mg, 1.5 mg, 1.67 mg, 2.5 mg, 3 mg, or 3.5 mg, or It may be included in a range set as an upper limit or a lower limit.
상기 암로디핀은 약제학적 허용가능한 염의 형태 예컨대 암로디핀 캄실레이트 또는 암로디핀 베실레이트로서 1 내지 4 mg, 1.3 내지 3.9 mg, 1.5 내지 4 mg, 1.8 내지 4 mg, 또는 1.96 내지 3.9 mg의 양으로 포함될 수 있다. 예를 들어, 상기 암로디핀의 약제학적으로 허용가능한 염 예컨대 암로디핀 캄실레이트 또는 암로디핀 베실레이트는 1.3 mg, 1.57 mg, 1.74 mg, 1.96 mg, 2.32 mg, 2.62 mg, 3.47 mg, 또는 3.92 mg의 양으로, 또는 상기 수치를 상한 또는 하한으로 하는 범위로 포함될 수 있다. The amlodipine may be included in the form of a pharmaceutically acceptable salt such as amlodipine camsylate or amlodipine besylate in an amount of 1 to 4 mg, 1.3 to 3.9 mg, 1.5 to 4 mg, 1.8 to 4 mg, or 1.96 to 3.9 mg. For example, the pharmaceutically acceptable salt of amlodipine such as amlodipine camsylate or amlodipine besylate is in an amount of 1.3 mg, 1.57 mg, 1.74 mg, 1.96 mg, 2.32 mg, 2.62 mg, 3.47 mg, or 3.92 mg, Or it may be included in a range having the numerical value as an upper limit or a lower limit.
상기 저용량 약제학적 복합제제에서 클로르탈리돈 자유 염기 형태로 환산했을 때 1 내지 7 mg, 2 내지 7 mg, 2 내지 6.5 mg, 2.1 내지 6.25 mg, 3 내지 6.25 mg 3.13 내지 6.25 mg, 3 내지 6.5 mg, 또는 3 내지 7 mg의 양으로 포함될 수 있다. 예를 들어, 상기 클로르탈리돈은 2.08 mg, 2.5 mg, 3.13 mg, 4.17 mg, 또는 6.25 mg의 양으로, 또는 상기 수치를 상한 또는 하한으로 하는 범위로 포함될 수 있다.1 to 7 mg, 2 to 7 mg, 2 to 6.5 mg, 2.1 to 6.25 mg, 3 to 6.25 mg 3.13 to 6.25 mg, 3 to 6.5 mg when converted to chlorthalidone free base form in the low-dose pharmaceutical combination preparation , or may be included in an amount of 3 to 7 mg. For example, the chlorthalidone may be included in an amount of 2.08 mg, 2.5 mg, 3.13 mg, 4.17 mg, or 6.25 mg, or in a range having the above value as an upper limit or a lower limit.
상기 저용량 약제학적 복합제제에서 로사르탄 또는 이의 약제학적 허용가능한 염은 로사르탄 자유 산 형태로 환산했을 때 5 내지 30 mg, 7 내지 30 mg, 7 내지 25 mg, 7.5 내지 23 mg, 7.6 내지 22.9 mg, 10 내지 30 mg, 11 내지 23 mg, 11 내지 22 mg, 11.4 내지 22.95 mg, 11.47 내지 22.93 mg, 11.5 내지 23 mg 또는 12 내지 25 mg의 양으로 포함될 수 있다. 예를 들어, 상기 로사르탄 자유 산은 약 7.64 mg, 9.17 mg, 11.47 mg, 12.5 mg, 15.29 mg, 16.67 mg, 22.93 mg, 또는 25 mg의 양으로, 또는 상기 수치를 상한 또는 하한으로 하는 범위로 포함될 수 있다.In the low-dose pharmaceutical combination preparation, losartan or a pharmaceutically acceptable salt thereof is 5 to 30 mg, 7 to 30 mg, 7 to 25 mg, 7.5 to 23 mg, 7.6 to 22.9 mg when converted to losartan free acid form. , 10 to 30 mg, 11 to 23 mg, 11 to 22 mg, 11.4 to 22.95 mg, 11.47 to 22.93 mg, 11.5 to 23 mg or 12 to 25 mg. For example, the losartan free acid may be included in an amount of about 7.64 mg, 9.17 mg, 11.47 mg, 12.5 mg, 15.29 mg, 16.67 mg, 22.93 mg, or 25 mg, or within a range having the upper or lower limit of the value. can
상기 로사르탄은 약제학적 허용가능한 염의 형태, 예컨대 로사르탄 칼륨으로서 8 내지 30 mg, 예를 들어 8.3 내지 25 mg, 10 내지 25 mg, 또는 12.5 내지 25 mg일 수 있다. 예를 들어, 상기 로사르탄의 약제학적으로 허용가능한 염 예컨대 로사르탄 칼륨은 약 8.33 mg, 10 mg, 12.5 mg, 16.67 mg, 또는 25 mg의 양으로, 또는 상기 수치를 상한 또는 하한으로 하는 범위로 포함될 수 있다.The losartan may be in the form of a pharmaceutically acceptable salt, such as 8 to 30 mg, such as 8.3 to 25 mg, 10 to 25 mg, or 12.5 to 25 mg, as losartan potassium. For example, the pharmaceutically acceptable salt of losartan such as losartan potassium may be in an amount of about 8.33 mg, 10 mg, 12.5 mg, 16.67 mg, or 25 mg, or in a range having the upper or lower limit of the value. may be included.
상기 저용량 약제학적 복합제제는 암로디핀 또는 이의 약제학적 허용가능한 염, 로사르탄 또는 이의 약제학적 허용가능한 염, 및 클로르탈리돈 또는 이의 약제학적 허용가능한 염을 각각 암로디핀 자유 염기, 로사르탄 자유 산, 및 클로르탈리돈 자유 염기 형태로 환산했을 때 각각, 0.5 내지 3 mg, 5 내지 30 mg, 및 1 내지 7 mg의 양으로; 0.8 내지 3 mg, 8 내지 30 mg, 및 2 내지 7 mg의 양으로; 0.62 내지 2.5 mg, 6.25 내지 25 mg, 및 1.56 내지 6.25 mg의 양; 0.8 내지 2.5 mg, 8.3 내지 25 mg, 및 2 내지 6.5 mg의 양; 0.8 내지 2.5 mg, 8 내지 25 mg, 및 2 내지 6.25 mg의 양; 1 내지 3 mg, 10 내지 30 mg, 및 3 내지 7 mg의 양; 1.25 내지 2.5 mg, 11 내지 23 mg, 및 3.13 내지 6.25 mg의 양; 1.25 내지 2.5 mg, 12 내지 27 mg, 및 3 내지 6.5 mg의 양; 1.25 내지 2.5 mg, 12.5 내지 25 mg의 양, 3.13 내지 6.25 mg의 양; 또는 1.5 내지 2.5 mg, 12.5 내지 25 mg, 및 3.13 내지 6.25 mg의 양으로 포함할 수 있다. The low-dose pharmaceutical combination preparation comprises amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and chlorthalidone or a pharmaceutically acceptable salt thereof, respectively, amlodipine free base, losartan free acid, and chlorin. in amounts of 0.5 to 3 mg, 5 to 30 mg, and 1 to 7 mg, respectively, converted to thalidone free base form; in amounts of 0.8 to 3 mg, 8 to 30 mg, and 2 to 7 mg; in amounts of 0.62 to 2.5 mg, 6.25 to 25 mg, and 1.56 to 6.25 mg; in amounts of 0.8 to 2.5 mg, 8.3 to 25 mg, and 2 to 6.5 mg; in amounts of 0.8 to 2.5 mg, 8 to 25 mg, and 2 to 6.25 mg; in amounts of 1 to 3 mg, 10 to 30 mg, and 3 to 7 mg; amounts of 1.25 to 2.5 mg, 11 to 23 mg, and 3.13 to 6.25 mg; amounts of 1.25 to 2.5 mg, 12 to 27 mg, and 3 to 6.5 mg; 1.25 to 2.5 mg, in an amount of 12.5 to 25 mg, in an amount of 3.13 to 6.25 mg; or 1.5 to 2.5 mg, 12.5 to 25 mg, and 3.13 to 6.25 mg.
예를 들어, 상기 저용량 약제학적 복합제제에서 암로디핀 또는 이의 약제학적 허용가능한 염, 로사르탄 또는 이의 약제학적 허용가능한 염, 클로르탈리돈 또는 이의 약제학적 허용가능한 염은 각각 암로디핀 자유 염기, 로사르탄 자유 산, 클로르탈리돈 자유 염기 형태로 환산했을 때 각각, 2.5 mg, 25 mg, 및 6.25 mg의 양; 2.5 mg, 23 mg, 및 6.5 mg의 양; 2.5 mg, 22.9 mg, 및 6.25 mg의 양; 1.7 mg, 15.3 mg, 및 4.2 mg의 양; 1.67 mg, 15.29 mg, 및 4.17 mg의 양; 1.25 mg, 11.47 mg, 및 3.13 mg의 양; 1.25 mg, 12.5 mg, 및 3.13 mg의 양; 1.67 mg, 16.67 mg, 및 4.17 mg의 양; 1 mg, 10 mg, 및 2.5 mg의 양; 1 mg, 9.2 mg, 및 2.5 mg의 양; 1 mg, 9 mg, 및 3 mg의 양; 1 mg, 9 mg, 및 2.5 mg의 양; 0.8 mg, 8 mg, 및 2 mg의 양; 또는 0.8 mg, 7.6 mg, 및 2 mg의 양, 또는 상기 범위를 상한 또는 하한으로 하는 범위로 포함될 수 있다.For example, in the low-dose pharmaceutical combination formulation, amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and chlorthalidone or a pharmaceutically acceptable salt thereof are respectively amlodipine free base and losartan free acid. , in amounts of 2.5 mg, 25 mg, and 6.25 mg, respectively, when converted to chlorthalidone free base form; amounts of 2.5 mg, 23 mg, and 6.5 mg; amounts of 2.5 mg, 22.9 mg, and 6.25 mg; amounts of 1.7 mg, 15.3 mg, and 4.2 mg; amounts of 1.67 mg, 15.29 mg, and 4.17 mg; amounts of 1.25 mg, 11.47 mg, and 3.13 mg; amounts of 1.25 mg, 12.5 mg, and 3.13 mg; amounts of 1.67 mg, 16.67 mg, and 4.17 mg; amounts of 1 mg, 10 mg, and 2.5 mg; amounts of 1 mg, 9.2 mg, and 2.5 mg; amounts of 1 mg, 9 mg, and 3 mg; amounts of 1 mg, 9 mg, and 2.5 mg; amounts of 0.8 mg, 8 mg, and 2 mg; or 0.8 mg, 7.6 mg, and 2 mg, or a range having the upper or lower limits of the range.
상기 용량은 환자의 나이, 성별, 체중, 병증의 정도, 연령, 인종, 투여경로 고려하여 달라질 수 있다. The dose may vary in consideration of the patient's age, sex, weight, degree of disease, age, race, and route of administration.
고혈압 치료제 임상시험 가이드라인을 참고할 때 고혈압 치료제의 유효성은 일반적으로 혈압 강하 효과 평가 시 치료 전, 후 좌위 수축기 혈압의 변화량을 우선적으로 일차 평가 항목으로 평가하고, 치료 전·후 좌위 이완기 혈압의 변화량을 이차 평가 항목으로 평가될 수 있다. When referring to the clinical trial guidelines for antihypertensive drugs, the effectiveness of antihypertensive drugs is generally evaluated by evaluating the amount of change in left systolic blood pressure before and after treatment as the primary evaluation item when evaluating the blood pressure lowering effect, and the amount of change in left diastolic blood pressure before and after treatment as the primary evaluation item. It can be evaluated as a secondary evaluation item.
본 명세서에서 고혈압 치료 반응 정도는 혈압의 정상화 비율 즉, 혈압 조절률(Control rate)(치료 후 수축기 혈압 140 mmHg 미만 및 이완기 혈압 90 mmHg 미만인 시험 대상자 비율)(sitSBP < 140mmHg 및 sitDBP < 90mmHg 시험대상자 비율)로 평가될 수 있다.In the present specification, the degree of response to treatment for hypertension refers to the normalization rate of blood pressure, that is, the blood pressure control rate (the proportion of subjects with systolic blood pressure less than 140 mmHg and diastolic blood pressure less than 90 mmHg after treatment) (ratio of subjects with sitSBP < 140 mmHg and sitDBP < 90 mmHg). ) can be evaluated.
또한, 본 명세서에서 고혈압 치료 반응 정도는 혈압 반응율(Responder rate)(치료 후 기저치 대비 수축기 혈압 20 mmHg 이상 감소 또는 이완기 혈압 10 mmHg 이상 감소된 시험대상자 비율)(기저치 대비 sitSBP 감소량 ≥ 20mmHg 또는 sitDBP 감소량 ≥ 10mmHg 시험대상자 비율)로 평가될 수 있다. In addition, in the present specification, the degree of response to treatment for hypertension is defined as the blood pressure response rate (responder rate) (the ratio of subjects with a decrease in systolic blood pressure of 20 mmHg or more or a decrease in diastolic blood pressure of 10 mmHg or more after treatment) (a decrease in sitSBP ≥ 20 mmHg or a decrease in sitDBP compared to the baseline value ≥ 10mmHg subject ratio).
또한, 본 명세서에서 고혈압 치료제의 유효성은 맥압(pulse pressure) 변화량, 예를 들어 평균 맥압 변화량(평균 sitSBP - sitDBP)에 기초하여 평가될 수 있다. In addition, in the present specification, the effectiveness of the antihypertensive agent may be evaluated based on a pulse pressure change amount, for example, a mean pulse pressure change amount (mean sitSBP - sitDBP).
일 구체예에 따른 저용량 약제학적 복합제제는 좌위 수축기 혈압의 변화량 및/또는 좌위 이완기 혈압의 변화량을 감소시킬 수 있고, 이와 동시에 또는 선택적으로 맥압 변화량을 감소시킬 수 있다. The low-dose pharmaceutical combination preparation according to one embodiment may reduce the amount of change in the left systolic blood pressure and/or the change in the left diastolic blood pressure, and simultaneously or selectively reduce the change in the pulse pressure.
일 구체예에 따른 상기 저용량 약제학적 복합제제는 경증 고혈압 내지는 중등증 정도의 고혈압을 가진 개체에서 안전하고도 신속하고 충분하게 혈압 상승을 억제하고, 혈압 강하 효과를 나타낼 수 있다. The low-dose pharmaceutical combination formulation according to one embodiment can safely, quickly and sufficiently inhibit blood pressure rise and exhibit a blood pressure lowering effect in individuals with mild to moderate hypertension.
일 구체예에 따른 상기 저용량 약제학적 복합제제는 고혈압 치료를 위한 초기 요법으로 사용될 수 있다. The low-dose pharmaceutical combination formulation according to one embodiment may be used as an initial therapy for the treatment of hypertension.
일 구체예에 따른 상기 저용량 약제학적 복합제제는 위약과 대비하여 우월한 혈압 개선 효과를 보이고, 암로디핀 5 mg 또는 10 mg을 투여하거나, 또는 로사르탄 100 mg을 투여 시와 유사한 혈압 개선 효과를 보일 수 있다. The low-dose pharmaceutical combination formulation according to one embodiment has a superior blood pressure improvement effect compared to placebo, and has a blood pressure improvement effect similar to that when amlodipine 5 mg or 10 mg is administered or losartan 100 mg is administered. .
일 구체예에 따른 저용량 약제학적 복합제제는 경증 고혈압 내지 중등증 고혈압의 치료에 효과적으로 사용될 수 있다. The low-dose pharmaceutical combination formulation according to one embodiment can be effectively used for the treatment of mild to moderate hypertension.
본 명세서에서 경증 고혈압은 수축기 혈압(mmHg)이 140이상 160미만 및/또는 이완기 혈압(mmHg)이 90이상 100미만인 경우를 말한다. 본 명세서에서 중등증 고혈압은 수축기 혈압(mmHg)이 160이상 180미만 및/또는 이완기 혈압(mmHg)이 100이상 110미만인 경우를 말한다. In the present specification, mild hypertension refers to a case in which systolic blood pressure (mmHg) is 140 or more and less than 160 and/or diastolic blood pressure (mmHg) is 90 or more and less than 100. In the present specification, moderate hypertension refers to a case in which the systolic blood pressure (mmHg) is 160 or more and less than 180 and/or the diastolic blood pressure (mmHg) is 100 or more and less than 110.
일 구체예에 따른 상기 저용량 약제학적 복합제제는 수축기 혈압(mmHg)이 140이상 180미만 및/또는 이완기 혈압(mmHg)이 90이상 110미만인 개체의 혈압을 효과적으로 개선할 수 있고, 위험성 대비 유익성이 우수할 수 있다. 예를 들어, 상기 복합제제는 수축기 혈압(mmHg)이 140이상 179이하 및/또는 이완기 혈압(mmHg)이 90이상 109이하인 개체의 혈압을 효과적으로 개선할 수 있다. The low-dose pharmaceutical combination formulation according to one embodiment can effectively improve the blood pressure of an individual having a systolic blood pressure (mmHg) of 140 or more and less than 180 and/or a diastolic blood pressure (mmHg) of 90 or more and less than 110, and the risk versus benefit is can be excellent For example, the combination formulation can effectively improve the blood pressure of an individual having a systolic blood pressure (mmHg) of 140 or more and 179 or less and/or a diastolic blood pressure (mmHg) of 90 or more and 109 or less.
일 구체예에서 경증 고혈압 내지 중등증 고혈압은 2018년 유럽고혈압학회(ESH) 가이드라인에 따를 때 고혈압 1기 내지 2기를 포함할 수 있다. In one embodiment, mild hypertension to moderate hypertension may include stages 1 to 2 of hypertension according to the European Society for Hypertension (ESH) guidelines in 2018.
일 구체예에 따른 저용량 약제학적 복합제제는 ESH(2018) 가이드라인에 따른 고혈압 1기(Grade 1) 또는 2기(Grade 2)의 치료에 효과적으로 사용될 수 있다. The low-dose pharmaceutical combination formulation according to one embodiment can be effectively used for the treatment of hypertension stage 1 (Grade 1) or stage 2 (Grade 2) according to the ESH (2018) guidelines.
본 명세서에서 고혈압 1기는 수축기 혈압(mmHg)이 140이상 159이하 및/또는 이완기 혈압(mmHg)이 90이상 99이하인 경우를 말한다. 본 명세서에서 고혈압 2기는 수축기 혈압(mmHg)이 160이상 179이하 및/또는 이완기 혈압(mmHg)이 100이상 109이하인 경우를 말한다. As used herein, stage 1 hypertension refers to a case in which systolic blood pressure (mmHg) is 140 or more and 159 or less and/or diastolic blood pressure (mmHg) is 90 or more and 99 or less. As used herein, the second stage of hypertension refers to a case in which the systolic blood pressure (mmHg) is 160 or more and 179 or less and/or the diastolic blood pressure (mmHg) is 100 or more and 109 or less.
일 구체예에 따른 상기 저용량 약제학적 복합제제는 수축기 혈압(mmHg)이 140이상 179이하 및/또는 이완기 혈압(mmHg)이 90이상 109이하인 개체의 혈압을 효과적으로 개선할 수 있다. 예를 들어, 상기 복합제제는 수축기 혈압(mmHg)이 140이상 159이하 및/또는 이완기 혈압(mmHg)이 90이상 99이하인 개체의 혈압을 효과적으로 개선할 수 있다. 일 구체예에 따른 저용량 약제학적 복합제제는 좌위 수축기 혈압(sitSBP)이 160 mmHg 미만인 개체의 혈압을 효과적으로 개선할 수 있다.The low-dose pharmaceutical combination formulation according to one embodiment can effectively improve the blood pressure of an individual having a systolic blood pressure (mmHg) of 140 or more and 179 or less and/or a diastolic blood pressure (mmHg) of 90 or more and 109 or less. For example, the combination formulation can effectively improve the blood pressure of an individual having a systolic blood pressure (mmHg) of 140 or more and 159 or less and/or a diastolic blood pressure (mmHg) of 90 or more and 99 or less. The low-dose pharmaceutical combination formulation according to one embodiment can effectively improve blood pressure in an individual having a sitting systolic blood pressure (sitSBP) of less than 160 mmHg.
일 구체예에 따른 저용량 약제학적 복합제제는 경증 고혈압 내지 중등증 고혈압 환자를 위한 효과적인 초기 요법 치료제를 제공할 수 있다. The low-dose pharmaceutical combination formulation according to one embodiment can provide an effective initial therapeutic agent for patients with mild to moderate hypertension.
일 구체예에 따른 저용량 약제학적 복합제제는 좌위 수축기 혈압(sitSBP)이 160 mmHg 미만인 고혈압에 효과적일 수 있다. 상기 복합제제는 sitSBP가 160 mmHg 미만인 개체에서 용량에 따라 비례적으로 증가된 혈압감소량을 나타낼 수 있다.The low-dose pharmaceutical combination formulation according to one embodiment may be effective for hypertension with a sitting systolic blood pressure (sitSBP) of less than 160 mmHg. The combination formulation may exhibit a proportionally increased blood pressure decrease according to the dose in subjects with sitSBP of less than 160 mmHg.
상기 저용량 약제학적 복합제제는 상기 언급된 함량의 암로디핀 또는 이의 약제학적 허용가능한 염, 로사르탄 또는 이의 약제학적 허용가능한 염, 및 클로르탈리돈 또는 이의 약제학적 허용가능한 염을 포함하는 고정용량 복합제형(fixed-dose combination formulation)으로 제제화될 수 있다. 상기 복합제제는 투여량에 따라 1일 1회 내지 수회 예를 들어, 1회 또는 3회 투여할 수 있다. The low-dose pharmaceutical combination formulation is a fixed-dose combination formulation comprising amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and chlorthalidone or a pharmaceutically acceptable salt thereof in the above-mentioned content ( fixed-dose combination formulation). The combination formulation may be administered once to several times a day, for example, once or three times, depending on the dosage.
일 구체예에 있어서, 상기 저용량 약제학적 복합제제는 1일 1회 투여용일 수 있다. 상기 복합제제는 1일 1회 투여함에 따라 환자 편의와 복약 순응도를 향상시킴과 아울러, 혈압강하 효과 면에서 최적의 약리학적 임상효과를 제공할 수 있다. 상기 복합제제는 투여 받을 대상의 병리 상태 및 그 심각도 등을 고려하여 적어도 4 주 또는 8주 동안, 또는 그 이상이나 이하로 투여될 수 있다. In one embodiment, the low-dose pharmaceutical combination preparation may be for administration once a day. The combination formulation can provide optimal pharmacological clinical effects in terms of blood pressure lowering effect while improving patient convenience and medication compliance by administering once a day. The combination formulation may be administered for at least 4 weeks or 8 weeks, or more or less, in consideration of the pathological condition and severity of the subject to be administered.
상기 저용량 약제학적 복합제제에서 암로디핀, 로사르탄, 또는 클로르탈리돈의 약제학적 허용가능한 염은 당해 기술분야에서 통상적인 방법에 따라 제조된 염을 의미하며, 이러한 제조방법은 당업자에게 공지되어 있다. 구체적으로, 상기 약제학적으로 허용 가능한 염은 약리학적 또는 생리학적으로 허용되는 하기 무기산과 유기산 및 염기로부터 유도된 염을 포함하지만 이것으로 제한되지는 않는다. 예를 들어, 적합한 산의 예로는 염산, 브롬화수소산, 황산, 질산, 과염소산, 푸마르산, 말레산, 인산, 글리콜산, 락트산, 살리실산, 숙신산, 톨루엔-p-설폰산, 타르타르산, 아세트산, 시트르산, 메탄설폰산, 포름산, 벤조산, 말론산, 나프탈렌-2-설폰산, 벤젠설폰산, 카르복실산, 베실산, 캄실산 등을 포함할 수 있다. 적합한 염기로부터 유도된 염은 알칼리 금속, 예를 들어, 나트륨, 또는 칼륨, 알칼리 토금속, 예를 들어, 칼슘, 마그네슘을 포함할 수 있으며 이에 제한되지 않는다.In the low-dose pharmaceutical combination preparation, the pharmaceutically acceptable salt of amlodipine, losartan, or chlorthalidone refers to a salt prepared according to a method conventional in the art, and the preparation method is known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic acids and organic acids and bases. For example, examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methane sulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, carboxylic acid, besylic acid, camsylic acid, and the like. Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium, or potassium, alkaline earth metals such as calcium, magnesium.
상기 암로디핀의 약제학적으로 허용가능한 염은 약제학적으로 허용가능한 음이온을 함유하는 비독성 산부가염을 형성하는 산으로부터 형성된 것으로서, 예를 들어, 염산염, 브롬화수소산염, 황산염, 인산염, 아세트산염, 말레산염, 푸마르산염, 락트산염, 주석산염, 구연산염, 글루코네이트, 베실레이트 및 캄실레이트 등을 들수 있으나, 이에 제한되는 것은 아니다. 예를 들어, 암로디핀 베실레이트염 또는 캄실레이트염을 사용할 수 있다. 상기 암로디핀은 암로디핀 라세미체 및 (S)-암로디핀을 포함한다. 상기 로사르탄의 약제학적으로 허용가능한 염은 바람직하게는 예를 들어 로사르탄 칼륨염을 사용할 수 있으나, 이에 제한되는 것은 아니다. The pharmaceutically acceptable salt of amlodipine is formed from an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate. , fumarate, lactate, tartrate, citrate, gluconate, besylate and camsylate, but are not limited thereto. For example, amlodipine besylate salt or camsylate salt can be used. The amlodipine includes amlodipine racemate and (S)-amlodipine. The pharmaceutically acceptable salt of losartan may be, for example, losartan potassium salt, but is not limited thereto.
일 구체예에서, 상기 복합제제는 암로디핀 캄실레이트(amlodipine camsylate), 로사르탄 칼륨(losartan potassium), 및 클로르탈리돈(chlorthalidone)을 포함할 수 있다. In one embodiment, the combination preparation may include amlodipine camsylate, losartan potassium, and chlorthalidone.
일 구체예에서, 상기 복합제제는 암로디핀 베실레이트(amlodipine besylate), 로사르탄 칼륨, 및 클로르탈리돈을 포함할 수 있다. In one embodiment, the combination preparation may include amlodipine besylate, losartan potassium, and chlorthalidone.
상기 저용량 약제학적 복합제제는 경구 사용 예컨대 산제, 정제, 캡슐제, 수성 또는 유성 현탁액, 유액 또는 분산성 분말 또는 과립, 비경구 투여 예컨대 정맥내, 피하내, 근육내 또는 혈관내 투여하기 위한 멸균 수성 또는 유성 용액 또는 현탁액, 국소 사용에 적합한 형태 예컨대 크림, 젤 또는 연고제, 또는 직장 투여용 좌제로서 존재할 수 있다. The low-dose pharmaceutical combination preparation is sterile aqueous for oral use such as powders, tablets, capsules, aqueous or oily suspensions, emulsions or dispersible powders or granules, parenteral administration such as intravenous, subcutaneous, intramuscular or intravascular administration or as oily solutions or suspensions, forms suitable for topical use such as creams, gels or ointments, or suppositories for rectal administration.
일 구체예에서, 상기 저용량 약제학적 복합제제는 정제, 캡슐제, 또는 캐플릿(caplet) 형태로 제형화될 수 있다. 일 구체예에서, 상기 복합제제는 단층정이다.In one embodiment, the low-dose pharmaceutical combination preparation may be formulated in the form of a tablet, capsule, or caplet. In one embodiment, the combination formulation is a single-layer tablet.
본 명세서에서 사용된 용어 "정제"는 모든 모양 및 크기의 압축된 제약 투여 형태를 포함하는 것을 지칭한다. As used herein, the term “tablet” is intended to include compressed pharmaceutical dosage forms of all shapes and sizes.
본 명세서에서 사용된 용어 "이층정"은 다른 두 가지 이상의 성분이 구획을 분리하여 두 개의 층에 독립적으로 존재하는 정제를 의미한다. As used herein, the term "double-layer tablet" refers to a tablet in which two or more different components are independently present in two layers by separating the compartments.
본 명세서에서 사용된 용어 "단층정"은 다른 두 가지 이상의 성분이 한 개의 층에 혼합되어 존재하는 정제를 의미한다. 일 구체예에 따른 단층정 복합제제에서 암로디핀, 클로르탈리돈 및 로사르탄은 구획을 분리하여 존재하지 않고 동일한 하나의 층에 존재할 수 있다. 상기 용어 단층정은 두 가지 이상의 성분이 구획을 분리하여 서로 다른 층에 독립적으로 존재하는 이층정, 삼층정 등의 다층정과 구분되어 사용된다. As used herein, the term “single-layer tablet” refers to a tablet in which two or more different components are mixed in one layer. In the single-layer tablet combination formulation according to one embodiment, amlodipine, chlorthalidone, and losartan do not exist in separate compartments, but may be present in the same single layer. The term single-layer tablet is used separately from multi-layered tablets such as double-layered tablets and three-layered tablets in which two or more components are independently present in different layers by separating compartments.
일 구체예에 따른 약제학적 복합제제는 단층정이며, 상기 로사르탄의 겔화 또는 이로 인한 용출 저하 또는 유연물질 발생 등의 문제점을 일으키지 않는다. The pharmaceutical combination preparation according to one embodiment is a single-layer tablet, and does not cause problems such as gelation of the losartan or reduced dissolution or generation of related substances.
암로디핀, 클로르탈리돈 및 로사르탄을 포함하는 복합 제제를 제조할 경우 로사르탄의 겔화(gelation)가 문제될 수 있다. 로사르탄은 정제수, pH 4.0, pH 6.8 등의 비교적 높은 pH에서 용출되는 경우에는 매우 양호한 용출 패턴을 나타낸다. 하지만, 로사르탄은 낮은 pH(예를 들어 pH 1.2, pH 2.0 등)에서는 겔화가 되어 천천히 용출된다. 이러한 현상은 경구제제의 복용시 제일 처음 붕해 및 용출이 일어나는 곳이, 낮은 pH의 소화액이 분비되는 위라는 점에서 제제의 용출률에 큰 영향을 미치며, 나아가 약물의 생체 내 흡수에도 영향을 줄 수 있다. 또한, 상기와 같이 로사르탄이 겔화됨에 따라 로사르탄과 혼합된 암로디핀과 클로르탈리돈 역시 겔 내부에 갇혀 용출이 저하되는 문제가 발생한다. Gelation of losartan may be a problem when preparing a complex formulation containing amlodipine, chlorthalidone and losartan. Losartan shows a very good dissolution pattern when eluted at a relatively high pH such as purified water, pH 4.0, and pH 6.8. However, at low pH (eg, pH 1.2, pH 2.0, etc.), losartan gels and elutes slowly. This phenomenon greatly affects the dissolution rate of the formulation in that the first place where disintegration and dissolution occurs when oral formulations are taken is the stomach where the digestive juice of low pH is secreted, and furthermore, it can affect the absorption of the drug in vivo. . In addition, as losartan gels as described above, amlodipine and chlorthalidone mixed with losartan are also trapped in the gel, resulting in a problem of reduced dissolution.
그런데 로사르탄을 저용량, 예를 들어 로사르탄 자유 산 형태로 환산했을 때 30 mg 이하, 예컨대 7 내지 30 mg로 포함하는 복합제제에서는 상기 로사르탄의 겔화로 인한 용출 저하가 발생하지 않을 수 있다. However, in a combination formulation containing losartan at a low dose, for example, 30 mg or less, for example, 7 to 30 mg when converted into losartan free acid form, a decrease in dissolution due to gelation of the losartan may not occur.
이에 따라, 암로디핀, 클로르탈리돈 및 로사르탄을 저용량으로 포함하는 단층정 복합제제는 이와 같은 겔화 문제를 일으키지 않으면서도 개선된 용출률, 안정성 및 생산성을 나타낸다. Accordingly, the single-layer tablet combination formulation containing amlodipine, chlorthalidone and losartan in a low dose exhibits improved dissolution rate, stability and productivity without causing such gelation problems.
따라서, 일 구체예에 따른 저용량 단층정 약제학적 복합제제는 함유 약물 성분의 용출률, 함량균일성, 보관 안전성, 타정 속도, 생산성을 개선할 수 있다.Therefore, the low-dose single-layered pharmaceutical combination formulation according to one embodiment can improve the dissolution rate, content uniformity, storage safety, tableting speed, and productivity of the drug components contained therein.
일 구체예에 따른 저용량 단층정 약제학적 복합제제는 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 및 로사르탄 또는 이의 약제학적으로 허용가능한 염을 혼합과립부로 포함한다. A low-dose single-layer pharmaceutical combination formulation according to an embodiment comprises amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof into a mixed granule part. include
상기 단층정 약제학적 복합제제는 유효성분을 혼합과립부 중에 포함하며, 유효성분을 분리과립부 중에 포함하여 이층정 또는 단층정으로 하는 경우와 비교하여도 유효성분의 용출률 저하 또는 유연물질의 증가를 나타내지 않고, 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 및 로사르탄 또는 이의 약제학적으로 허용가능한 염의 용출률 및 복합제제의 안정성이 우수하다. The single-layered pharmaceutical combination formulation contains the active ingredient in the mixed granulation part, and the dissolution rate of the active ingredient is reduced or the increase in related substances is reduced compared to the case where the active ingredient is included in the separate granular part to form a double-layered tablet or a single-layered tablet. The dissolution rate of amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof and the stability of the combination formulation are excellent.
일 구체예에서, 심혈관계 질환의 예방 또는 치료용 약제학적 단층정 복합제제의 총 중량은 350 mg 이하일 수 있다. 일 구체예에서, 상기 복합제제의 총 중량은 330 mg 이하, 300 mg 이하, 200 mg 이하, 170 mg 이하, 또는 165 mg 이하 일 수 있다. 상기 복합제제의 총 중량을 330 mg 이하, 300 mg 이하, 200 mg 이하, 170 mg 이하, 또는 165 mg 이하로 함에 따라 보다 개선된 암로디핀, 클로르탈리돈 및 로사르탄의 용출률을 나타낼 수 있다. In one embodiment, the total weight of the pharmaceutical monolayer tablet combination formulation for the prevention or treatment of cardiovascular disease may be 350 mg or less. In one embodiment, the total weight of the combination formulation may be 330 mg or less, 300 mg or less, 200 mg or less, 170 mg or less, or 165 mg or less. As the total weight of the combined formulation is 330 mg or less, 300 mg or less, 200 mg or less, 170 mg or less, or 165 mg or less, more improved dissolution rates of amlodipine, chlorthalidone and losartan may be exhibited.
상기 복합제제의 총 중량은 42 mg 이상, 40 mg 이상, 50 mg 이상, 60 mg 이상, 70 mg 이상, 또는 80 mg일 수 있다. The total weight of the combined formulation may be 42 mg or more, 40 mg or more, 50 mg or more, 60 mg or more, 70 mg or more, or 80 mg.
일 구체예에서, 심혈관계 질환의 예방 또는 치료용 약제학적 단층정 복합제제의 총 중량이 70 mg 이상 350 mg 이하일 수 있다. In one embodiment, the total weight of the pharmaceutical monolayer tablet combination formulation for the prevention or treatment of cardiovascular disease may be 70 mg or more and 350 mg or less.
복합제제의 총 중량을 상기 언급된 범위로 함에 따라 유효성분의 용출률이 향상될 수 있으며, 이와 동시에 제제 균일성을 확보할 수 있고, 우수한 품질로 복합제제를 제조할 수 있다.As the total weight of the combination preparation falls within the above-mentioned range, the dissolution rate of the active ingredient may be improved, and at the same time, uniformity of the preparation may be secured, and the combination preparation may be manufactured with excellent quality.
일 구체예에서, 복합제제 중 유효성분으로서 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 및 로사르탄 또는 이의 약제학적으로 허용가능한 염의 총 중량이 15 mg 이상일 수 있다. In one embodiment, the total weight of amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in the combination preparation is 15 mg or more can
복합제제 중 유효성분의 총 중량을 상기 언급된 범위로 함에 따라 유효성분의 용출률이 향상될 수 있으며, 이와 동시에 제제 균일성을 확보할 수 있고, 우수한 품질로 복합제제를 제조할 수 있다.By setting the total weight of the active ingredient in the composite formulation to the above-mentioned range, the dissolution rate of the active ingredient can be improved, and at the same time, uniformity of the formulation can be secured, and the composite formulation can be manufactured with excellent quality.
일 구체예에서, 복합제제 총 중량을 기준으로 상기 유효성분은 10% 이상으로 포함될 수 있다. In one embodiment, based on the total weight of the combination formulation, the active ingredient may be included in an amount of 10% or more.
일 구체예에서, 복합제제 총 중량을 기준으로 상기 유효성분은 20% 이상으로 포함될 수 있다. In one embodiment, based on the total weight of the combination formulation, the active ingredient may be included in an amount of 20% or more.
복합제제 중 상기 유효성분을 상기 언급된 중량 범위로 포함함에 따라 용출률이 향상될 수 있고, 우수한 품질로 복합제제를 제조할 수 있다.By including the active ingredient in the above-mentioned weight range in the combination formulation, the dissolution rate can be improved, and the composite formulation can be prepared with excellent quality.
일 구체예에서, 붕해제를 더 포함하고, 이 때 붕해제의 함량은 복합제제 총 중량을 기준으로 1 내지 15%일 수 있다. In one embodiment, it further comprises a disintegrant, in which case the content of the disintegrant may be 1 to 15% based on the total weight of the combined formulation.
복합제제 총 중량을 기준으로 붕해제를 1% 미만으로 포함할 때는 빠른 용출 양상을 달성할 수 없고, 15%를 초과할 때는 제제의 안정성이 저하되는 반면에, 붕해제를 복합제제 총 중량을 기준으로 1 내지 15%로 포함함에 따라 원하는 용출률 및 제제 안정성을 달성할 수 있다. When it contains less than 1% of the disintegrant based on the total weight of the combination formulation, a fast dissolution aspect cannot be achieved, and when it exceeds 15%, the stability of the formulation is lowered, whereas the disintegrant is added based on the total weight of the combination formulation. By including 1 to 15% as a desired dissolution rate and formulation stability can be achieved.
일 구체예에서, 붕해제를 더 포함하고, 이 때 붕해제의 함량은 복합제제 총 중량을 기준으로 2% 이상, 3% 이상, 4% 이상, 또는 5% 이상일 수 있다. In one embodiment, it further comprises a disintegrant, wherein the content of the disintegrant may be 2% or more, 3% or more, 4% or more, or 5% or more based on the total weight of the combination formulation.
일 구체예에서, 붕해제를 더 포함하고, 이 때 붕해제의 함량은 복합제제 총 중량을 기준으로 4 내지 15%일 수 있다. In one embodiment, it further comprises a disintegrant, wherein the content of the disintegrant may be 4 to 15% based on the total weight of the combined formulation.
일 구체예에서, 붕해제를 더 포함하고, 이 때 붕해제의 함량은 복합제제 총 중량을 기준으로 4.5 내지 10%일 수 있다. In one embodiment, it further comprises a disintegrant, wherein the content of the disintegrant may be 4.5 to 10% based on the total weight of the combined formulation.
일 구체예에서, 붕해제를 더 포함하고, 이 때 붕해제의 함량은 복합제제 총 중량을 기준으로 9 내지 15%일 수 있다. In one embodiment, it further comprises a disintegrant, wherein the content of the disintegrant may be 9 to 15% based on the total weight of the combined formulation.
복합제제 중 붕해제를 상기 언급된 중량 범위로 포함함에 따라 용출률이 향상될 수 있고, 우수한 품질로 복합제제를 제조할 수 있다.By including the disintegrant in the above-mentioned weight range in the composite formulation, the dissolution rate can be improved, and the composite formulation can be prepared with excellent quality.
일 구체예에서, 상기 복합제제는 희석제, 붕해제, 활택제, 및 이들의 조합 중에서 선택되는 약제학적 첨가제를 더 포함할 수 있다. In one embodiment, the combination preparation may further include a pharmaceutical additive selected from a diluent, a disintegrant, a lubricant, and combinations thereof.
일 구체예에서, 상기 희석제는 미결정 셀룰로오스, 전분, 전호화전분, 제2인산칼슘, 락토오스, 저치환도 히드록시프로필셀룰로오스 및 이들의 조합 중에서 선택되는 어느 하나일 수 있다. In one embodiment, the diluent may be any one selected from microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate, lactose, low-substituted hydroxypropyl cellulose, and combinations thereof.
일 구체예에서, 상기 붕해제는 크로스포비돈, 크로스카르멜로즈 나트륨, 전분 글리콘산 나트륨, 전분, 전호화전분 또는 이들의 조합 중에서 선택되는 어느 하나일 수 있다. In one embodiment, the disintegrant may be any one selected from crospovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch, or a combination thereof.
일 구체예에서, 상기 활택제는 스테아르산 마그네슘, 팔미트산, 활석(탈크), 스테아르산 마그네슘, 스테아르산 아연, 스테아르산 칼슘 또는 이들의 조합 중에서 선택되는 어느 하나일 수 있다. In one embodiment, the lubricant may be any one selected from magnesium stearate, palmitic acid, talc (talc), magnesium stearate, zinc stearate, calcium stearate, or a combination thereof.
일 구체예에서, 상기 복합제제는 결합제를 더 포함할 수 있다. In one embodiment, the combination preparation may further include a binder.
일 구체예에서, 결합제는 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스, 폴리비닐피롤리돈, 젤라틴, 아카시아 검 및 이들의 조합 중에서 선택되는 어느 하나일 수 있다. In one embodiment, the binder may be any one selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, acacia gum, and combinations thereof.
일 구체예에서, 복합제제 중 암로디핀 또는 이의 약제학적으로 허용 가능한 염은 0.1 내지 7 중량%로 포함할 수 있다. 예를 들어, 0.5 내지 3 중량%로 포함할 수 있다. In one embodiment, amlodipine or a pharmaceutically acceptable salt thereof in the combination preparation may be included in an amount of 0.1 to 7% by weight. For example, it may be included in an amount of 0.5 to 3% by weight.
일 구체예에서, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염은 0.3 내지 9 중량%로 포함할 수 있다. 예를 들어, 1 내지 5 중량%로 포함할 수 있다. In one embodiment, chlorthalidone or a pharmaceutically acceptable salt thereof may be included in an amount of 0.3 to 9% by weight. For example, it may be included in an amount of 1 to 5% by weight.
일 구체예에서, 로사르탄 또는 이의 약제학적으로 허용가능한 염은 1 내지 40 중량%로 포함할 수 있다. 예를 들어, 5 내지 20 중량%로 포함할 수 있다. In one embodiment, losartan or a pharmaceutically acceptable salt thereof may be included in an amount of 1 to 40% by weight. For example, it may be included in an amount of 5 to 20% by weight.
일 구체예에서, 희석제는 40 내지 95 중량%로 포함할 수 있다. 예를 들어, 50 내지 90 중량%로 포함할 수 있다. In one embodiment, the diluent may be included in an amount of 40 to 95% by weight. For example, it may be included in an amount of 50 to 90% by weight.
일 구체예에서, 붕해제는 1 내지 20 중량%로 포함할 수 있다. 예를 들어, 1.5 내지 15 중량%로 포함할 수 있다. In one embodiment, the disintegrant may be included in an amount of 1 to 20% by weight. For example, it may be included in an amount of 1.5 to 15% by weight.
일 구체예에서, 활택제는 0.1 내지 2 중량%로 포함할 수 있다. 예를 들어, 0.5 내지 1.5 중량%로 포함할 수 있다. In one embodiment, the lubricant may be included in an amount of 0.1 to 2% by weight. For example, it may be included in an amount of 0.5 to 1.5% by weight.
일 구체예에서, 결합제는 0 내지 10 중량%로 포함할 수 있다. 예를 들어, 0.1 내지 10 중량%로 포함할 수 있다. 예를 들어, 0.5 내지 5 중량%로 포함할 수 있다. In one embodiment, the binder may be included in an amount of 0 to 10% by weight. For example, it may be included in an amount of 0.1 to 10% by weight. For example, it may be included in an amount of 0.5 to 5% by weight.
상기 복합제제는 필요에 따라 pH조절제, 현탁화제, 보존제, 착향제, 착색제, 감미제, 흡착제, 가용화제 등을 더 포함할 수 있다. 상기 첨가제의 함량은 본 발명에서 특별히 제한되지 않고 필요에 따라 적절히 조절될 수 있다.The complex formulation may further include a pH adjuster, a suspending agent, a preservative, a flavoring agent, a colorant, a sweetener, an adsorbent, a solubilizer, and the like, if necessary. The content of the additive is not particularly limited in the present invention and may be appropriately adjusted as necessary.
일 구체예에서, 저치환도 히드록시프로필셀룰로오스를 제외한 희석제 대 저치환도 히드록시프로필셀룰로오스의 중량비가 6:1 내지 1:1가 되도록 희석제를 포함할 수 있다. In one embodiment, the diluent may be included so that the weight ratio of the diluent to the low-substituted hydroxypropyl cellulose is 6:1 to 1:1 except for the low-substituted hydroxypropyl cellulose.
일 구체예에서, 희석제로 미결정 셀룰로오스 및 저치환도 히드록시프로필셀룰로오스를 더 포함하고, 이 때 미결정 셀룰로오스 대 저치환도 히드록시프로필셀룰로오스의 중량비가 2:1 내지 1:1일 수 있다. In one embodiment, the diluent further comprises microcrystalline cellulose and low-substituted hydroxypropyl cellulose, wherein the weight ratio of microcrystalline cellulose to low-substituted hydroxypropyl cellulose may be 2:1 to 1:1.
예를 들어, 상기 중량비는 6:1 내지 1:1, 5:1 내지 1:1, 4:1 내지 1:1, 또는 2:1 내지 1.5:1 일 수 있다. For example, the weight ratio may be 6:1 to 1:1, 5:1 to 1:1, 4:1 to 1:1, or 2:1 to 1.5:1.
저치환도 히드록시프로필셀룰로오스를 상기 함량 범위로 사용할 경우 향상된 타정성과 용출율을 나타낼 수 있다. 구체적으로는 정제의 흐름성 및 타정성을 높이고, 클로르탈리돈의 용츨률을 개선할 수 있다.When the low-substituted hydroxypropyl cellulose is used in the above content range, improved tabletting and dissolution rate may be exhibited. Specifically, it is possible to increase the flowability and tabletting properties of the tablet, and to improve the dissolution rate of chlorthalidone.
상기 함량 범위보다 적을 경우 타정 작업 시 타정 장애가 발생하고, 상기 함량 범위보다 많으면 필요 이상으로 큰 제형이 만들어지는 문제가 발생한다. If the content is less than the content range, a tableting disorder occurs during the tableting operation, and if the content is greater than the content range, a problem occurs in that a larger formulation is made than necessary.
따라서, 저치환도 히드록시프로필셀룰로오스를 제외한 희석제 대 저치환도 히드록시프로필셀룰로오스, 예를 들어 미결정 셀룰로오스 대 저치환도 히드록시프로필셀룰로오스를 전술한 함량 범위로 사용함으로써 품질이 개선된 정제의 제조가 가능해진다. Therefore, by using a diluent other than low-substituted hydroxypropyl cellulose to low-substituted hydroxypropyl cellulose, for example, microcrystalline cellulose to low-substituted hydroxypropyl cellulose in the above-mentioned content range, it is possible to manufacture tablets with improved quality. it becomes possible
일 구체예에서, 유효성분으로서 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 및 로사르탄 또는 이의 약제학적으로 허용가능한 염의 총 중량 대 희석제를 중량비 1:2 내지 1:9로 더 포함할 수 있다. In one embodiment, as an active ingredient, the total weight of amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof to the diluent is 1:2 to 1:9 may be further included.
복합제제 중 유효성분 및 희석제를 상기 중량비로 포함함에 따라 유효성분의 용출률이 향상될 수 있고, 우수한 품질로 복합제제를 제조할 수 있다.By including the active ingredient and the diluent in the combined preparation in the above weight ratio, the dissolution rate of the active ingredient can be improved, and the complex preparation can be manufactured with excellent quality.
일 구체예에서, 상기 단층정 복합제제는 경구의약품 용출규격 설정 가이드라인에 따라 용출시험시, 30분 이내에 유효성분의 용출률이 각각 80% 이상일 수 있다. In one embodiment, the single-layer tablet combination formulation may have a dissolution rate of 80% or more of the active ingredient within 30 minutes during a dissolution test according to the oral drug dissolution standard setting guidelines.
일 구체예에서, 상기 복합제제는 경구의약품 용출규격 설정 가이드라인에 따라 용출시험시, 30분 이내에 암로디핀의 용출률이 80% 이상일 수 있다. In one embodiment, the combination formulation may have a dissolution rate of 80% or more of amlodipine within 30 minutes during a dissolution test according to the guidelines for setting dissolution standards for oral pharmaceuticals.
일 구체예에서, 상기 복합제제는 경구의약품 용출규격 설정 가이드라인에 따라 용출시험시, 30분 이내에 클로르탈리돈의 용출률이 80 % 이상일 수 있다. In one embodiment, the combination formulation may have a dissolution rate of 80% or more of chlorthalidone within 30 minutes during a dissolution test according to the guidelines for setting dissolution standards for oral pharmaceuticals.
일 구체예에서, 상기 복합제제는 경구의약품 용출규격 설정 가이드라인에 따라 용출시험시, 30분 이내에 로사르탄의 용출률이 80 % 이상일 수 있다In one embodiment, the combination formulation may have a dissolution rate of 80% or more of losartan within 30 minutes during a dissolution test according to the guidelines for setting dissolution standards for oral drugs
일 구체예에서, 상기 단층정 복합제제는 미국 약전 용출 시험 항목 패들법에 따라 100 ± 5 rpm, 37 ± 0.5 ℃, 0.01 M 염산용액, 900 mL에서 용출 시험 시, 30분 이내 암로디핀의 용출률이 80 % 이상일 수 있다. In one embodiment, the monolayer tablet combination formulation has a dissolution rate of amlodipine within 30 minutes at 100 ± 5 rpm, 37 ± 0.5 ° C, 0.01 M hydrochloric acid, 900 mL according to the US Pharmacopoeia dissolution test item paddle method. % or more.
일 구체예에서, 상기 단층정 복합제제는 미국약전 클로르탈리돈 타블렛 항의 용출 시험 항목에 따라 패들법으로 75 rpm ± 2 rpm, 37 ± 0.5 ℃, 정제수 900 mL에서 용출 시험 시, 30분 이내에 클로르탈리돈의 용출률이 80 % 이상일 수 있다. In one embodiment, the single-layer tablet combination formulation is a dissolution test at 75 rpm ± 2 rpm, 37 ± 0.5 ° C, 900 mL of purified water by the paddle method according to the dissolution test item of the US Pharmacopoeia chlorthalidone tablet section, chlorthalidone within 30 minutes The dissolution rate of money may be 80% or more.
일 구체예에서, 상기 단층정 복합제제는 미국약전 로사르탄 칼륨 타블렛 항의 용출 시험 항목에 따라 패들법으로 75 rpm ± 2 rpm, 37 ± 0.5 ℃, 정제수 900 mL에서 용출 시험 시 용출시험시, 30분 이내 로사르탄의 용출률이 80 % 이상일 수 있다. In one embodiment, the single-layer tablet combination formulation is a dissolution test at 75 rpm ± 2 rpm, 37 ± 0.5 ° C, 900 mL of purified water by the paddle method according to the dissolution test item of the US Pharmacopoeia Losartan potassium tablet dissolution test, 30 minutes Within that time, the dissolution rate of losartan may be 80% or more.
상기 복합제제는 미국약전 용출 시험 항목의 패들법에 따라 용출 시험 시, 각 유효성분의 용출률이 30분 이내에 85 % 이상, 일 구체 예에서 15분 이내에 용출률이 85 % 이상일 수 있다.The combined formulation may have a dissolution rate of 85% or more within 30 minutes of each active ingredient during a dissolution test according to the paddle method of the US Pharmacopoeia dissolution test item, and in one embodiment, a dissolution rate of 85% or more within 15 minutes.
일 구체예에서, 상기 단층정 중에 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 및 로사르탄 또는 이의 약제학적으로 허용가능한 염은 하나의 혼합부 또는 과립부 중에 존재할 수 있다. In one embodiment, in the monolayer tablet, amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof are combined in one mixed part or a granular part may exist in
상기 복합제제에서 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 및 로사르탄 또는 이의 약제학적으로 허용가능한 염을 하나의 혼합부 또는 과립부 중에 포함하는 경우, 상기 약물을 분리된 혼합부 또는 과립부 중에 포함하는 경우 보다 최대 타정 속도, 타정 공정 수율이 높고, 함량 균일성이 우수하다. When amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof are included in one mixing part or a granulation part in the combination formulation, The maximum tableting speed, the tableting process yield are higher, and the content uniformity is better than when the drug is included in the separate mixing part or the granulation part.
상기 복합제제는 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 및 로사르탄 또는 이의 약제학적으로 허용가능한 염과, 약제학적 첨가제 예컨대 희석제 및 붕해제를 혼합하여 혼합부로 할 수 있다. 상기 혼합부는 통상의 과립화 방법, 예를 들어 압축과립법에 의해 과립화 후 타정될 수 있다. 다른 구체예에서, 상기 혼합부는 롤러압축공정을 거친 과립형태일 수 있다. 상기 압축과립화된 혼합부를 활택제와 혼합하여 최종과립부로 할 수 있다. The combination preparation is prepared by mixing amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutical additive such as a diluent and a disintegrant. It can be done as a mixing part. The mixing part may be tableted after granulation by a conventional granulation method, for example, a compression granulation method. In another embodiment, the mixing unit may be in the form of granules subjected to a roller compaction process. The compressed granulated mixing part may be mixed with a lubricant to obtain a final granulated part.
상기 혼합부 또는 최종과립부를 단층정으로 타정하는 경우, 암로디핀, 클로르탈리돈 및 로사르탄의 용출률이 우수하며, 로사르탄의 겔화 없이 원하는 용출양상을 나타내며, 복합제제의 안정성이 우수하다.When the mixed portion or the final granular portion is tableted as a single-layer tablet, the dissolution rate of amlodipine, chlorthalidone and losartan is excellent, the desired dissolution pattern without gelation of losartan is exhibited, and the stability of the composite formulation is excellent.
또한, 상기 복합제제를 단층정으로 타정하는 경우 이층정으로 타정하는 경우보다 최대 타정 속도, 타정 공정 수율이 높고, 함량 균일성이 우수하다. In addition, when the composite formulation is compressed into a single-layer tablet, the maximum tableting speed, the tableting process yield are higher, and the content uniformity is excellent compared to that of the double-layer tablet.
상기 복합제제 중 클로르탈리돈 또는 이의 약제학적 허용 가능한 염의 입도(D90)는 약 0.5 내지 50 μm, 예를 들어 0.5 내지 25 μm, 또는 예를 들어 0.5 내지 10 μm일 수 있다. 클로르탈리돈의 입자를 상기와 같이 미분화 할 경우, 유효성분의 용출율, 함량 균일성 및 열 안정성을 향상시킬 수 있다. 상기 입도는 Mie 이론에 의거한 레이저 회절ㆍ산란법에 의거하여 시판의 장치를 이용하여 행할 수 있다. 예를 들면, HELOS (Helium-neon Laser for Optical Spectrometry, Sympatec사) 레이저 회절 장치 등의 시판의 장치를 이용하여 측정할 수 있다. 이 장치는 헬륨-네온 레이저빔을 입자에 조사하면 산란이 일어나 디텍터에 광 산란 패턴이 나타나고, 이 광 산란 패턴을 Mie 이론에 따라 해석함으로써 입자 지름 분포를 구하는 것일 수 있다. The particle size (D90) of chlorthalidone or a pharmaceutically acceptable salt thereof in the combination formulation may be about 0.5 to 50 μm, for example 0.5 to 25 μm, or, for example, 0.5 to 10 μm. When the particles of chlorthalidone are pulverized as described above, the dissolution rate, content uniformity and thermal stability of the active ingredient can be improved. The particle size can be performed using a commercially available apparatus based on a laser diffraction/scattering method based on the Mie theory. For example, it can measure using commercially available apparatuses, such as a HELOS (Helium-neon Laser for Optical Spectrometry, Sympatec) laser diffraction apparatus. In this device, when a helium-neon laser beam is irradiated to particles, scattering occurs and a light scattering pattern appears on the detector, and the particle size distribution can be obtained by analyzing the light scattering pattern according to the Mie theory.
상기 복합제제 제조에서의 입도 조절 방법은 특별히 제한되지 않으며 당 업계에 공지된 방법을 적절히 선택할 수 있다. 구체적으로, 상기 클로르탈리돈은 제트 밀(Jet mill), 해머 밀(hammer mill), 볼 밀(ball mill), 플루이드 에너지 밀(fluid energy mill) 등 입자를 미분화할 수 있는 통상의 밀을 사용하여 분쇄할 수 있다. 또한, 체(sieve)를 사용하여 수행되는 체과법 또는 기류 분급(air current classification) 등의 분급법(size classification method)이 사용하여 약물의 입도를 세분화할 수 있다. The method for controlling the particle size in the preparation of the combination preparation is not particularly limited and a method known in the art may be appropriately selected. Specifically, the chlorthalidone is a jet mill, a hammer mill, a ball mill, a fluid energy mill, etc. using a conventional mill capable of pulverizing particles. can be crushed In addition, a sieve method performed using a sieve or a size classification method such as air current classification may be used to subdivide the particle size of the drug.
다른 일 양상은 암로디핀 또는 이의 약제학적 허용가능한 염, 클로르탈리돈 또는 이의 약제학적 허용가능한 염, 및 로사르탄 또는 이의 약제학적 허용가능한 염을 저용량으로 단층정에 포함하는 심혈관계 질환의 예방 또는 치료용 약제학적 복합제제의 제조방법을 제공한다.Another aspect is for the prevention or treatment of cardiovascular diseases comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof in a monolayer tablet at a low dose Provided is a method for preparing a pharmaceutical combination preparation.
상기 제조방법은 약제학적으로 허용가능한 첨가제를 혼합하는 단계를 포함한다. 상기 제조방법은, 암로디핀 자유 염기 형태로 환산했을 때 0.5 내지 5 mg의 양에 해당하는 암로디핀 또는 이의 약제학적 가능한 염, 클로르탈리돈 자유 염기 형태로 환산했을 때 1 내지 7 mg의 양에 해당하는 클로르탈리돈 또는 이의 약제학적 허용 가능한 염, 로사르탄 자유 산 형태로 환산했을 때 7 내지 30 mg의 양에 해당하는 로사르탄 또는 이의 약제학적 허용 가능한 염, 및 약제학적으로 허용가능한 첨가제를 혼합하는 단계를 포함할 수 있다. The manufacturing method includes mixing a pharmaceutically acceptable additive. In the above preparation method, when converted into amlodipine free base form, amlodipine or a pharmaceutically acceptable salt thereof, in an amount of 0.5 to 5 mg when converted into amlodipine free base form, when converted into chlorthalidone free base form, chlorin corresponding to an amount of 1 to 7 mg Mixing thalidone or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof in an amount of 7 to 30 mg when converted to losartan free acid form, and a pharmaceutically acceptable additive; may include
상기 제조방법은, 암로디핀 자유 염기 형태로 환산했을 때 0.8 내지 3 mg의 양에 해당하는 암로디핀 또는 이의 약제학적 가능한 염, 클로르탈리돈 자유 염기 형태로 환산했을 때 2 내지 7 mg의 양에 해당하는 클로르탈리돈 또는 이의 약제학적 허용 가능한 염, 로사르탄 자유 산 형태로 환산했을 때 7 내지 30 mg의 양에 해당하는 로사르탄 또는 이의 약제학적 허용 가능한 염, 및 약제학적으로 허용가능한 첨가제를 혼합하는 단계를 포함할 수 있다. In the above preparation method, amlodipine or a pharmaceutically acceptable salt thereof corresponding to an amount of 0.8 to 3 mg when converted into amlodipine free base form, when converted into chlorthalidone free base form, chlorin corresponding to an amount of 2 to 7 mg Mixing thalidone or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof in an amount of 7 to 30 mg when converted to losartan free acid form, and a pharmaceutically acceptable additive; may include
상기 제조방법은, 암로디핀 자유 염기 형태로 환산했을 때 1 내지 3 mg의 양에 해당하는 암로디핀 또는 이의 약제학적 가능한 염, 클로르탈리돈 자유 염기 형태로 환산했을 때 3 내지 7 mg의 양에 해당하는 클로르탈리돈 또는 이의 약제학적 허용 가능한 염, 로사르탄 자유 산 형태로 환산했을 때 10 내지 30 mg의 양에 해당하는 로사르탄 또는 이의 약제학적 허용 가능한 염, 및 약제학적으로 허용가능한 첨가제를 혼합하는 단계를 포함할 수 있다. The above preparation method is amlodipine in an amount of 1 to 3 mg when converted into amlodipine free base form, or a pharmaceutically acceptable salt thereof, when converted to chlorthalidone free base form, chlorin corresponding to an amount of 3 to 7 mg Mixing thalidone or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof in an amount of 10 to 30 mg when converted to losartan free acid form, and a pharmaceutically acceptable additive; may include
상기 제조방법은 암로디핀 또는 이의 약제학적 허용가능한 염, 클로르탈리돈 또는 이의 약제학적 허용가능한 염, 로사르탄 또는 이의 약제학적 허용가능 한 염, 및 약제학적으로 허용가능한 첨가제를 혼합하여 혼합물로 하는 단계 (1), The preparation method comprises the steps of mixing amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to form a mixture ( One),
상기 혼합물을 과립화하여 과립부를 제조하는 단계 (2); granulating the mixture to prepare a granular part (2);
상기 과립부를 약제학적으로 허용가능한 첨가제와 혼합하여 최종과립부로 하는 단계 (3); 및(3) mixing the granular part with a pharmaceutically acceptable additive to obtain a final granular part; and
상기 최종과립부를 타정하여 단층정을 제조하는 단계 (4)를 포함할 수 있다. It may include the step (4) of manufacturing a single-layer tablet by tableting the final granular portion.
상기 단계 (1)에서 혼합되는 약제학적 허용가능한 첨가제는 희석제, 붕해제, 및 이들의 조합을 포함할 수 있다. The pharmaceutically acceptable additive mixed in step (1) may include a diluent, a disintegrant, and a combination thereof.
상기 단계 (2)에서 혼합되는 약제학적 허용가능한 첨가제는 활택제를 포함할 수 있다. The pharmaceutically acceptable additive mixed in step (2) may include a lubricant.
다른 일 양상은 암로디핀 또는 이의 약제학적 허용가능한 염, 클로르탈리돈 또는 이의 약제학적 허용가능한 염, 및 로사르탄 또는 이의 약제학적 허용가능한 염을 저용량으로 단층정에 포함하는 포함하는 복합제제를 투여함에 따른 초기 심혈관계 질환의 치료 방법을 제공한다.Another aspect is the administration of a combination formulation comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof in a monolayer tablet at a low dose. A method of treating early cardiovascular disease is provided.
일 구체예에 따른 치료 방법은 경증 고혈압 내지 중등증 고혈압 치료에 대한 초기 요법으로서 효과적일 수 있다. The treatment method according to one embodiment may be effective as an initial therapy for the treatment of mild to moderate hypertension.
상기 복합제제 또는 조성물에 포함되는 암로디핀 또는 이의 약제학적 허용가능한 염, 클로르탈리돈 또는 이의 약제학적 허용가능한 염, 및 로사르탄 또는 이의 약제학적 허용가능한 염은 개체 또는 환자의 치료 또는 예방에 유효한 양으로서, 목적하는 바에 따라 경구 또는 비경구의 다양한 투여방법으로 투여할 수 있다. 상기 투여 방법은 특정 개체 또는 환자에 대한 투여 용량은 환자의 체중, 연령, 인종, 성별, 건강 상태, 식이, 투여 시간, 투여 방법, 질환의 중증도 등의 여러 관련 인자에 비추어 결정되어야 하는 것이고 전문가에 의해 적절히 가감될 수 있는 것으로 이해되어야 하며, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하기 위한 것은 아니다. 관련 기술 분야의 통상의 기술을 갖는 의사는 사용되는 화합물의 투여량을 필요에 따라 용이하게 결정 및 처방할 수 있다. 예를 들어, 의사는 제약 조성물에 사용되는 본 발명의 화합물의 용량을 목적하는 치료효과를 달성하는데 요구되는 것보다 낮은 수준에서 출발하여, 목적하는 효과가 달성될 때까지 투여량을 점진적으로 증가시킬 수 있다.Amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof, included in the combination preparation or composition, may be used in an amount effective for treatment or prevention of an individual or patient. , it can be administered by various administration methods, either oral or parenteral, depending on the intended purpose. As for the administration method, the administration dose for a specific individual or patient should be determined in light of several related factors such as the patient's weight, age, race, sex, health status, diet, administration time, administration method, and the severity of the disease. It should be understood that it can be appropriately increased or decreased by the above dosage, and the above dosage is not intended to limit the scope of the present invention in any way. A physician having ordinary skill in the related art can easily determine and prescribe the dosage of the compound to be used as needed. For example, a physician may start a dose of a compound of the present invention used in a pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. can
본 명세서에서 사용된 용어 “치료”는 질병의 치료(treatment), 개선(improvement), 완화(amelioration) 또는 관리(management)를 모두 포함하는 개념으로서 사용된다. 본 명세서에서 용어 "치료하는" 또는 "치료"는 질환을 저해하는 것, 예를 들어, 질환, 병태 또는 장애의 병리 또는 징후를 경험하거나 또는 나타내는 개체에서 질환, 병태 또는 장애를 저해하는 것, 병리 및/또는 징후의 추가적인 발생을 막는 것, 질환을 개선시키는 것, 또는 병리 및/또는 징후를 반전시키는 것, 예컨대 질환 중증도를 감소시키는 것을 말한다.As used herein, the term “treatment” is used as a concept including all treatment, improvement, amelioration, or management of a disease. As used herein, the term "treating" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptom of a disease, condition or disorder, pathology. and/or preventing further occurrence of symptoms, ameliorating the disease, or reversing the pathology and/or symptoms, such as reducing disease severity.
본 명세서에서 사용된 용어 "예방하는" 또는 "예방"은 질환을 예방하는 것, 예를 들어 질환, 병태 또는 장애의 성향이 있을 수 있지만 질환의 병리 또는 징후를 아직 경험하지 않았거나 나타내지 않는 개체에서 질환, 병태 또는 장애를 예방하는 것을 말한다.As used herein, the term "preventing" or "prevention" refers to preventing a disease, e.g., in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or exhibit the pathology or signs of the disease. To prevent a disease, condition or disorder.
본 명세서에서 사용된 용어 “개체” 또는 “환자”는 포유류, 예를 들어, 마우스, 래트, 기타 설치류, 토끼, 개, 고양이, 돼지, 소, 양, 말 또는 영장류 및 인간을 포함하는 임의의 동물을 말한다.As used herein, the term “subject” or “patient” refers to any animal, including mammals, eg, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates and humans. say
일 구체예에 따른 치료방법에서 상기 암로디핀 또는 이의 약제학적 허용가능한 염, 클로르탈리돈 또는 이의 약제학적 허용가능한 염, 및 로사르탄 또는 이의 약제학적 허용가능한 염을 포함하는 하나의 단일 제형으로 투여되거나, 각각을 개별적으로 포함하는 복수 제형으로 투여될 수 있다. 상기 성분들은 하나의 단일 투여형으로 존재하거나, 각각 개별 투여형으로 존재하여 병용 투여될 수 있다. 상기 단일 투여형 또는 개별 투여형은 정제 또는 캡슐 형태일 수 있다. 예를 들어, 개별 투여형으로 존재하여 투여될 경우 상이한 경로로 투여될 수 있다. 상기 활성 성분의 투여가 순차적이거나 개별적일 경우, 제 2 성분을 투여하는데 있어서의 지연이 바람직하게는, 예를 들면, 병용 요법의 이로운 효과를 손상시키지 않아야 한다. 이러한 맥락에서, 순차 투여는 또한 (제한되지 않고), 예를 들면, 활성 성분의 교호 투여를 포함할 수 있다.In the treatment method according to one embodiment, the amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof are administered as a single dosage form, or It may be administered in multiple dosage forms comprising each individually. The components may be present in one single dosage form, or each may be present in separate dosage forms and administered in combination. The single dosage form or individual dosage form may be in the form of a tablet or capsule. For example, when administered in separate dosage forms, it may be administered by different routes. If the administration of the active ingredients is sequential or separate, a delay in administering the second ingredient should preferably not impair, for example, the beneficial effects of the combination therapy. In this context, sequential administration may also include (but not limited to), for example, alternating administration of the active ingredients.
일 구체예에 따른 치료방법에서 약물의 투여량은 투여 받을 대상의 연령, 성별, 체중, 병리 상태 및 그 심각도, 투여 경로 또는 처방자의 판단에 따라 달라질 수 있다. 이러한 인자에 기초한 적용량의 결정은 당업자의 수준 내에 있다. 또한, 필요에 따라 하나 이상의 다른 심혈관계 질환 예방 또는 치료용 의약품과 병용하여 투여될 수 있다.The dosage of the drug in the treatment method according to one embodiment may vary depending on the age, sex, weight, pathological condition and severity of the subject to be administered, the route of administration, or the judgment of the prescriber. Determination of the amount to be applied based on these factors is within the level of one of ordinary skill in the art. In addition, if necessary, it may be administered in combination with one or more other pharmaceuticals for preventing or treating cardiovascular diseases.
본 명세서에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한, 본 명세서에는 바람직한 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 명세서의 범주에 포함된다. All technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, unless otherwise defined. In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present specification.
본 명세서에 참고문헌으로 기재되는 모든 간행물의 내용은 전체가 본 명세서에 참고로 통합된다. 본 명세서에 기재된 수치는 명시하지 않아도 "약"의 의미를 포함하는 것으로 간주하며, 본 명세서에서 사용된 용어, "약"은 언급하는 값이 어느 정도 변할 수 있다는 것을 의미한다. 예를 들어, 상기 값은 10%, 5%, 2%, 또는 1%로 변할 수 있다. 예를 들어, "약 5 "는 4.5 및 5.5 사이, 4.75 및 5.25 사이, 또는 4.9 및 5.1 사이, 또는 4.95 및 5.05 사이의 임의의 값을 포함하는 것을 의미한다. 본 명세서에서 용어 "내지"를 이용하여 표시된 수치 범위는 용어 "내지" 전과 후에 기재되는 수치를 각각 하한 및 상한으로서 포함하는 범위를 말한다. 본 명세서에서 사용된 용어, "가진다", "가질 수 있다", "포함한다", 또는 "포함할 수 있다" 등의 표현은 해당 특징(예: 수치, 또는 성분 등의 구성요소)의 존재를 가리키며, 추가적인 특징의 존재를 배제하지 않는다.The contents of all publications incorporated herein by reference are hereby incorporated by reference in their entirety. Numerical values set forth herein are considered to include the meaning of “about” even if not specified, and the term “about” as used herein means that the referenced value may vary to some extent. For example, the value may vary by 10%, 5%, 2%, or 1%. For example, “about 5” is meant to include any value between 4.5 and 5.5, between 4.75 and 5.25, or between 4.9 and 5.1, or between 4.95 and 5.05. In this specification, the numerical range indicated using the term "to" refers to a range including the numerical values described before and after the term "to" as the lower limit and the upper limit, respectively. As used herein, the terms “has”, “may have”, “comprises”, or “may include” indicate the presence of a corresponding characteristic (eg, a numerical value or a component such as an ingredient). and does not exclude the presence of additional features.
이하, 본 발명을 하기 실시예에 의거하여 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.
[실시예][Example]
제조예 1: 시험 대상자 선정 및 임상 시험 의약품의 투여Preparation Example 1: Selection of test subjects and administration of clinical trial drugs
1. 시험 대상자의 선정1. Selection of test subjects
하기 선정 기준 및 제외 기준에 기초하여 시험 대상자를 선정하였다. Test subjects were selected based on the following selection criteria and exclusion criteria.
(1) 선정 기준(1) Selection criteria
1) 만 19세 이상의 본태성 고혈압 환자 1) Patients with essential hypertension over the age of 19
2) 임상시험의 과정을 이해하고, 동의서에 서명한 시험대상자 2) Subjects who understand the clinical trial process and sign the consent form
3) 제1차 방문(Visit 1) 및 제2차 방문(Visit 2)에서 측정한 평균 혈압이 140 mmHg ≤ sitSBP <180 mmHg이면서 sitDBP <110 mmHg인 환자 3) Patients with a mean blood pressure of 140 mmHg ≤ sitSBP <180 mmHg and sitDBP <110 mmHg at Visit 1 (Visit 1) and Visit 2 (Visit 2)
단, 하기 예시한 제외 기준에 기초하여 임상시험계획서에서 설정된 기준에 따라 임상시험에 적절하지 않은 경우 대상자에서 제외하였다. However, based on the exclusion criteria exemplified below, subjects were excluded from the subjects if they were not appropriate for the clinical trial according to the criteria set in the clinical trial protocol.
(2) 제외 기준(2) Exclusion criteria
1) 제1차 방문에서 양쪽 팔에서 측정한 혈압의 평균값의 차이가 sitSBP 20 mmHg 이상이거나 sitDBP 10 mmHg 이상인 환자 1) Patients with a difference between the mean blood pressure values measured in both arms at visit 1 sitSBP of 20 mmHg or more or sitDBP 10 mmHg or more
2) 제1차 방문과 제2차 방문 사이의 평균 sitSBP 차이가 15 mmHg 를 초과하는 환자 2) Patients with mean sitSBP difference greater than 15 mmHg between Visit 1 and Visit 2
3) 제1차 방문과 제2차 방문에서 평균 sitSBP가 180 mmHg 이상 또는 평균 sitDBP가 110 mmHg 이상인 환자 3) Patients with mean sitSBP ≥180 mmHg or mean sitDBP ≥110 mmHg at visits 1 and 2
4) 이차성 고혈압 또는 이차성 고혈압이 의심되는 환자(대동맥축착증, 원발성 알도스테론증, 신동맥협착, 신성고혈압, 갈색세포종, 쿠싱 증후군 등) 4) Patients with secondary hypertension or suspected secondary hypertension (aortic stenosis, primary aldosteronism, renal artery stenosis, renal hypertension, pheochromocytoma, Cushing's syndrome, etc.)
5) 제1차 방문을 기준으로 2주 이내에 항고혈압 약물을 복용하였거나, 시험기간 중 병용금기약물에 제시된 약물을 복용해야 하는 환자(본문 82 병용약물 및 투여 금지 약물) 5) Patients who have taken antihypertensive drugs within 2 weeks of the first visit or who need to take drugs listed in Contraindications during the trial period (Text 82 Concomitant Drugs and Prohibited Drugs)
6) 제1형 당뇨병 환자 또는 조절되지 않는 제2형 당뇨병 환자(제1차 방문에서 HbA1c ≥ 9%) 등 6) patients with type 1 diabetes or uncontrolled type 2 diabetes (HbA1c ≥ 9% at visit 1), etc.
2. 임상시험의약품의 준비 및 투여 방법2. Preparation and administration of investigational drugs
(1) 시험용 의약품의 준비(1) Preparation of investigational drugs
선정된 대상군에 투여할 시험약으로 하기 함량을 포함하는 시험용 의약품을 준비하였다. 경증 고혈압 내지 중등증 고혈압 환자를 대상으로 한 치료제 개발을 위해서는, 적절한 수준의 혈압 감소 효과를 입증할 필요가 있다. 이에 본 발명자들은 안전성과 유효성을 모두 고려하여 적정한 용량의 저용량 복합제제 개발을 위해 아모잘탄플러스TM정의 최저 용량인 암로디핀, 로사르탄 및 클로르탈리돈의 각 5/50/12.5mg을 기준으로 주요 성분간 비율을 동일하게 유지한 채 일정한 비율로 감량하여 용량을 탐색하였다. 그 결과 본 발명자들은 다음과 같은 비율의 시험용 의약품을 제시하게 되었다. As a test drug to be administered to the selected target group, a test drug containing the following content was prepared. In order to develop a therapeutic agent for patients with mild to moderate hypertension, it is necessary to demonstrate an appropriate level of blood pressure reduction effect. Therefore, the present inventors have developed a low-dose combination formulation with an appropriate dose in consideration of both safety and effectiveness, based on 5/50/12.5 mg of amlodipine, losartan, and chlorthalidone, which are the lowest doses of Amosartan Plus TM, respectively, between major components. The dose was searched for by reducing the dose at a constant ratio while maintaining the same ratio. As a result, the present inventors came to present the test drug in the following ratio.
1) HCP1803-2.5/25/6.25 : 암로디핀 2.5mg, 로사르탄 칼륨 25mg, 클로르탈리돈 6.25mg 1) HCP1803-2.5/25/6.25: amlodipine 2.5mg, losartan potassium 25mg, chlorthalidone 6.25mg
2) HCP1803-1.67/16.67/4.17 : 암로디핀 1.67mg, 로사르탄 칼륨 16.67mg, 클로르탈리돈 4.17mg 2) HCP1803-1.67/16.67/4.17: amlodipine 1.67 mg, losartan potassium 16.67 mg, chlorthalidone 4.17 mg
3) HCP1803-1.25/12.5/3.13 : 암로디핀 1.25mg, 로사르탄 칼륨 12.5mg, 클로르탈리돈 3.13mg3) HCP1803-1.25/12.5/3.13: Amlodipine 1.25mg, Losartan Potassium 12.5mg, Chlorthalidone 3.13mg
(2) 대조용 의약품(활성대조군)의 준비(2) Preparation of control drug (active control)
대조용 의약품으로는 HGP0904 (노바스크TM정 5 mg)(암로디핀으로서 5 mg)(한국화이자제약(주)) 및 코자TM정 100 mg (로사르탄 칼륨으로서 100mg)(한국엠에스디(유))를 준비하였다. As control drugs, HGP0904 (Novasc TM tablets 5 mg) (Amlodipine 5 mg) (Pfizer Korea Co., Ltd.) and Koza TM tablets 100 mg (Losartan potassium 100 mg) (MSD Korea Co., Ltd.) were prepared. .
(3) 위약(Placebo)의 준비 (3) Preparation of Placebo
1) HGP0904 (암로디핀 5 mg)의 위약 (흰색의 팔각형 정제) 1) placebo of HGP0904 (amlodipine 5 mg) (white octagonal tablets)
2) HCP1803-1.25/12.5/3.13의 위약 (흰색의 원형 필름코팅정제)2) Placebo of HCP1803-1.25/12.5/3.13 (white, round, film-coated tablets)
(4) 이중눈가림을 위한 DB캡슐 제조(4) DB capsule manufacturing for double blinding
이중눈가림을 확보하기 위하여 (1) 내지 (3)에서 준비된 정제를 DB캡슐 (DB caps® size A; Capsugel, USA)에 포장하여 임상시험을 진행하였다.In order to secure double-blindness, the tablets prepared in (1) to (3) were packaged in DB capsules (DB caps ® size A; Capsugel, USA) and a clinical test was conducted.
각 투여군별로 복용하게 되는 DB캡슐의 무게를 유사하게 하기 위해서, 시험약 또는 대조약과 HGP0904의 위약 또는 HCP1803-1.25/12.5/3.13의 위약을 DB캡슐에 함께 충진하였다. 단, 암로디핀 10mg투여군에서는 DB캡슐의 size를 고려하여 HGP0904 2정을 DB capsule에 충진하였다. In order to make the weight of the DB capsule to be taken for each administration group similar, the test drug or control drug and a placebo of HGP0904 or a placebo of HCP1803-1.25/12.5/3.13 were filled together in the DB capsule. However, in the group receiving 10 mg of amlodipine, 2 tablets of HGP0904 were filled into the DB capsule in consideration of the size of the DB capsule.
(5) 투여 방법(5) method of administration
모든 시험대상자들은 2주 간의 도입기(run-in period) 기간 동안, 노바스크정 5mg의 위약 1정을 단일눈가림하여 복용하고, 8주 간의 처리 기간(treatment period) 동안 무작위배정 된 투여군에 따라 임상시험용의약품 1캡슐을 1일 1회 식사와 관계없이 아침에 경구 투여하였다. During the two-week run-in period, all subjects took a single-blind dose of Novask 5 mg of placebo, and during the 8-week treatment period, the drug for clinical trials according to the randomly assigned administration group. 1 capsule was orally administered in the morning regardless of meal once a day.
3. 임상시험 계획 및 방법3. Clinical Trial Plan and Method
본 임상시험은 다기관 공동, 무작위배정, 이중눈가림, 평행설계방식 임상시험으로 설계되었다.This clinical trial was designed as a multicenter, joint, randomized, double-blind, parallel design trial.
제1차 방문(Visit 1)에서 선정/제외 기준에 적합한 대상자는 2주의 도입기(run-in period)를 진행하며, 식사(식염 섭취량), 흡연, 알코올 섭취, 체중 및 운동량 등을 조절하도록 하였다. 제2차 방문(Visit 2)에서 선정/제외기준에 적합한 환자를 sitSBP 160mmHg를 기준으로 층화하여 7군으로 나누어 1:1:1:1:1:1:1의 비율로 무작위배정하고, 8주 동안 해당하는 임상시험용의약품을 투여하였다. 처리 기간(treatment period) 중 시험대상자는 0주(Visit 2), 4주(Visit 3), 8주(Visit 4)째에 시험기관에 방문하여 유효성 및 안전성 평가를 시행하며, 시험 기간 동안 임상시험용의약품의 용량 조절 없이 같은 치료방법을 유지하였다. 또한 모든 대상자들은 임상시험 전 기간 동안 식사(식염 섭취량), 흡연, 알코올 섭취, 체중 및 운동량 등 혈압 측정 결과에 영향을 미칠 수 있는 생활습관을 일정하게 유지하도록 하였다. Subjects who met the selection/exclusion criteria at the first visit (Visit 1) were subjected to a two-week run-in period, and diet (salt intake), smoking, alcohol intake, body weight and exercise were controlled. At visit 2 (Visit 2), patients who met the inclusion/exclusion criteria were stratified based on sitSBP 160 mmHg, divided into 7 groups, and randomized at a ratio of 1:1:1:1:1:1:1, 8 weeks The corresponding clinical investigational drug was administered during the period. During the treatment period, the test subject visits the laboratory at week 0 (Visit 2), week 4 (Visit 3), and week 8 (Visit 4) to evaluate efficacy and safety, and during the trial period, The same treatment method was maintained without adjusting the dose of the drug. In addition, all subjects were asked to maintain constant lifestyle habits that could affect blood pressure measurement results, such as diet (salt intake), smoking, alcohol intake, weight and exercise during the entire clinical trial period.
도 1은 상술한 임상시험 계획에 따라 임상시험 대상자에게 도입기(run-in period)를 거쳐서 처리 기간(treatment period) 동안 상술한 시험용 의약품(암로디핀 2.5mg, 로사르탄 칼륨 25mg, 클로르탈리돈 6.25mg; 암로디핀 1.67mg, 로사르탄 칼륨 16.67mg, 클로르탈리돈 4.17mg; 또는 암로디핀 1.25mg, 로사르탄 칼륨 12.5mg, 클로르탈리돈 3.13mg), 대조용 의약품(암로디핀 5 mg; 암로디핀 10 mg; 로사르탄 칼륨 100mg), 또는 위약(placebo)을 투여하는 방법을 도시한다. 1 shows the above-described investigational drugs (amlodipine 2.5 mg, losartan potassium 25 mg, chlorthalidone 6.25 mg; Amlodipine 1.67 mg, losartan potassium 16.67 mg, chlorthalidone 4.17 mg; or amlodipine 1.25 mg, losartan potassium 12.5 mg, chlorthalidone 3.13 mg), control drug (amlodipine 5 mg; amlodipine 10 mg; losartan potassium 100 mg) ), or a placebo.
4. 임상시험 결과 평가 기준 4. Criteria for Evaluation of Clinical Trial Results
다음과 같은 유효성 및 안전성 평가 항목을 기준으로 임상시험 결과를 평가하였다. The clinical trial results were evaluated based on the following efficacy and safety evaluation items.
(1) 유효성 평가 (1) Efficacy evaluation
1) 1차 유효성 평가 항목 1) Primary efficacy evaluation items
① 기저치 대비 8주 후의 평균 sitSBP 변화량 ① Average sitSBP change after 8 weeks from baseline
2) 2차 유효성 평가 항목 2) Secondary efficacy evaluation items
① 기저치 대비 4주 후의 평균 sitSBP 변화량 ① Average sitSBP change after 4 weeks from baseline
② 기저치 대비 4, 8주 후의 평균 sitDBP 변화량 ② Average sitDBP change after 4 or 8 weeks from baseline
③ 4, 8주에서의 혈압 조절률(sitSBP/sitDBP < 140/90mmHg 시험대상자 비율) ③ Blood pressure control rate at 4 and 8 weeks (sitSBP/sitDBP < 140/90mmHg subject ratio)
④ 4, 8주에서의 혈압 반응률 (Responder rate) (기저치 대비 sitSBP/sitDBP 감소량 ≥ 20/10mmHg 시험대상자 비율) ④ Blood pressure response rate at 4 and 8 weeks (reduction of sitSBP/sitDBP compared to baseline ≥ 20/10mmHg ratio of subjects)
⑤ 기저치 대비 4, 8주 후의 평균 맥압 변화량 (평균 sitSBP - sitDBP) ⑤ Average pulse pressure change after 4 or 8 weeks compared to baseline (average sitSBP - sitDBP)
(2) 안전성 평가 (2) safety evaluation
1) 이상반응1) Adverse reaction
2) 활력 징후, 임상실험실검사, 신체 검사, 심전도(electrocardiogram: ECG)2) Vital signs, laboratory tests, physical examination, electrocardiogram (ECG)
(3) 용량 선정(3) Capacity selection
각 투여군의 유효성과 안전성을 종합적으로 평가하여 제3상 확증시험에 적합한 용량을 선정하였다.The appropriate dose for the phase 3 confirmation study was selected by comprehensively evaluating the efficacy and safety of each administration group.
5. 통계 분석 방법5. Statistical analysis method
상기 임상시험 평가 항목에 기초하여 얻은 결과 값을 다음과 같은 방법으로 통계 분석하였다. 유효성 평가분석은 모든 분석 대상자군(Full analysis set: FA set 또는 FAS)(무작위 배정된 이후 임상시험용의약품을 1회 이상 복용한 시험대상자 중, 임상시험용의약품 투여 후 임상시험 종료 시까지 한번이라도 sitSBP을 측정한 시험대상자)을 주 분석대상으로 하고, 계획서 순응 임상시험대상자군(Per protocol set: PP set 또는 PPS)을 보조분석대상으로 하였다. The result values obtained based on the clinical trial evaluation items were statistically analyzed in the following way. Efficacy evaluation analysis was conducted for all analysis subjects (Full analysis set: FA set or FAS) (from among the subjects who took the investigational drug at least once after being randomly assigned, sitSBP was administered at least once until the end of the clinical trial after administration of the investigational drug. The measured test subject) was used as the main analysis target, and the protocol-compliant clinical test group (Per protocol set: PP set or PPS) was used as the secondary analysis target.
(1) 유효성 평가 분석 (1) Efficacy evaluation analysis
1) 1차 유효성 평가 1) Primary efficacy evaluation
① 기저치 대비 8주 후의 평균 sitSBP 변화량① Average sitSBP change after 8 weeks from baseline
시험군의 기저치 대비 8주 후 sitSBP 변화가 위약대조군에 비해 우월한지를 검정하기 위해 기저치를 공변량(Covariate)으로 하는 공분산분석(ANCOVA)을 실시하였다. In order to test whether the change in sitSBP after 8 weeks compared to the baseline in the test group was superior to that in the placebo control group, analysis of covariance (ANCOVA) was performed with the baseline value as the covariate.
2) 2차 유효성 평가 2) Secondary efficacy evaluation
① 기저치 대비 8주 후의 평균 sitSBP 변화량① Average sitSBP change after 8 weeks from baseline
기저치 대비 8주 후 sitSBP 변화에 대해 시험군과 대조군을 비교하기 위해 기저치를 공변량 (Covariate)으로 하는 공분산분석 (ANCOVA)을 실시하였다. (1차 평가변수인 시험약과 위약과의 비교 제외)Analysis of covariance (ANCOVA) was performed with the baseline value as a covariate to compare the test group and the control group for the change in sitSBP after 8 weeks compared to the baseline value. (Excluding comparisons between test drug and placebo, which are the primary endpoints)
② 기저치 대비 4주 후의 평균 sitSBP 변화량 ② Average sitSBP change after 4 weeks from baseline
기저치 대비 4주 후 sitSBP 변화에 대해 시험군과 대조군을 비교하기 위해 기저치를 공변량 (Covariate)으로 하는 공분산분석 (ANCOVA)을 실시하였다. Analysis of covariance (ANCOVA) was performed with the baseline value as a covariate to compare the test group and the control group for the change in sitSBP after 4 weeks compared to the baseline value.
③ 기저치 대비 4, 8주 후의 평균 sitDBP 변화량 ③ Average sitDBP change after 4 or 8 weeks from baseline
기저치 대비 4, 8주 후 sitDBP 변화에 대해 시험군과 대조군을 비교하기 위해 기저치 및 층화변수를 공변량 (Covariate)으로 하는 공분산분석 (ANCOVA)을 실시하였다. Analysis of covariance (ANCOVA) was performed using the baseline value and the stratified variable as covariates to compare the test group and the control group for the change in sitDBP after 4 or 8 weeks from the baseline value.
④ 4, 8주에서의 혈압 조절률(sitSBP < 140mmHg 및 sitDBP < 90mmHg 시험대상자 비율) ④ Blood pressure control rate at 4 and 8 weeks (sitSBP < 140 mmHg and sitDBP < 90 mmHg proportion of subjects)
4, 8주 시점의 시험군과 대조군의 혈압조절률을 비교하기 위해 Pearson's chi-square test 또는 Fisher's exact test를 실시하여 투여군간 비교하였다. In order to compare the blood pressure control rates of the test group and the control group at 4 and 8 weeks, Pearson's chi-square test or Fisher's exact test was performed to compare between administration groups.
⑤ 4, 8주에서의 혈압 반응률 (Responder rate) (기저치 대비 sitSBP 감소량 ≥ 20mmHg 또는 sitDBP 감소량 ≥ 10mmHg 시험대상자 비율) ⑤ Blood pressure response rate at 4 and 8 weeks (ratio of subjects with sitSBP decrease ≥ 20 mmHg or sitDBP decrease ≥ 10 mmHg compared to baseline)
4, 8주 시점의 시험군과 대조군의 혈압반응률을 비교하기 위해 Pearson's chi-square test 또는 Fisher's exact test를 실시하여 투여군간 비교하였다. To compare the blood pressure response rates of the test group and the control group at 4 and 8 weeks, Pearson's chi-square test or Fisher's exact test was performed to compare between administration groups.
⑥ 기저치 대비 4, 8주 후의 평균 맥압 변화량(평균 sitSBP - sitDBP)⑥ Average pulse pressure change after 4 or 8 weeks compared to baseline (average sitSBP - sitDBP)
기저치 대비 4, 8 주 후 맥압 변화에 대해 시험군과 대조군을 비교하기 위해 기저치 및 층화변수를 공변량(Covariate)으로 하는 공분산분석(ANCOVA)을 실시하였다. Analysis of covariance (ANCOVA) with baseline and stratified variables as covariates was performed to compare the test group and the control group for changes in pulse pressure after 4 and 8 weeks compared to baseline.
(2) 안전성 평가 분석(2) safety evaluation analysis
안전성 분석은 무작위배정된 이후 임상시험용의약품을 1회 이상 복용한 시험대상자 중, 임상시험용의약품 복용 후 임상시험 종료 시까지 시험자가 안전성 관련 데이터를 최소한 한번 이상 확인한 시험대상자를 대상으로 하였다. The safety analysis was conducted on subjects who had taken the investigational drug at least once after being randomized, and the investigator checked safety-related data at least once until the end of the clinical trial after taking the investigational drug.
1) 이상반응 1) Adverse reaction
이상반응이란 임상시험용의약품을 투여한 시험대상자에게 발생한 모든 유해하고 의도하지 않은 증후(sign: 실험실 검사치의 이상), 증상(symptom) 또는 질병을 말하며, 해당 임상시험용의약품과 반드시 인과관계를 가져야 하는 것은 아니다. 시험자는 시험 중 발생하는 모든 이상반응을 기록하고 평가하였다. Adverse reaction refers to all harmful and unintended signs (abnormalities in laboratory test values), symptoms, or diseases that occur in subjects who have administered the investigational drug, and must have a causal relationship with the investigational drug. no. The investigator recorded and evaluated any adverse events that occurred during the trial.
무작위 배정 전에 발현되었던 이상반응(pre-existing AEs)에 대하여 리스팅으로 제시하였고, 무작위배정 이후 발현된 이상반응(TEAEs; Treatment Emergent Adverse Events)에 대해서는 투여군 별로 그리고, 중대한 이상반응의 여부, 중증도 및 임상시험용의약품과의 연관성에 대하여 시험대상자 수와 발현율(%)을 제시하여 비교 평가하였다. Pre-existing AEs that occurred before randomization were presented as a listing, and Treatment Emergent Adverse Events (TEAEs) that occurred after randomization were presented by treatment group, and the presence, severity, and clinical trial of serious adverse events. For the correlation with the investigational drug, the number of subjects and the expression rate (%) were presented for comparative evaluation.
2) 활력징후, 임상실험실검사, 신체검사, 심전도(ECG) 2) Vital signs, clinical laboratory tests, physical examination, electrocardiogram (ECG)
각 투여군별로 정상, 임상적으로 유의하지 않은 비정상(NCS), 임상적으로 유의한 비정상(CS)에 대해 시점별로 shift table을 제시하고 McNemar's test를 실시하여 투여 전/후 군내 변화에 대한 통계적 유의성 검정을 실시하였다. 연속형 변수의 경우, 각 측정시점별로 기술통계량(시험대상자 수, 산술평균, 표준편차, 중앙값, 최소값, 최대값)을 제시하였다. For each administration group, a shift table was presented for each time point for normal, clinically non-significant abnormality (NCS), and clinically significant abnormality (CS), and McNemar's test was performed to test the statistical significance of changes within groups before and after administration. was carried out. For continuous variables, descriptive statistics (number of subjects, arithmetic mean, standard deviation, median, minimum, maximum) were presented for each measurement time point.
임상시험예 1: 시험 대상자군에서 저용량 고혈압 치료제를 투여함에 따른 중대한 이상반응 및 약물이상반응의 관찰Clinical Trial Example 1: Observation of serious adverse reactions and adverse drug reactions following administration of a low-dose antihypertensive agent in the test subject group
약물이상반응은 임상시험용 의약품의 임의 용량에서 발생한 모든 유해하고 의도하지 않은 반응으로서 임상시험용의약품과의 인과관계를 배제할 수 없는 경우를 말한다. 본 임상시험에서는 인과관계가 '있다'고 평가된 이상반응을 약물이상반응으로 분류하였다. Adverse drug reaction refers to any adverse and unintended reaction that occurs at any dose of an investigational drug, and a causal relationship with the investigational drug cannot be excluded. In this clinical trial, adverse reactions evaluated as having a causal relationship were classified as adverse drug reactions.
중대한 이상반응, 약물이상반응(Serious AE, ADR)이란 임상시험용의약품의 임의 용량에서 발생한 이상반응 또는 약물이상반응 중에서 다음의 어느 하나에 해당하는 경우를 말한다. Serious AE, ADR refers to a case that falls under any of the following among the adverse reactions or drug reactions occurring at any dose of the investigational drug.
1) 사망하거나 생명에 대한 위험이 발생한 경우 1) In case of death or danger to life
2) 입원할 필요가 있거나 입원 기간을 연장할 필요가 있는 경우 2) When it is necessary to be hospitalized or to extend the hospitalization period
3) 영구적이거나 중대한 장애 및 기능 저하를 가져온 경우 3) Causes permanent or significant disability or functional decline
4) 태아에게 기형 또는 이상이 발생한 경우 4) In case of malformation or abnormality in the fetus
5) 1)에서 4)까지의 사례 외에 약물 의존성이나 남용의 발생 또는 혈액질환 등 그 밖에 의학적으로 중요한 상황이 발생하는 사례 5) In addition to cases 1) to 4), cases of drug dependence or abuse or other medically important circumstances such as blood disease
본 임상시험에 따른 임상시험용 의약품 중 저용량 고혈압 치료제(암로디핀 2.5mg, 로사르탄 칼륨 25mg, 클로르탈리돈 6.25mg; 암로디핀 1.67mg, 로사르탄 칼륨 16.67mg, 클로르탈리돈 4.17mg ; 또는 암로디핀 1.25mg, 로사르탄 칼륨 12.5mg, 클로르탈리돈 3.13mg)의 투여는 임상적으로 유의미한 중대한 이상반응 또는 약물이상반응을 보이지 않았다. Low-dose antihypertensive drugs (amlodipine 2.5mg, losartan potassium 25mg, chlorthalidone 6.25mg; amlodipine 1.67mg, losartan potassium 16.67mg, chlorthalidone 4.17mg ; or amlodipine 1.25mg, rosa Administration of rutan potassium 12.5 mg, chlorthalidone 3.13 mg) did not show any clinically significant serious adverse reactions or adverse drug reactions.
임상시험예 2: 경증 고혈압 내지 중등증 고혈압 환자에서 저용량 고혈압 치료제를 투여함에 따른 혈압 개선 효과Clinical Trial Example 2: Blood pressure improvement effect by administration of a low-dose antihypertensive agent in patients with mild to moderate hypertension
(1) 대상군의 약물 투여 전 혈압 측정 (1) Blood pressure measurement before drug administration in the target group
시험용 의약품 투여 전 시험대상자 군의 수축기 혈압 및 이완기 혈압을 측정 하였다. The systolic and diastolic blood pressures of the test subjects were measured before administration of the test drug.
(2) 저용량 고혈압 치료제 투여에 따른 혈압 개선 효과(2) Blood pressure improvement effect of low-dose antihypertensive treatment
상기 대상군에서 시험용 의약품 투여에 따른 수축기 혈압 및 이완기 혈압을 측정하였고, 대조약 또는 위약을 투여한 결과와 비교하였다. 그 결과, 시험용 의약품으로 준비한 저용량 고혈압 치료제(HCP1803-2.5/25/6.25, HCP1803-1.67/16.67/4.17, HCP1803-1.25/12.5/3.13)는 위약과 대비하여 우월한 혈압 개선 효과를 보였고, 암로디핀 5 mg 또는 10 mg을 투여 시, 또는 로사르탄 100 mg을 투여 시와 유사한 혈압 개선 효과를 보였다. 상기 시험용 의약품은 경증 고혈압 내지 중등증 고혈압 환자에서 과도한 혈압 감소를 나타내지 않음과 동시에 혈압 조절에 충분한 평균 혈압강하 효과를 보여서 안전성 및 내약성이 우수함을 확인하였다. 또한, 상기 대상군에서 시험용 의약품은 대조약 또는 위약 보다 경증 또는 중등증의 고혈압, 예컨대 ESH(2018) 가이드라인에 따른 1기 내지 2기 고혈압에서 위험성 대비 유익성이 우수함을 확인하였다. Systolic blood pressure and diastolic blood pressure according to the administration of the test drug in the target group were measured, and compared with the results of administration of the control drug or placebo. As a result, low-dose antihypertensive drugs (HCP1803-2.5/25/6.25, HCP1803-1.67/16.67/4.17, HCP1803-1.25/12.5/3.13) prepared as an investigational drug showed superior blood pressure improvement compared to placebo, and amlodipine 5 mg Alternatively, when 10 mg was administered, or when losartan 100 mg was administered, blood pressure improvement effects were similar. The test drug did not show an excessive decrease in blood pressure in patients with mild to moderate hypertension, and at the same time showed an average blood pressure lowering effect sufficient to control blood pressure, confirming that it was excellent in safety and tolerability. In addition, it was confirmed that the test drug in the target group was superior to the risk versus benefit in mild or moderate hypertension, such as stage 1 to 2 hypertension according to the ESH (2018) guidelines, than the reference drug or placebo.
임상시험예 3: 혈압 정상화율 측정Clinical Trial Example 3: Measurement of blood pressure normalization rate
임상시험 의약품으로 저용량 고혈압 치료제(암로디핀 2.5mg, 로사르탄 칼륨 25mg, 클로르탈리돈 6.25mg; 암로디핀 1.67mg, 로사르탄 칼륨 16.67mg, 클로르탈리돈 4.17mg; 또는 암로디핀 1.25mg, 로사르탄 칼륨 12.5mg, 클로르탈리돈 3.13mg)를 투여함에 따라 ESH(2018) 가이드라인에 따른 고혈압 1기 또는 2기를 포함하는, 경증 또는 중등증 고혈압 환자군에서 위약과 대비하여 우월한 혈압 개선 효과를 보였고, 저용량 투여에도 불구하고 상용량의 암로디핀 또는 상용량의 로사르탄 투여 시와 유사한 효과를 보였다. 구체적으로는 대조약으로서 암로디핀 5 mg 또는 10 mg, 또는 로사르탄 100 mg을 투여한 경우와 비교하여, 시험용 의약품으로 준비한 저용량 고혈압 치료제(HCP1803-2.5/25/6.25, HCP1803-1.67/16.67/4.17, HCP1803-1.25/12.5/3.13)는 ESH(2018) 가이드라인에 따른 고혈압 1기 또는 2기를 포함하는 경증 고혈압 내지 중등증 고혈압에서 개선된 혈압 정상화율을 보였다. As a clinical trial drug, low-dose antihypertensive drugs (amlodipine 2.5 mg, losartan potassium 25 mg, chlorthalidone 6.25 mg; amlodipine 1.67 mg, losartan potassium 16.67 mg, chlorthalidone 4.17 mg; or amlodipine 1.25 mg, losartan potassium 12.5 mg; Chlorthalidone 3.13 mg) showed superior blood pressure improvement compared to placebo in patients with mild or moderate hypertension, including stage 1 or 2 hypertension, according to the ESH (2018) guidelines. The effect was similar to that of the usual dose of amlodipine or losartan. Specifically, compared to the case of administering 5 mg or 10 mg of amlodipine or 100 mg of losartan as a reference drug, a low-dose antihypertensive agent (HCP1803-2.5/25/6.25, HCP1803-1.67/16.67/4.17, HCP1803-1.25/12.5/3.13) showed an improved blood pressure normalization rate in mild to moderate hypertension including stage 1 or 2 hypertension according to the ESH (2018) guidelines.
<1차 유효성 평가 결과><Result of primary efficacy evaluation>
임상시험예 4: 기저치 대비 8주 후의 평균 sitSBP 변화량Clinical Trial Example 4: Average sitSBP change after 8 weeks from baseline
기저치 대비 8 주 후의 sitSBP 변화에 대해 시험군과 위약대조군을 비교하기 위하여, 기저치에서의 평균 sitSBP를 공변량으로 보정한 공분산 분석 (ANCOVA)을 시행하였다. In order to compare the test group and the placebo control group with respect to the change in sitSBP after 8 weeks from baseline, analysis of covariance (ANCOVA), in which the mean sitSBP at baseline was adjusted as a covariate, was performed.
공분산 분석 결과로 추정된 기저치 대비 8 주 후 sitSBP 변화량의 최소제곱평균 ± 표준오차 (LS Mean ± SE)에 대하여 FAS를 기준으로 각 시험군과 위약대조군을 비교한 결과는 다음과 같다.The results of comparing each test group and the placebo control group based on the FAS with respect to the least squares mean ± standard error (LS Mean ± SE) of the change in sitSBP after 8 weeks compared to the baseline estimated as a result of the covariance analysis are as follows.
본 임상시험의 일차 유효성 평가 변수인 기저치 대비 8 주 후 sitSBP 변화량의 최소제곱평균 ± 표준오차(LS Mean ± SE)는 암로디핀/ 로사르탄 칼륨/클로르탈리돈 1.25/12.5/3.13mg (이하, A/L/C-1.25/12.5/3.13), 암로디핀/로사르탄 칼륨/클로르탈리돈 1.67/16.67/4.17mg (이하, A/L/C-1.67/16.67/4.17), 암로디핀/로사르탄 칼륨/클로르탈리돈 2.5/25/6.25mg (이하, A/L/C-2.5/25/6.25) 투여군이 위약 투여군에 비해 각각 -14.91 ± 3.89 mmHg, -19.49 ± 4.36 mmHg, -17.21 ± 3.60 mmHg 더 컸으며, 이는 통계적으로 유의한 차이를 나타내었다(p=0.0003, p<0.0001, p<0.0001). 이를 통해 시험약 HCP1803의 모든 용량에 대하여 기저치 대비 8 주 후 sitSBP 변화가 위약 대비 우월함을 통계적으로 입증하였다. The least squares mean ± standard error (LS Mean ± SE) of the change in sitSBP after 8 weeks from baseline, the primary efficacy evaluation variable of this clinical trial, was amlodipine/losartan potassium/chlorthalidone 1.25/12.5/3.13 mg (hereinafter, A/ L/C-1.25/12.5/3.13), amlodipine/losartan potassium/chlorthalidone 1.67/16.67/4.17 mg (hereinafter, A/L/C-1.67/16.67/4.17), amlodipine/losartan potassium/chlorthali Don 2.5/25/6.25 mg (hereafter, A/L/C-2.5/25/6.25) group was -14.91 ± 3.89 mmHg, -19.49 ± 4.36 mmHg, and -17.21 ± 3.60 mmHg greater than the placebo group, respectively, This showed a statistically significant difference (p=0.0003, p<0.0001, p<0.0001). Through this, for all doses of the test drug HCP1803, it was statistically verified that the change in sitSBP after 8 weeks from baseline was superior to that of placebo.
<2차 유효성 평가 결과><Result of secondary efficacy evaluation>
임상시험예 5: 기저치 대비 8주 후의 평균 sitSBP 변화량Clinical Trial Example 5: Average sitSBP change after 8 weeks from baseline
- 모든 분석 대상자군(FAS)에서 sitSBP 기저치로부터의 변화 측정- Measure change from baseline sitSBP in all analysis subjects (FAS)
기저치 대비 8 주 후의 sitSBP 변화에 대해 시험군과 활성대조군을 비교하기 위하여, 기저치에서의 평균 sitSBP를 공변량으로 보정한 공분산 분석 (ANCOVA)을 시행하였다. In order to compare the test group and the active control group with respect to the change in sitSBP after 8 weeks from the baseline, analysis of covariance (ANCOVA) was performed in which the mean sitSBP at baseline was corrected as a covariate.
공분산 분석 결과로 추정된 기저치 대비 8 주 후 sitSBP 변화량의 최소제곱평균 ± 표준오차 (LS Mean ± SE)에 대하여 FAS를 기준으로 각 시험군과 활성대조군을 비교한 결과를 표 2와 도 2에 나타내었다.Table 2 and Figure 2 show the results of comparing each test group with the active control group based on the FAS for the least squares mean ± standard error (LS Mean ± SE) of the change in sitSBP after 8 weeks compared to the baseline estimated as a result of the covariance analysis. it was
[표 2][Table 2]
Figure PCTKR2021006285-appb-I000002
Figure PCTKR2021006285-appb-I000002
Figure PCTKR2021006285-appb-I000003
Figure PCTKR2021006285-appb-I000003
Figure PCTKR2021006285-appb-I000004
Figure PCTKR2021006285-appb-I000004
Figure PCTKR2021006285-appb-I000005
Figure PCTKR2021006285-appb-I000005
Figure PCTKR2021006285-appb-I000006
Figure PCTKR2021006285-appb-I000006
Figure PCTKR2021006285-appb-I000007
Figure PCTKR2021006285-appb-I000007
Figure PCTKR2021006285-appb-I000008
Figure PCTKR2021006285-appb-I000008
도 2는 8주차에 모든 분석 대상자군(FAS)에서 기저치(baseline)로부터의 sitSBP 변화를 나타낸다. Figure 2 shows the sitSBP change from baseline in all analyzed subjects (FAS) at week 8.
A/L/C-1.25/12.5/3.13 투여군의 기저치 대비 8주 후 sitSBP 변화량을 암로디핀 5mg (이하, A5) 투여군, 암로디핀 10mg (이하, A10) 투여군, 로사르탄 칼륨 100mg (이하, L100) 투여군과 각각 비교하였을 때, 투여군 간 변화량의 차이 (LS Mean ± SE)는 각각 -3.83 ± 3.14 mmHg, 3.43 ± 2.87 mmHg, -5.13 ± 3.38 mmHg으로, A/L/C-1.25/12.5/3.13 투여군은 모든 활성대조군과 통계적으로 유의한 차이를 나타내지 않았다 (p=0.2280, p=0.2355, p=0.1339).The amount of sitSBP change after 8 weeks compared to the baseline in the A/L/C-1.25/12.5/3.13 group was compared with the group administered with amlodipine 5 mg (hereinafter, A5), the group administered with amlodipine 10 mg (hereinafter, referred to as A10), and the group administered with losartan potassium 100 mg (hereinafter, L100). When compared, the difference in the amount of change between the administration groups (LS Mean ± SE) was -3.83 ± 3.14 mmHg, 3.43 ± 2.87 mmHg, and -5.13 ± 3.38 mmHg, respectively, and the A/L/C-1.25/12.5/3.13 administration group showed that all There was no statistically significant difference with the active control group (p=0.2280, p=0.2355, p=0.1339).
A/L/C-1.67/16.67/4.17 투여군의 기저치 대비 8주 후 sitSBP 변화량을 A5 투여군, A10 투여군, L100 투여군과 각각 비교하였을 때, 투여군 간 변화량의 차이 (LS Mean ± SE)는 각각 -8.64 ± 3.64 mmHg, -1.42± 3.35 mmHg, -10.06 ± 3.80 mmHg으로, A/L/C-1.67/16.67/4.17 투여군은 A5 투여군, L100 투여군과 통계적으로 유의한 차이를 나타내었다 (p=0.0205, p=0.6745, p=0.0102).When the sitSBP change after 8 weeks compared to the baseline in the A/L/C-1.67/16.67/4.17 administration group was compared with the A5 administration group, A10 administration group, and L100 administration group, the difference in the change between the administration groups (LS Mean ± SE) was -8.64, respectively. ± 3.64 mmHg, -1.42 ± 3.35 mmHg, -10.06 ± 3.80 mmHg, A/L/C-1.67/16.67/4.17 administration group showed a statistically significant difference from A5 administration group and L100 administration group (p=0.0205, p =0.6745, p=0.0102).
A/L/C-2.5/25/6.25 투여군의 기저치 대비 8주 후 sitSBP 변화량을 A5 투여군, A10 투여군, L100 투여군과 각각 비교하였을 때, 투여군 간 변화량의 차이 (LS Mean ± SE)는 각각 -5.68 ± 2.85 mmHg, 1.48 ± 2.57 mmHg, -6.84 ± 3.18 mmHg 으로, A/L/C-2.5/25/6.25 투여군은 L100 투여군과 통계적으로 유의한 차이를 나타내었다 (p=0.0502, p=0.5673, p=0.0353).When the A/L/C-2.5/25/6.25 administration group compared the sitSBP change after 8 weeks compared to the baseline with the A5 administration group, A10 administration group, and L100 administration group, respectively, the difference in the change between the administration groups (LS Mean ± SE) was -5.68, respectively. At ± 2.85 mmHg, 1.48 ± 2.57 mmHg, -6.84 ± 3.18 mmHg, the A/L/C-2.5/25/6.25 administration group showed a statistically significant difference from the L100 administration group (p=0.0502, p=0.5673, p =0.0353).
시험군 간에는 통계적으로 유의한 차이를 나타내지 않았다.There was no statistically significant difference between the test groups.
임상시험예 6: 기저치 대비 8주 후의 평균 sitDBP 변화량Clinical Trial Example 6: Average sitDBP change after 8 weeks from baseline
기저치 대비 8 주 후의 sitDBP 변화에 대해 시험군과 대조군을 비교하기 위하여, 기저치에서의 평균 sitDBP 및 층화변수를 공변량으로 보정한 공분산 분석 (ANCOVA)을 시행하였다. In order to compare the test group and the control group with respect to the change in sitDBP after 8 weeks from the baseline, analysis of covariance (ANCOVA) was performed in which the mean sitDBP at baseline and stratification variables were corrected as covariates.
- 모든 분석 대상자군(FAS)에서 sitDBP 기저치로부터의 변화 측정 - Measure change from baseline sitDBP in all analysis subjects (FAS)
공분산 분석 결과로 추정된 기저치 대비 8 주 후 sitDBP 변화량의 최소제곱평균 ± 표준오차 (LS Mean ± SE)에 대하여 FAS를 기준으로 각 시험군과 대조군을 비교한 결과를 도 3에 나타내었다. Figure 3 shows the results of comparing each test group and the control group based on the FAS with respect to the least squares mean ± standard error (LS Mean ± SE) of the change in sitDBP after 8 weeks compared to the baseline estimated as a result of the covariance analysis.
도 3은 8주차에 FAS에서 기저치로부터의 sitDBP 변화를 나타낸다. 3 shows sitDBP change from baseline in FAS at week 8.
A/L/C-1.25/12.5/3.13 투여군의 기저치 대비 8주 후 sitDBP 변화량을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, 투여군 간 변화량의 차이(LS Mean ± SE)는 각각 0.44 ± 1.77 mmHg, 4.07 ± 1.87 mmHg, -4.12 ± 1.93 mmHg, -8.17 ± 2.27 mmHg으로, A/L/C-1.25/12.5/3.13 투여군은 A10 투여군, L100 투여군, Placebo 투여군과 통계적으로 유의한 차이를 나타내었다(p=0.8033, 0.0333, p=0.0362, p=0.0006).When the sitDBP change after 8 weeks from the baseline in the A/L/C-1.25/12.5/3.13 administration group was compared with the A5 administration group, A10 administration group, L100 administration group, and Placebo administration group, the difference in the change between the administration groups (LS Mean ± SE) was 0.44 ± 1.77 mmHg, 4.07 ± 1.87 mmHg, -4.12 ± 1.93 mmHg, -8.17 ± 2.27 mmHg respectively Differences were shown (p=0.8033, 0.0333, p=0.0362, p=0.0006).
A/L/C-1.67/16.67/4.17 투여군의 기저치 대비 8주 후 sitDBP 변화량을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, 투여군 간 변화량의 차이(LS Mean ± SE)는 각각 -1.59 ± 1.66 mmHg, 1.63 ± 1.74 mmHg, -6.02 ± 1.73 mmHg, -10.03 ± 2.16 mmHg으로, A/L/C-1.67/16.67/4.17 투여군은 L100 투여군, Placebo 투여군과 통계적으로 유의한 차이를 나타내었다(p=0.3415, p=0.3533, p=0.0009, p<0.0001).When the A/L/C-1.67/16.67/4.17 administration group compared the sitDBP change after 8 weeks compared to the baseline with the A5 administration group, A10 administration group, L100 administration group, and Placebo administration group, the difference in the change between the administration groups (LS Mean ± SE) was -1.59 ± 1.66 mmHg, 1.63 ± 1.74 mmHg, -6.02 ± 1.73 mmHg, -10.03 ± 2.16 mmHg, respectively (p=0.3415, p=0.3533, p=0.0009, p<0.0001).
A/L/C-2.5/25/6.25 투여군의 기저치 대비 8주 후 sitDBP 변화량을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, 투여군 간 변화량의 차이(LS Mean ± SE)는 각각 -0.69 ± 1.58 mmHg, 2.62 ± 1.68 mmHg, -5.52 ± 1.69 mmHg, -9.36 ± 2.06 mmHg으로, A/L/C-2.5/25/6.25 투여군은 L100 투여군, Placebo 투여군과 통계적으로 유의한 차이를 나타내었다(p=0.6620, p=0.1253, p=0.0018, p<0.0001).When the sitDBP change after 8 weeks compared to the baseline in the A/L/C-2.5/25/6.25 administration group was compared with the A5 administration group, A10 administration group, L100 administration group, and placebo administration group, the difference in the change between the administration groups (LS Mean ± SE) was -0.69 ± 1.58 mmHg, 2.62 ± 1.68 mmHg, -5.52 ± 1.69 mmHg, -9.36 ± 2.06 mmHg, respectively. (p=0.6620, p=0.1253, p=0.0018, p<0.0001).
시험군 간에는 통계적으로 유의한 차이를 나타내지 않았다.There was no statistically significant difference between the test groups.
임상시험예 7: 8주 시점에서의 혈압조절률Clinical Trial Example 7: Blood pressure control rate at 8 weeks
임상시험용의약품 투여 8 주 후 sitSBP 140 mmHg 미만 및 sitDBP 90 mmHg 미만으로 조절된 시험대상자의 비율을 투여군 간 비교하기 위하여 Pearson's chi-square test 또는 Fisher's exact test를 시행하였으며, FAS를 기준으로 각 시험군과 대조군을 비교한 결과는 다음과 같다. Eight weeks after administration of the investigational drug, Pearson's chi-square test or Fisher's exact test was performed to compare the proportion of subjects adjusted to sitSBP less than 140 mmHg and sitDBP less than 90 mmHg between the administration groups. The results of comparison with the control group are as follows.
도 4는 8주차에 FAS에서 혈압 조절을 달성한 대상체 비율을 나타낸다. 이 때, 혈압 조절의 달성은 sitSBP < 140mmHg 및 sitDBP < 90mmHg 로 정의한다.4 shows the proportion of subjects who achieved blood pressure control in FAS at Week 8. Here, achievement of blood pressure control is defined as sitSBP < 140 mmHg and sitDBP < 90 mmHg.
임상시험용의약품 투여 8 주 후 sitSBP 140 mmHg 미만 및 sitDBP 90 mmHg 미만으로 조절된 시험대상자의 비율은 A/L/C-1.25/12.5/3.13 투여군이 57.14%(20 / 35명), A/L/C-1.67/16.67/4.17 투여군이 69.70%(23 / 33명), A/L/C-2.5/25/6.25 투여군이 63.89%(23 / 36명), A5 투여군이 44.12%(15 / 34명), A10 투여군이 66.67%(22 / 33명), L100 투여군이 41.18%( 14 / 34명), Placebo 투여군이 18.18%(6 / 33명)이었다.After 8 weeks of administration of the investigational drug, the proportion of subjects adjusted to sitSBP less than 140 mmHg and sitDBP less than 90 mmHg was 57.14% (20 / 35 patients) in the A/L/C-1.25/12.5/3.13 group, A/L/ C-1.67/16.67/4.17 administration group 69.70% (23 / 33 patients), A/L/C-2.5/25/6.25 administration group 63.89% (23 / 36 patients), A5 administration group 44.12% (15 / 34 patients) ), 66.67% (22 / 33 patients) in the A10 administration group, 41.18% (14 / 34 patients) in the L100 administration group, and 18.18% (6 / 33 patients) in the Placebo administration group.
임상시험용의약품 투여 8 주 후 A/L/C-1.25/12.5/3.13 투여군의 혈압조절률을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, A/L/C-1.25/12.5/3.13 투여군은 Placebo 투여군과 통계적으로 유의한 차이를 나타내었다 (p=0.0010).When the blood pressure control rate of the A/L/C-1.25/12.5/3.13 administration group after 8 weeks of administration of the clinical trial drug was compared with the A5 administration group, A10 administration group, L100 administration group, and Placebo administration group, A/L/C-1.25/12.5 The /3.13 administration group showed a statistically significant difference from the placebo administration group (p=0.0010).
임상시험용의약품 투여 8 주 후 A/L/C-1.67/16.67/4.17 투여군의 혈압조절률을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, A/L/C-1.67/16.67/4.17 투여군은 A5 투여군, L100 투여군, Placebo 투여군과 통계적으로 유의한 차이를 나타내었다 (p=0.0346, p=0.0189, p=0.0000).When the blood pressure control rate of the A/L/C-1.67/16.67/4.17 administration group was compared with the A5 administration group, A10 administration group, L100 administration group, and Placebo administration group after 8 weeks of administration of the clinical trial drug, A/L/C-1.67/16.67 The /4.17 administration group showed a statistically significant difference from the A5 administration group, L100 administration group, and Placebo administration group (p=0.0346, p=0.0189, p=0.0000).
임상시험용의약품 투여 8 주 후 A/L/C-2.5/25/6.25 투여군의 혈압조절률을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, A/L/C-2.5/25/6.25 투여군은 Placebo 투여군과 통계적으로 유의한 차이를 나타내었다 (p=0.0001).When the blood pressure control rate of the A/L/C-2.5/25/6.25 administration group after 8 weeks of administration of the clinical trial drug was compared with the A5 administration group, A10 administration group, L100 administration group, and Placebo administration group, A/L/C-2.5/25 The /6.25 administration group showed a statistically significant difference from the placebo administration group (p=0.0001).
시험군 간에는 통계적으로 유의한 차이를 나타내지 않았다.There was no statistically significant difference between the test groups.
임상시험예 8: 8주 시점에서의 혈압반응률Clinical Trial Example 8: Blood pressure response rate at 8 weeks
임상시험용의약품 투여 8 주 후 기저치 대비 sitSBP 감소량이 20 mmHg 이상 또는 sitDBP 감소량이 10 mmHg 이상인 시험대상자의 비율을 투여군 간 비교하기 위하여 Pearson's chi-square test 또는 Fisher's exact test를 시행하였으며, FAS를 기준으로 각 시험군과 대조군을 비교한 결과는 다음과 같다. After 8 weeks of administration of the investigational drug, Pearson's chi-square test or Fisher's exact test was performed to compare the ratio of subjects with a decrease in sitSBP of 20 mmHg or more or a decrease in sitDBP of 10 mmHg or more compared to baseline between the administration groups. The results of comparing the test group and the control group are as follows.
도 5는 8주차에 FAS에서 혈압 반응자의 비율을 나타낸다. 이 때, 혈압 반응자는 기저치 대비 sitSBP 감소량 ≥ 20 mmHg 또는 sit DBP 감소량 ≥ 10 mmHg 시험대상자를 지칭한다.5 shows the proportion of blood pressure responders in FAS at week 8. In this case, blood pressure responders refer to subjects with sitSBP decrease ≥ 20 mmHg or sit DBP decrease ≥ 10 mmHg compared to baseline.
임상시험용의약품 투여 8 주 후 기저치 대비 sitSBP 감소량 ≥ 20 mmHg 또는 sitDBP 감소량 ≥ 10 mmHg 인 시험대상자의 비율은 A/L/C-1.25/12.5/3.13 투여군이 51.43%(18 / 35명), A/L/C-1.67/16.67/4.17 투여군이 60.61%(20 / 33명), A/L/C-2.5/25/6.25 투여군이 58.33%(21 / 36명), A5 투여군이 47.06%(16 / 34명), A10 투여군이 63.64%(21 / 33명), L100 투여군이 32.35%(11 / 34명), Placebo 투여군이 21.21%(7 / 33명)이었다.After 8 weeks of administration of the investigational drug, the proportion of subjects with sitSBP decrease ≥ 20 mmHg or sitDBP decrease ≥ 10 mmHg compared to baseline was 51.43% (18 / 35 patients) in the A/L/C-1.25/12.5/3.13 group, A/ L/C-1.67/16.67/4.17 administration group 60.61% (20 / 33 patients), A/L/C-2.5/25/6.25 administration group 58.33% (21 / 36 patients), A5 administration group 47.06% (16 / 34), 63.64% (21 / 33 patients) in the A10 administration group, 32.35% (11 / 34 patients) in the L100 administration group, and 21.21% (7 / 33 patients) in the Placebo administration group.
임상시험용의약품 투여 8 주 후 A/L/C-1.25/12.5/3.13 투여군의 혈압반응률을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, A/L/C-1.25/12.5/3.13 투여군은 Placebo 투여군과 통계적으로 유의한 차이를 나타내었다 (p=0.0098).When the blood pressure response rate of the A/L/C-1.25/12.5/3.13 administration group after 8 weeks of administration of the clinical investigational drug was compared with the A5 administration group, A10 administration group, L100 administration group, and Placebo administration group, A/L/C-1.25/12.5/ The 3.13 administration group showed a statistically significant difference from the placebo administration group (p=0.0098).
임상시험용의약품 투여 8 주 후 A/L/C-1.67/16.67/4.17 투여군의 혈압반응률을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, A/L/C-1.67/16.67/4.17 투여군은 L100 투여군, Placebo 투여군과 통계적으로 유의한 차이를 나타내었다 (p=0.0204, p=0.0011).When the blood pressure response rate of the A/L/C-1.67/16.67/4.17 administration group after 8 weeks of administration of the clinical trial drug was compared with the A5 administration group, A10 administration group, L100 administration group, and Placebo administration group, A/L/C-1.67/16.67/ The 4.17 administration group showed a statistically significant difference from the L100 administration group and the Placebo administration group (p=0.0204, p=0.0011).
임상시험용의약품 투여 8 주 후 A/L/C-2.5/25/6.25 투여군의 혈압반응률을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, A/L/C-2.5/25/6.25 투여군은 L100 투여군, Placebo 투여군과 통계적으로 유의한 차이를 나타내었다 (p=0.0292, p=0.0017).When the blood pressure response rate of the A/L/C-2.5/25/6.25 administration group was compared with the A5 administration group, A10 administration group, L100 administration group, and Placebo administration group after 8 weeks of administration of the clinical trial drug, A/L/C-2.5/25/ The 6.25 administration group showed a statistically significant difference from the L100 administration group and the Placebo administration group (p=0.0292, p=0.0017).
시험군 간에는 통계적으로 유의한 차이를 나타내지 않았다.There was no statistically significant difference between the test groups.
임상시험예 9: 기저치 대비 8주 후의 평균 맥압 변화량 (평균 sitSBP - sitDBP)Clinical Trial Example 9: Mean pulse pressure change after 8 weeks from baseline (mean sitSBP - sitDBP)
기저치 대비 8 주 후의 맥압(sitSBP - sitDBP) 변화에 대해 시험군과 대조군을 비교하기 위하여, 기저치에서의 평균 맥압(평균 sitSBP - sitDBP) 및 층화변수를 공변량으로 보정한 공분산 분석 (ANCOVA)을 시행하였다.In order to compare the test group and the control group for changes in pulse pressure (sitSBP - sitDBP) after 8 weeks from baseline, analysis of covariance (ANCOVA) was performed in which mean pulse pressure at baseline (mean sitSBP - sitDBP) and stratification variables were corrected as covariates. .
- 모든 분석 대상자군(FAS)에서 8주 후의 평균 맥압 변화량 측정 - Measurement of mean pulse pressure change after 8 weeks in all analysis subjects (FAS)
공분산 분석 결과로 추정된 기저치 대비 8 주 후 맥압 변화량의 최소제곱평균 ± 표준오차 (LS Mean ± SE)에 대하여 FAS를 기준으로 각 시험군과 대조군을 비교한 결과를 도 6에 나타내었다. 6 shows the results of comparing each test group and the control group based on the FAS with respect to the least squares mean ± standard error (LS Mean ± SE) of the change in pulse pressure after 8 weeks compared to the baseline estimated as a result of the covariance analysis.
도 6은 8주차에 FAS에서 기저치로부터의 맥압 변화를 나타낸다. 6 shows the change in pulse pressure from baseline in FAS at week 8.
A/L/C-1.25/12.5/3.13 투여군의 기저치 대비 8주 후 맥압 변화량을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, 투여군 간 변화량의 차이(LS Mean ± SE)는 각각 -4.23 ± 2.10 mmHg, 0.05 ± 1.93 mmHg, -0.92 ± 2.31 mmHg, -6.85 ± 2.82 mmHg으로, A/L/C-1.25/12.5/3.13 투여군은 A5 투여군, Placebo 투여군과 통계적으로 유의한 차이를 나타내었다(p=0.0483, p=0.9801, p=0.6910, p=0.0180).When comparing the change in pulse pressure after 8 weeks of the A/L/C-1.25/12.5/3.13 group compared to the baseline with the A5 group, A10 group, L100 group, and Placebo group, the difference (LS Mean ± SE) was -4.23 ± 2.10 mmHg, 0.05 ± 1.93 mmHg, -0.92 ± 2.31 mmHg, -6.85 ± 2.82 mmHg, respectively (p=0.0483, p=0.9801, p=0.6910, p=0.0180).
A/L/C-1.67/16.67/4.17 투여군의 기저치 대비 8주 후 맥압 변화량을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, 투여군 간 변화량의 차이(LS Mean ± SE)는 각각 -6.71 ± 2.54 mmHg, -2.67 ± 2.40 mmHg, -3.86 ± 2.65mmHg, -9.43 ± 3.18 mmHg으로, A/L/C-1.67/16.67/4.17 투여군은 A5 투여군, Placebo 투여군과 통계적으로 유의한 차이를 나타내었다(p=0.0104, p=0.02710, p=0.1503, p=0.0043).When comparing the change in pulse pressure after 8 weeks of the A/L/C-1.67/16.67/4.17 group compared to the baseline with the A5 group, A10 group, L100 group, and Placebo group, the difference in the change between the groups (LS Mean ± SE) was They were -6.71 ± 2.54 mmHg, -2.67 ± 2.40 mmHg, -3.86 ± 2.65 mmHg, and -9.43 ± 3.18 mmHg, respectively. A/L/C-1.67/16.67/4.17 administration group had a statistically significant difference from A5 administration group and Placebo administration group, respectively. (p=0.0104, p=0.02710, p=0.1503, p=0.0043).
A/L/C-2.5/25/6.25 투여군의 기저치 대비 8주 후 맥압 변화량을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, 투여군 간 변화량의 차이(LS Mean ± SE)는 각각 -4.88 ± 1.91 mmHg, -0.73 ± 1.80 mmHg, -1.88 ± 2.27 mmHg, -7.54 ±2.71 mmHg으로, A/L/C-2.5/25/6.25 투여군은 A5 투여군, Placebo 투여군과 통계적으로 유의한 차이를 나타내었다(p=0.0157, p=0.6855, p=0.4109, p=0.0071).When the pulse pressure change after 8 weeks compared to the baseline in the A/L/C-2.5/25/6.25 administration group was compared with the A5 administration group, A10 administration group, L100 administration group, and placebo administration group, the difference in the change between the administration groups (LS Mean ± SE) was -4.88 ± 1.91 mmHg, -0.73 ± 1.80 mmHg, -1.88 ± 2.27 mmHg, -7.54 ±2.71 mmHg, respectively (p=0.0157, p=0.6855, p=0.4109, p=0.0071).
시험군 간에는 통계적으로 유의한 차이를 나타내지 않았다.There was no statistically significant difference between the test groups.
임상시험예 10: 하위그룹 분석 : 기저치 대비 8 주 후의 평균 sitSBP 변화량 측정 (기저치 혈압 sitSBP < 160 mmHg)Clinical Trial Example 10: Subgroup analysis: Mean change in sitSBP after 8 weeks from baseline (basal blood pressure sitSBP < 160 mmHg)
기저치 대비 8주 후의 평균 sitSBP 변화량에 대하여, FAS 대상자를 층화변수에 따라 기저치 혈압이 sitSBP < 160 mmHg 인 대상자(178명)에 대해서 추가분석 하였다.Regarding the average change in sitSBP after 8 weeks from baseline, FAS subjects were additionally analyzed for subjects (178 subjects) with baseline blood pressure of sitSBP < 160 mmHg according to stratification variables.
기저치 혈압이 sitSBP < 160 mmHg 인 대상자의 기저치 대비 8 주 후의 sitSBP 변화에 대해 시험군과 대조군을 비교하기 위하여, 기저치에서의 평균 sitSBP를 공변량으로 보정한 공분산 분석 (ANCOVA)을 시행하였다. In order to compare the test group and the control group on the change in sitSBP after 8 weeks from baseline in subjects with baseline blood pressure sitSBP < 160 mmHg, analysis of covariance (ANCOVA) was performed, in which the mean sitSBP at baseline was corrected as a covariate.
공분산 분석 결과로 추정된 기저치 대비 8 주 후 sitSBP 변화량의 최소제곱평균 ± 표준오차 (LS Mean ± SE)에 대하여 FAS를 기준으로 각 시험군과 대조군을 비교한 결과를 표 3과 도 7에 나타내었다. Table 3 and Figure 7 show the results of comparing each test group with the control group based on the FAS with respect to the least squares mean ± standard error (LS Mean ± SE) of the change in sitSBP after 8 weeks compared to the baseline estimated as a result of the covariance analysis. .
도 7은 8주차에 FAS (sitSBP < 160 mmHg)에서 기저치로부터의 sitSBP 변화를 나타낸다. 7 shows sitSBP change from baseline in FAS (sitSBP < 160 mmHg) at 8 weeks.
A/L/C-1.25/12.5/3.13 투여군의 기저치 대비 8주 후 sitSBP 변화량을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, 투여군 간 변화량의 차이(LS Mean ± SE)는 각각 -1.40 ± 3.74 mmHg, 5.44 ± 3.25 mmHg, -7.02 ± 3.62 mmHg, -13.13 ± 4.06 mmHg으로, A/L/C-1.25/12.5/3.13 투여군은 Placebo 투여군과 통계적으로 유의한 차이를 나타내었다(p=0.7100, p=0.1013, p=0.0586, p=0.0022).When the sitSBP change after 8 weeks compared to the baseline in the A/L/C-1.25/12.5/3.13 administration group was compared with the A5 administration group, A10 administration group, L100 administration group, and placebo administration group, the difference in the change between the administration groups (LS Mean ± SE) was -1.40 ± 3.74 mmHg, 5.44 ± 3.25 mmHg, -7.02 ± 3.62 mmHg, -13.13 ± 4.06 mmHg, respectively, the A/L/C-1.25/12.5/3.13 administration group showed a statistically significant difference from the placebo administration group ( p=0.7100, p=0.1013, p=0.0586, p=0.0022).
A/L/C-1.67/16.67/4.17 투여군의 기저치 대비 8주 후 sitSBP 변화량을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, 투여군 간 변화량의 차이(LS Mean ± SE)는 각각 -4.42 ± 4.27 mmHg, 1.17 ± 3.78 mmHg, -9.94 ± 4.19 mmHg, -16.11 ± 4.59 mmHg으로, A/L/C-1.67/16.67/4.17 투여군은 L100 투여군, Placebo 투여군과 통계적으로 유의한 차이를 나타내었다(p=0.3503, p=0.6524, p=0.0220, p=0.0010).When the A/L/C-1.67/16.67/4.17 administration group compared the sitSBP change after 8 weeks compared to the baseline with the A5 administration group, A10 administration group, L100 administration group, and Placebo administration group, the difference in the change between the administration groups (LS Mean ± SE) was They were -4.42 ± 4.27 mmHg, 1.17 ± 3.78 mmHg, -9.94 ± 4.19 mmHg, and -16.11 ± 4.59 mmHg, respectively. (p=0.3503, p=0.6524, p=0.0220, p=0.0010).
A/L/C-2.5/25/6.25 투여군의 기저치 대비 8주 후 sitSBP 변화량을 A5 투여군, A10 투여군, L100 투여군, Placebo 투여군과 각각 비교하였을 때, 투여군 간 변화량의 차이(LS Mean ± SE)는 각각 -6.07 ± 3.40 mmHg, 1.29 ± 2.77 mmHg, -11.94 ± 3.26 mmHg, -17.77 ± 3.71 mmHg으로, A/L/C-2.5/25/6.25 투여군은 L100 투여군(, Placebo 투여군(과 통계적으로 유의한 차이를 나타내었다(p=0.0806, p=0.6427, p=-0.0006, p<0.0001).When the sitSBP change after 8 weeks compared to the baseline in the A/L/C-2.5/25/6.25 administration group was compared with the A5 administration group, A10 administration group, L100 administration group, and placebo administration group, the difference in the change between the administration groups (LS Mean ± SE) was -6.07 ± 3.40 mmHg, 1.29 ± 2.77 mmHg, -11.94 ± 3.26 mmHg, -17.77 ± 3.71 mmHg, respectively. There was a difference (p=0.0806, p=0.6427, p=-0.0006, p<0.0001).
시험군 간에는 통계적으로 유의한 차이를 나타내지 않았다.There was no statistically significant difference between the test groups.
[표 3][Table 3]
Figure PCTKR2021006285-appb-I000009
Figure PCTKR2021006285-appb-I000009
Figure PCTKR2021006285-appb-I000010
Figure PCTKR2021006285-appb-I000010
Figure PCTKR2021006285-appb-I000011
Figure PCTKR2021006285-appb-I000011
Figure PCTKR2021006285-appb-I000012
Figure PCTKR2021006285-appb-I000012
Figure PCTKR2021006285-appb-I000013
Figure PCTKR2021006285-appb-I000013
Figure PCTKR2021006285-appb-I000014
Figure PCTKR2021006285-appb-I000014
임상시험예 11: 부종검사를 통한 기저치 대비 8주 후의 평균 발목 둘레 변화량Clinical Trial Example 11: Average ankle circumference change after 8 weeks compared to baseline through edema test
임상시험용의약품 투여군 별로 발목둘레를 측정하여 부종검사를 실시하였다. 기저치 대비 8주 후의 발목둘레 변화에 대해 시험약 투여군과 암로디핀 단일제 투여군의 군간 비교를 위해 Wilcoxon rank sum test를 시행하였으며, 각각의 군내 변화에 대한 통계적 유의성을 확인하고자 Wilcoxon signed-rank test를 시행하였다. 분석 시, 각 대상자의 양쪽 발목 중 기저치 대비 8주 후 발목둘레 변화의 절대값이 큰 발목을 선택하였고, 양쪽 발목 둘레 변화의 절대값이 같을 경우에는 발목 둘레가 증가한 발목을 선택하였으며, 그 결과를 도 8에 나타내었다.The edema test was performed by measuring the ankle circumference for each clinical trial drug administration group. The Wilcoxon rank sum test was performed to compare the changes in ankle circumference after 8 weeks compared to the baseline between the test drug administration group and the amlodipine single drug administration group. In the analysis, the ankle with the largest absolute value of the change in ankle circumference after 8 weeks compared to the baseline value was selected among both ankles of each subject. 8 shows.
도 8은 암로디핀 2.5mg, 로사르탄 칼륨 25mg, 클로르탈리돈 6.25mg; 암로디핀 1.67mg, 로사르탄 칼륨 16.67mg, 클로르탈리돈 4.17mg; 또는 암로디핀 1.25mg, 로사르탄 칼륨 12.5mg, 클로르탈리돈 3.13mg을 각각 포함하는 시험용 의약품 투여군, 또는 암로디핀 5 mg 및 10 mg 을 각각 포함하는 대조용 의약품 투여군의 8주차 FAS에서 발목 둘레의 기저치로부터의 변화(양쪽 발목 중 기저치로부터 8주차 발목 둘레 변화의 절대값이 큰 발목을 기준으로 함)를 나타낸다.8 is amlodipine 2.5 mg, losartan potassium 25 mg, chlorthalidone 6.25 mg; amlodipine 1.67 mg, losartan potassium 16.67 mg, chlorthalidone 4.17 mg; or in the study drug group containing amlodipine 1.25 mg, losartan potassium 12.5 mg, and chlorthalidone 3.13 mg, respectively, or in the control drug group containing amlodipine 5 mg and 10 mg, respectively, at Week 8 FAS from baseline around the ankle circumference. Changes (based on the ankle with the largest absolute value of the change in ankle circumference at week 8 from baseline among both ankles) are shown.
도 8에서와 같이, 기저치 대비 8 주 후 발목둘레 변화량의 평균 ± 표준편차 (Mean ± SD)는 시험약 투여군이 -0.76 ± 6.33 mm, 암로디핀 단일제 투여군이 2.48 ± 8.79 mm 이었다. 시험약 투여군 보다 암로디핀 단일제 투여군에서 발목둘레가 3.23 mm 더 증가하였으며, 이는 통계적으로도 유의한 차이를 나타내었다(p=0.0033). 또한 시험약 투여군에서는 기저치 대비 8주 후의 발목둘레의 변화가 통계적으로 유의한 차이를 나타내지 않았으며 (p=0.2668), 암로디핀 단일제 투여군에서는 기저치 대비 8주 후의 발목둘레가 통계적으로 유의하게 증가하였다 (p=0.0150).As shown in FIG. 8 , the mean ± standard deviation (Mean ± SD) of the change in ankle circumference after 8 weeks compared to the baseline was -0.76 ± 6.33 mm in the test drug administration group and 2.48 ± 8.79 mm in the amlodipine single agent administration group. The ankle circumference increased by 3.23 mm more in the amlodipine single drug administration group than in the test drug administration group, which also showed a statistically significant difference (p=0.0033). In addition, in the test drug administration group, the change in ankle circumference after 8 weeks compared to the baseline did not show a statistically significant difference (p=0.2668), and in the group administered with amlodipine single agent, the ankle circumference after 8 weeks compared to the baseline increased statistically significantly (p =0.0150).
[약어의 설명][Explanation of Abbreviations]
A2.5, A1.67, A1.25 : 각각 암로디핀(amlodipine: A) 2.5 (mg), 1.67 (mg), 1.25 (mg)A2.5, A1.67, A1.25: amlodipine (A) 2.5 (mg), 1.67 (mg), 1.25 (mg), respectively
L25, L16.67, L12.5: 각각 로사르탄 칼륨(losartan potassium: L) 25 (mg), 16.67 (mg), 12.5 (mg)L25, L16.67, L12.5: losartan potassium (L) 25 (mg), 16.67 (mg), 12.5 (mg) respectively
C6.25, C4.17, C3.13 : 각각 클로르탈리돈(chlorthalidone: C) 6.25 (mg), 4.17 (mg), 3.13 (mg)C6.25, C4.17, C3.13: chlorthalidone (C) 6.25 (mg), 4.17 (mg), 3.13 (mg), respectively
DBP : 이완기 혈압(diastolic blood pressure)DBP: diastolic blood pressure
SBP : 수축기 혈압(systolic blood pressure)SBP: systolic blood pressure
sitDBP : 좌위 이완기 혈압(sitting diastolic blood pressure)sitDBP: sitting diastolic blood pressure
sitSBP : 좌위 수축기 혈압(sitting systolic blood pressure)sitSBP: sitting systolic blood pressure
HbA1c : 당화혈색소(Hemoglobin A1c)HbA1c: glycated hemoglobin (Hemoglobin A 1c )
ANCOVA : 공분산분석(analysis of covariance)ANCOVA: analysis of covariance
<복합제제의 제조> <Manufacture of complex formulation>
실시예 1 내지 6 : 암로디핀, 클로르탈리돈 및 로사르탄을 포함하는 단층정의 제조Examples 1 to 6: Preparation of single-layer tablets containing amlodipine, chlorthalidone and losartan
하기 표 4에 기재된 조성에 따라 암로디핀, 클로르탈리돈, 로사르탄 미결정셀룰로오스(Microcystalline Cellulose) 및 저치환도 히드록시프로필셀룰로오스(Low-Substituted Hydroxypropyl Cellulose)와 크로스포비돈(Crospovidone)을 취하여 10분간 혼합한다. 혼합물을 컴팩팅하여 슬러그를 만든 후, 1.0 mm 체눈 크기의 체로 정립하여 과립부를 제조한다. 이 과립부를 스테아르산 마그네슘(Magnesium Steartate)를 넣고 5분간 혼합하여 최종과립부를 만든다. 최종과립부를 이용하여 단층정 복합제를 생산하였다.According to the composition shown in Table 4 below, amlodipine, chlorthalidone, losartan microcrystalline cellulose and low-substituted hydroxypropyl cellulose (Low-Substituted Hydroxypropyl Cellulose) and crospovidone were taken and mixed for 10 minutes. The mixture is compacted to make slugs, and then sieved through a 1.0 mm sieve to prepare granules. Magnesium stearate is added to this granular part and mixed for 5 minutes to make the final granular part. A single-layer tablet composite was produced using the final granular part.
실시예 1 내지 6에 따른 약제학적 복합제제의 조성을 하기 표 4에 나타내었다.The compositions of the pharmaceutical combination formulations according to Examples 1 to 6 are shown in Table 4 below.
[표 4][Table 4]
Figure PCTKR2021006285-appb-I000015
Figure PCTKR2021006285-appb-I000015
비교예 1 내지 4 : 암로디핀, 클로르탈리돈을 포함하는 과립부 I 과 로사르탄을 포함하는 과립부 II 를 포함하는 이층정 또는 단층정의 제조Comparative Examples 1 to 4: Preparation of a double-layered or single-layered tablet comprising a granular part I containing amlodipine and chlorthalidone and a granular part II containing losartan
하기 표 5에 기재된 조성에 따라 암로디핀, 클로르탈리돈, 미결정셀룰로오스 및 및 저치환도 히드록시프로필셀룰로오스와 크로스포비돈을 취하여 10분간 혼합한다. 혼합물을 컴팩팅하여 슬러그를 만든 후, 1.0 mm 체눈 크기의 체로 정립한다. 이 과립부를 스테아르산 마그네슘을 넣고 5분간 혼합하여 과립부 I 을 제조한다.According to the composition shown in Table 5 below, amlodipine, chlorthalidone, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose and crospovidone were taken and mixed for 10 minutes. The mixture is compacted to make a slug, and then sieved through a 1.0 mm sieve size. Magnesium stearate was added to this granular part and mixed for 5 minutes to prepare granular part I.
또한 로사르탄, 미결정셀룰로오스 및 크로스포비돈을 취하여 10분간 혼합한다. 혼합물을 컴팩팅하여 슬러그를 만든 후, 1.0 mm 체눈 크기의 체로 정립한다. 이 과립과 스테아르산 마그네슘과 5분간 혼합하여 과립부 II을 제조한다.Also, take losartan, microcrystalline cellulose and crospovidone and mix for 10 minutes. The mixture is compacted to make a slug, and then sieved through a 1.0 mm sieve size. The granules were mixed with magnesium stearate for 5 minutes to prepare a granular part II.
비교예 1, 3 : 과립부 I을 상층과립부로, 과립부 II를 하층과립부로 하여 이층정을 생산한다.Comparative Examples 1 and 3: A two-layer tablet was produced by using the granular part I as the upper granular part and the granular part II as the lower granular part.
비교예 2, 4 : 과립부 I과 과립부 II를 최종혼합하여 단층정을 생산한다.Comparative Examples 2 and 4: The granular part I and the granular part II were finally mixed to produce a single-layer tablet.
[표 5][Table 5]
Figure PCTKR2021006285-appb-I000016
Figure PCTKR2021006285-appb-I000016
비교예 5 내지 8 : 암로디핀, 클로르탈리돈을 포함하는 과립부 I 과 로사르탄을 포함하는 과립부 II 를 포함하는 단층정의 제조Comparative Examples 5 to 8: Preparation of a single-layer tablet comprising a granular part I containing amlodipine and chlorthalidone and a granular part II containing losartan
하기 표 6에 기재된 조성에 따라 암로디핀, 클로르탈리돈, 미결정셀룰로오스 및 및 저치환도 히드록시프로필셀룰로오스와 크로스포비돈을 취하여 10분간 혼합한다. 혼합물을 컴팩팅하여 슬러그를 만든 후, 1.0 mm 체눈 크기의 체로 정립한다. 이 과립부를 스테아르산 마그네슘을 넣고 5분간 혼합하여 과립부 I 을 제조한다.According to the composition shown in Table 6 below, amlodipine, chlorthalidone, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose and crospovidone were taken and mixed for 10 minutes. The mixture is compacted to make a slug, and then sieved through a 1.0 mm sieve size. Magnesium stearate was added to this granular part and mixed for 5 minutes to prepare granular part I.
또한 로사르탄, 미결정셀룰로오스 및 크로스포비돈을 취하여 10분간 혼합한다. 혼합물을 컴팩팅하여 슬러그를 만든 후, 1.0 mm 체눈 크기의 체로 정립한다. 이 과립과 스테아르산 마그네슘과 5분간 혼합하여 과립부 II을 제조한다.Also, take losartan, microcrystalline cellulose and crospovidone and mix for 10 minutes. The mixture is compacted to make a slug, and then sieved through a 1.0 mm sieve size. The granules were mixed with magnesium stearate for 5 minutes to prepare a granular part II.
비교예 5 내지 8에 따른 약제학적 복합제제의 조성을 하기 표 5에 나타내었다.The compositions of the pharmaceutical combination formulations according to Comparative Examples 5 to 8 are shown in Table 5 below.
[표 6][Table 6]
Figure PCTKR2021006285-appb-I000017
Figure PCTKR2021006285-appb-I000017
시험예test example
시험예 1: 로사르탄 함량에 의한 겔화(Gelling)에 따른 암로디핀과 클로르탈리돈의 용출 시험Test Example 1: Dissolution test of amlodipine and chlorthalidone according to gelling by losartan content
비교예 1 내지 6의 정제를 이용하여 하기 조건에 따라 암로디핀과 클로르탈리돈의 용출률을 확인하였다. 용출 조건 및 HPLC 분석 조건은 하기와 같다.Using the tablets of Comparative Examples 1 to 6, the dissolution rates of amlodipine and chlorthalidone were confirmed under the following conditions. Elution conditions and HPLC analysis conditions are as follows.
[용출 조건][Elution conditions]
장 치 : USP <711> Dissolution항목 중 Apparatus 2법 (패들법)Apparatus: Apparatus 2 method (paddle method) among USP <711> Dissolution items
시 험 액 : 0.01 M 염산용액, 900 mLTest solution: 0.01 M hydrochloric acid solution, 900 mL
용출온도 : 37 ± 0.5 ℃Elution temperature: 37 ± 0.5 ℃
회 전 수 : 100 ± 5 rpmNumber of revolutions: 100 ± 5 rpm
[분석 조건][Analysis Conditions]
검 출 기 : 자외부흡광관도계 (측정파장 : 240 mm)Detector: UV absorption spectrophotometer (measurement wavelength: 240 mm)
컬 럼 : Inertsil ODS-4, 4.6 x 250 mm, 5μm 혹은 이와 동등한 수준의 컬럼Column: Inertsil ODS-4, 4.6 x 250 mm, 5 μm or equivalent column
이 동 상 : 10 mM 헥산설폰산나트륨수화물 (pH2.5) : ACN = 64 : 36 (v/v)Mobile phase: 10 mM sodium hexanesulfonate hydrate (pH2.5): ACN = 64: 36 (v/v)
컬럼온도 : 35 ℃Column temperature: 35 ℃
분석시간 : 25 분Analysis time: 25 minutes
유 속 : 1.3 mL/분Flow rate: 1.3 mL/min
주 입 량 : 40 μLInjection volume: 40 μL
암로디핀과 클로르탈리돈의 용출 시험 결과를 도 9 내지 도 11에 나타내었다. The dissolution test results of amlodipine and chlorthalidone are shown in FIGS. 9 to 11 .
도 9는 비교예 1 및 2의 시간에 따른 (a)암로디핀 베실레이트, (b)클로르탈리돈의 용출률(%)을 나타낸다. 9 shows the dissolution rates (%) of (a) amlodipine besylate and (b) chlorthalidone according to time in Comparative Examples 1 and 2.
도 10은 실시예 1과 비교예 3 및 4의 시간에 따른 (a)암로디핀 베실레이트, (b)클로르탈리돈의 용출률(%)을 나타낸다. 10 shows the dissolution rates (%) of (a) amlodipine besylate and (b) chlorthalidone according to time in Example 1 and Comparative Examples 3 and 4.
도 11은 실시예 4와 비교예 5 및 6의 시간에 따른 (a)암로디핀 베실레이트, (b)클로르탈리돈의 용출률(%)을 나타낸다. 11 shows the dissolution rates (%) of (a) amlodipine besylate and (b) chlorthalidone according to time in Example 4 and Comparative Examples 5 and 6.
도 9에서 보는 바와 같이, 고용량(50 mg)의 로사르탄을 암로디핀 또는 클로르탈리돈과 분리된 과립부 중에 포함하고 이층정인 비교예 1은, 동일한 조건에서 단층정인 비교예 2와 비교하여 암로디핀 및 클로르탈리돈의 용출률이 높게 나타났다.As shown in FIG. 9 , Comparative Example 1, a double-layered tablet containing a high dose (50 mg) of losartan in the granular portion separated from amlodipine or chlorthalidone, compared with Comparative Example 2, a single-layered tablet, amlodipine and chlorin under the same conditions. The dissolution rate of thalidon was high.
그러나, 도 10에서 보는 바와 같이, 저용량(25 mg)의 로사르탄을 암로디핀 및 클로르탈리돈과 분리된 과립부 중에 포함하고 이층정인 비교예 3과, 동일한 조건에서 단층정인 비교예 4는 암로디핀, 클로르탈리돈의 용출률의 차이가 크지 않았다. However, as shown in FIG. 10 , Comparative Example 3, a double-layered tablet, containing losartan in a low dose (25 mg) in a granular portion separated from amlodipine and chlorthalidone, and Comparative Example 4, a single-layered tablet, under the same conditions were amlodipine and chlorthalidone. There was no significant difference in the dissolution rate of thalidon.
또한, 도 10에서 보는 바와 같이, 저용량(25 mg)의 로사르탄을 암로디핀 및 클로르탈리돈과 분리된 과립부 중에 포함하고 단층정인 비교예 4와, 저용량(25 mg)의 로사르탄을 암로디핀 및 클로르탈리돈과 혼합된 과립부 중에 포함하고 단층정인 실시예 1은 유사한 용출률을 보였다. In addition, as shown in FIG. 10 , Comparative Example 4, a single-layer tablet containing a low dose (25 mg) of losartan in a granular portion separated from amlodipine and chlorthalidone, and a low dose (25 mg) of losartan were mixed with amlodipine and chlorthalidone. Example 1, which was included in the granular part mixed with thalidone and was a single-layer tablet, showed a similar dissolution rate.
또한, 도 11에서 보는 바와 같이, 고용량(각각 50 mg 또는 33.33 mg)의 로사르탄을 암로디핀 및 클로르탈리돈과 혼합된 과립부 중에 포함하고 단층정인 비교예 5 및 비교예 6은, 저용량(25 mg)의 로사르탄을 암로디핀 및 클로르탈리돈과 혼합된 과립부 중에 포함하고 단층정인 실시예 4와 비교하여 낮은 용출률을 보였다. In addition, as shown in FIG. 11, Comparative Examples 5 and 6, which contain a high dose (50 mg or 33.33 mg, respectively) of losartan in the granule part mixed with amlodipine and chlorthalidone, and are single-layer tablets, have a low dose (25 mg ) containing losartan in the granule part mixed with amlodipine and chlorthalidone, and showed a lower dissolution rate compared to Example 4, which is a single-layer tablet.
이로부터 복합제제 중 로사르탄의 용량에 따른 겔화 정도로 인해 암로디핀과 클로르탈리돈의 용출률이 영향을 받을 수 있는 점과, 특히 로사르탄 용량이 고용량인 경우 겔화로 인해 암로디핀과 클로르탈리돈의 용출률이 낮아짐을 확인하였다. From this, the dissolution rate of amlodipine and chlorthalidone may be affected due to the degree of gelation according to the dose of losartan in the combination formulation, and in particular, when the dose of losartan is high, the dissolution rate of amlodipine and chlorthalidone is lowered due to gelation. was confirmed.
또한, 로사르탄을 고용량으로 포함할 경우 정제의 형태(단층정, 이층정)가 암로디핀과 클로르탈리돈의 용출률에 영향을 미치지만(도 9), 로사르탄을 저용량으로 포함할 경우에는 복합제제의 정제 형태(단층정, 이층정) 또는 과립 형태(혼합과립부, 분리과립부)가 암로디핀과 클로르탈리돈의 용출률에 미치는 영향이 크지 않음을 확인하였다(도 10, 도 11). In addition, when losartan is included in a high dose, the shape of the tablet (single-layer tablet, double-layer tablet) affects the dissolution rate of amlodipine and chlorthalidone (FIG. 9), but when losartan is included in a low dose, the combination It was confirmed that the tablet form (single-layer tablet, double-layer tablet) or granular form (mixed granular part, separated granular part) did not have a significant effect on the dissolution rate of amlodipine and chlorthalidone ( FIGS. 10 and 11 ).
시험예 2: 정제 및 과립 형태에 따른 안정성 시험Test Example 2: Stability test according to the form of tablets and granules
- 분리과립 이층정, 분리과립 단층정 및 혼합과립 단층정의 유연물질 시험- Tests for related substances in separated granular double-layered tablets, separated granular single-layered tablets and mixed granulated single-layered tablets
비교예 3의 분리과립 이층정, 비교예 4의 분리과립 단층정, 실시예 1의 혼합과립 단층정을 대상으로 하기 가혹 보관 조건하에서 암로디핀, 클로르탈리돈 및 로사르탄 유연물질의 함량 변화를 측정하여 정제의 안정성을 평가하였다.The content changes of amlodipine, chlorthalidone and losartan related substances were measured for the separated granular bilayer tablet of Comparative Example 3, the separated granular monolayer tablet of Comparative Example 4, and the mixed granular monolayer tablet of Example 1 under the following severe storage conditions. The stability of the tablets was evaluated.
[가혹 보관 시험조건][Severe storage test conditions]
보관조건 : 60 ℃에서 HDPE(High Density Polyethylene)병 포장Storage conditions: Packed in HDPE (High Density Polyethylene) bottle at 60 ℃
시험조건 : 초기, 1주, 2주Test conditions: Initial, 1 week, 2 weeks
분석대상 : 암로디핀, 클로르탈리돈, 로사르탄Analysis target: amlodipine, chlorthalidone, losartan
[분석조건][Analysis Conditions]
[표 7][Table 7]
Figure PCTKR2021006285-appb-I000018
Figure PCTKR2021006285-appb-I000018
검 출 기 : 자외부흡광관도계 (측정파장 : 239 mm)Detector: UV absorption spectrophotometer (measured wavelength: 239 mm)
컬 럼 : Zorbax SB-C18, 4.6 x 250 mm, 5μm 혹은 이와 동등한 수준의 컬럼Column: Zorbax SB-C18, 4.6 x 250 mm, 5 μm or equivalent column
이동상 : A - 17 mM 헥산설폰산나트륨/0.05 % (v/v) 인산Mobile phase: A - 17 mM sodium hexanesulfonate/0.05% (v/v) phosphoric acid
B - 17 mM 헥산설폰산나트륨/0.05 % (v/v) 인산 : ACN = 10 : 90 (v/v)B - 17 mM sodium hexanesulfonate/0.05 % (v/v) phosphoric acid: ACN = 10: 90 (v/v)
컬럼온도 : 35 ℃Column temperature: 35 ℃
분석시간 : 110 분Analysis time: 110 minutes
유 속 : 1.0 mL/분Flow rate: 1.0 mL/min
주 입 량 : 40 μLInjection volume: 40 μL
도 12는 비교예 3, 비교예 4, 및 실시예 1에서 클로르탈리돈의 (a) impurity B (Imp B)와 (b) 미지 유연물질 (Unknown max)의 유연물질 함량(%)을 측정하여 유연물질 발생 여부를 확인한 결과를 나타낸다. 12 is a diagram showing the content (%) of related substances (%) of (a) impurity B (Imp B) and (b) unknown related substances (Unknown max) of chlorthalidone in Comparative Examples 3, 4, and 1 Shows the result of checking whether related substances are generated.
도 12에서 보는 바와 같이, 비교예 3, 비교예 4, 및 실시예 1은 가혹 조건 2주 동안 유연물질 함량(%)이 (a) Imp B (1.00%) (b) Unknown max (0.3%)로 일정하여 유연물질의 함량 증가 없이 복합제제가 매우 안정한 양상을 나타내는 것을 확인 할 수 있었다. As shown in Figure 12, Comparative Example 3, Comparative Example 4, and Example 1, the content of related substances (%) for 2 weeks under severe conditions (a) Imp B (1.00%) (b) Unknown max (0.3%) It was confirmed that the combination formulation showed a very stable aspect without increasing the content of related substances.
또한, 비교예 3의 분리과립 이층정, 비교예 4의 분리과립 단층정, 실시예 1의 혼합과립 단층정 모두에서 암로디핀, 로사르탄의 유연물질은 검출되지 않았다. 도 12와 같이 클로르탈리돈의 (a)Imp B와 (b)Unknown max 유연물질 발생도 거의 없어 복합제제가 안정한 것으로 확인하였다. In addition, amlodipine and losartan related substances were not detected in all of the separated granular bilayer tablet of Comparative Example 3, the separated granular monolayer tablet of Comparative Example 4, and the mixed granular monolayer tablet of Example 1. As shown in FIG. 12 , it was confirmed that the combination formulation was stable because there was almost no generation of (a) Imp B and (b) Unknown max related substances of chlorthalidone.
이로부터 복합제제 중 로사르탄을 저용량(25 mg)으로 포함할 경우 복합제제의 정제 형태(단층정, 이층정) 또는 과립 형태(혼합과립부, 분리과립부)가 복합제제로부터 유연물질 발생에 거의 영향을 미치지 않은 것을 확인하였다. From this, when losartan is included in a low dose (25 mg) of the combination preparation, the tablet form (single-layer tablet, double-layer tablet) or granular form (mixed granule part, separate granular part) of the combination preparation is almost impossible to generate related substances from the complex preparation. It was confirmed that there was no influence.
시험예 3: 암로디핀, 로사르탄, 클로르탈리돈의 용출 시험Test Example 3: Dissolution test of amlodipine, losartan, and chlorthalidone
- 복합제제 중 유효성분 또는 붕해제 함량, 또는 복합제제 총 중량에 따른 용출 시험- Dissolution test according to the content of active ingredient or disintegrant in the combination formulation, or the total weight of the combination formulation
상기 실시예 1 내지 6에서 얻은 정제를 이용하여 용출 시험을 진행하였다. 용출 조건 및 HPLC 분석 조건은 하기와 같다. A dissolution test was performed using the tablets obtained in Examples 1 to 6. Elution conditions and HPLC analysis conditions are as follows.
[용출 조건 - 암로디핀][Elution conditions - Amlodipine]
장 치 : USP <711> Dissolution항목 중 Apparatus 2법 (패들법)Apparatus: Apparatus 2 method (paddle method) among USP <711> Dissolution items
시 험 액 : 0.01 M 염산용액, 900 mLTest solution: 0.01 M hydrochloric acid solution, 900 mL
용출온도 : 37 ± 0.5 ℃Elution temperature: 37 ± 0.5 ℃
회 전 수 : 100 ± 5 rpmNumber of revolutions: 100 ± 5 rpm
판정조건 : 30분 후 용출률 80 % 이상Judgment condition: 80% or more dissolution rate after 30 minutes
[용출 조건 - 로사르탄, 클로르탈리돈][Elution conditions - losartan, chlorthalidone]
장 치 : USP <711> Dissolution항목 중 Apparatus 2법 (패들법)Apparatus: Apparatus 2 method (paddle method) among USP <711> Dissolution items
시 험 액 : 정제수, 900 mLTest solution: purified water, 900 mL
용출온도 : 37 ± 0.5 ℃Elution temperature: 37 ± 0.5 ℃
회 전 수 : 75 ± 2 rpmNumber of revolutions: 75 ± 2 rpm
판정조건 : 30분 후 용출률 80 % 이상Judgment condition: 80% or more dissolution rate after 30 minutes
[분석 조건][Analysis Conditions]
검 출 기 : 자외부흡광관도계 (측정파장 : 240 mm)Detector: UV absorption spectrophotometer (measurement wavelength: 240 mm)
컬 럼 : Inertsil ODS-4, 4.6 x 250 mm, 5μm 혹은 이와 동등한 수준의 컬럼Column: Inertsil ODS-4, 4.6 x 250 mm, 5 μm or equivalent column
이 동 상 : 10 mM 헥산설폰산나트륨수화물 (pH2.5) : ACN = 64 : 36 (v/v)Mobile phase: 10 mM sodium hexanesulfonate hydrate (pH2.5): ACN = 64: 36 (v/v)
컬럼온도 : 35 ℃Column temperature: 35 ℃
분석시간 : 25 분Analysis time: 25 minutes
유 속 : 1.3 mL/분Flow rate: 1.3 mL/min
주 입 량 : 40 μLInjection volume: 40 μL
도 13 내지 14에 암로디핀, 클로르탈리돈 및 로사르탄 용츌률 결과를 나타냈다.13 to 14 show the dissolution rates of amlodipine, chlorthalidone and losartan.
도 13은 실시예 1 및 2의 시간에 따른 (a)암로디핀 베실레이트, (b)로사르탄 칼륨, (c)클로르탈리돈의 용출률(%)을 나타낸다. 13 shows the dissolution rates (%) of (a) amlodipine besylate, (b) losartan potassium, and (c) chlorthalidone over time in Examples 1 and 2.
도 14은 실시예 2 내지 6의 시간에 따른 (a)암로디핀 베실레이트, (b)로사르탄 칼륨, (c)클로르탈리돈의 용출률(%)을 나타낸다. 14 shows the dissolution rates (%) of (a) amlodipine besylate, (b) losartan potassium, and (c) chlorthalidone over time in Examples 2 to 6.
도 13에서 보는 바와 같이, 실시예 1 과 2의 용출률을 측정한 결과, 실시예 1 보다 정제 총 중량을 50%로 감소시킨 실시예 2에서 암로디핀, 클로르탈리돈 및 로사르탄의 용출률이 더 높게 나타냈다. As shown in FIG. 13 , as a result of measuring the dissolution rates of Examples 1 and 2, the dissolution rates of amlodipine, chlorthalidone and losartan were higher in Example 2, in which the total tablet weight was reduced by 50%, than in Example 1. .
도 14에서 보는 바와 같이, 실시예 2 보다 붕해제의 함량을 증량한 실시예 3 내지 4에서, 붕해제의 함량이 증가할수록 높은 용출률을 보였다(실시예 2 내지 4의 정제 경도 18 kp). 14, in Examples 3 to 4, in which the content of the disintegrant was increased than in Example 2, the higher the content of the disintegrant was, the higher the dissolution rate was (Tablet hardness of Examples 2 to 4 18 kp).
또한, 도 14에서 보는 바와 같이, 실시예 4의 정제 총 중량과 각각의 성분의 함량을 1/2로 감량한 실시예 5와, 정제 총 중량과 각각의 성분의 함량을 2/3으로 감량한 실시예 6은 각각 실시예 4와 유사한 용출률을 보였다(실시예 5 내지 6의 정제 경도 16 kp). 또한, 실시예 4 내지 6의 정제 모두 제제균일성의 판정조건에 만족하였다(시험예 4).In addition, as shown in FIG. 14, Example 5 in which the total weight of the tablet and the content of each component of Example 4 were reduced by 1/2, and the tablet total weight and the content of each component were reduced by 2/3 Example 6 showed a dissolution rate similar to that of Example 4, respectively (Tablet hardness of Examples 5 to 6 16 kp). In addition, all of the tablets of Examples 4 to 6 satisfied the conditions for determining the uniformity of the formulation (Test Example 4).
시험예 4: 암로디핀, 클로르탈리돈 및 로사르탄의 제제균일성 시험Test Example 4: Preparation uniformity test of amlodipine, chlorthalidone and losartan
실시예 4 내지 5, 비교예 7 내지 8의 정제를 이용하여 1정에 따른 암로디핀, 클로르탈리돈 및 로사르탄의 제제균일성을 확인하였다.Formulation uniformity of amlodipine, chlorthalidone and losartan according to one tablet was confirmed using the tablets of Examples 4 to 5 and Comparative Examples 7 to 8.
[분석 조건][Analysis Conditions]
검 출 기 : 자외부흡광관도계 (측정파장 : 240 mm)Detector: UV absorption spectrophotometer (measurement wavelength: 240 mm)
컬 럼 : Inertsil ODS-4, 4.6 x 250 mm, 5μm 혹은 이와 동등한 수준의 컬럼Column: Inertsil ODS-4, 4.6 x 250 mm, 5 μm or equivalent column
이 동 상 : 10 mM 헥산설폰산나트륨수화물 (pH2.5) : ACN = 64 : 36 (v/v)Mobile phase: 10 mM sodium hexanesulfonate hydrate (pH2.5): ACN = 64: 36 (v/v)
컬럼온도 : 35 ℃Column temperature: 35 ℃
분석시간 : 25 분Analysis time: 25 minutes
유 속 : 1.3 mL/분Flow rate: 1.3 mL/min
주 입 량 : 10 μLInjection volume: 10 μL
암로디핀, 클로르탈리돈 및 로사르탄 제제균일성 결과를 표 8에 나타냈다. Table 8 shows the uniformity results of amlodipine, chlorthalidone and losartan formulations.
[표 8][Table 8]
Figure PCTKR2021006285-appb-I000019
Figure PCTKR2021006285-appb-I000019
표 8에서 보는 바와 같이, 주성분의 함량이 높은 실시예 4 내지 6에서는 제제균일성 판정에서 98.0 ~ 102.0% 이내에 결과 값이 나왔으며, 편차가 2.0% 이하로 나와 판정조건에 만족하였다. As shown in Table 8, in Examples 4 to 6 with a high content of the main component, the result value came out within 98.0 to 102.0% in the formulation uniformity determination, and the deviation was 2.0% or less, which satisfies the determination condition.
하지만 주성분의 함량이 낮은 비교예 7 내지 8의 경우 각 샘플별 값의 편차가 2.0% 이상으로 매우 크게 나타났다. 이는 주성분의 함량이 적을수록 1정의 정제안에 일정한 양으로 균일하지 않음을 의미한다.However, in Comparative Examples 7 to 8 with a low content of the main component, the deviation of the values for each sample was 2.0% or more, which was very large. This means that the smaller the content of the main ingredient, the less uniform it is in a certain amount in one tablet.
시험예 5: 생산성(타정속도) 및 품질(함량균일성) 시험Test Example 5: Productivity (compression speed) and quality (content uniformity) test
동일한 중량인 비교예 3의 이층정과 실시예 1의 단층정을 생산을 하는 경우 생산성(타정속도) 및 타정속도에 따른 품질(함량균일성)을 확인하였다.When the double-layer tablet of Comparative Example 3 and the single-layer tablet of Example 1 having the same weight were produced, productivity (compression speed) and quality (content uniformity) according to the tableting speed were confirmed.
[표 9][Table 9]
Figure PCTKR2021006285-appb-I000020
Figure PCTKR2021006285-appb-I000020
표 9에서 보는 바와 같이, 동일한 양의 정제를 생산할 때 비교예 3의 이층정의 경우 타정속도는 5만 T/h의 속도까지 정제를 생산이 가능하였지만, 실시예 1 단층정의 경우 18만 T/h의 속도로 비교예 3보다 3.6배나 빠른 속도로 정제를 생산 할 수 있었다. As shown in Table 9, when producing the same amount of tablets, in the case of the double-layered tablet of Comparative Example 3, the tableting speed was 50,000 T/h, but in the case of the single-layered tablet of Example 1, 180,000 T/h It was possible to produce tablets at a rate 3.6 times faster than Comparative Example 3 at a rate of .
즉, 분리된 과립을 상하층으로 타정한 이층정(비교예 3)보다 혼합과립부를 단층정(실시예 1)으로 타정하여 생산하는 경우 보다 높은 생산성을 나타낸다. 또한, 분리과립부를 포함하는 단층정 보다도 혼합과립부를 단층정으로 타정 시 높은 생산성을 나타낸다. That is, it exhibits higher productivity than when the mixed granule portion is compressed into a single-layer tablet (Example 1) and produced compared to a two-layer tablet (Comparative Example 3) obtained by tableting the separated granules into upper and lower layers. In addition, it exhibits higher productivity when tableting the mixed granular portion into a single-layered tablet than a single-layered tablet including a separate granular portion.
또한, 표 9에서 타정공정 수율의 경우 이층정의 경우 각 층의 중량을 맞추는데 소비되는 양과 호퍼내 잔류량이 단층정에 비해 많기 때문에, 비교예 3의 이층정보다 실시예 1의 단층정에서 생산 수율이 더 높게 확인되었다.In addition, in the case of the tableting process yield in Table 9, in the case of the double-layered tablet, the amount consumed to match the weight of each layer and the residual amount in the hopper are higher than that of the single-layered tablet. was found to be higher.
도 15는 (a) 비교예 3 및 (b) 실시예 1 각각에서 타정 속도에 따른 함량판정치(%)를 나타낸다. 15 shows the content determination value (%) according to the tableting speed in each of (a) Comparative Example 3 and (b) Example 1.
도 15에서 보는 바와 같이, 비교예 3의 이층정의 경우 타정속도가 높아질수록 함량균일성이 고르지 못하였지만, 실시예 1의 단층정의 경우 타정속도가 높아져도 함량균일성이 고르게 나타났다. 이는 이층정으로 분리될 경우 각 층별 중량이 낮기 때문에, 각 유효성분의 함량균일성이 고르게 나타나기 어렵기 때문이다.As shown in FIG. 15 , in the case of the double-layer tablet of Comparative Example 3, the content uniformity was not uniform as the tableting speed increased, but in the case of the single-layer tablet of Example 1, the content uniformity was uniform even as the tableting speed increased. This is because, when separated into a two-layer tablet, the weight of each layer is low, so it is difficult to show uniformity in the content of each active ingredient evenly.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로, 상기 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다. So far, the present invention has been looked at with respect to preferred embodiments thereof. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims (21)

  1. 유효성분으로서 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 및 로사르탄 또는 이의 약제학적으로 허용가능한 염을 저용량으로 포함하는 심혈관계 질환의 예방 또는 치료용 약제학적 단층정 복합제제. A drug for the prevention or treatment of cardiovascular diseases, comprising, as an active ingredient, amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof in a low dose single-layer tablet combination formulation.
  2. 청구항 1에 있어서, 암로디핀 또는 이의 약제학적 가능한 염은 암로디핀 자유 염기 형태로 환산했을 때 0.5 내지 5 mg의 양으로 포함하는 것인 약제학적 단층정 복합제제. The pharmaceutical single-layer tablet combination formulation according to claim 1, wherein amlodipine or a pharmaceutically acceptable salt thereof is included in an amount of 0.5 to 5 mg when converted to amlodipine free base form.
  3. 청구항 1에 있어서, 클로르탈리돈 또는 이의 약제학적 허용 가능한 염은 클로르탈리돈 자유 염기 형태로 환산했을 때 1 내지 7 mg의 양으로 포함하는 것인 약제학적 단층정 복합제제. The pharmaceutical single-layer tablet combination formulation of claim 1, wherein the chlorthalidone or a pharmaceutically acceptable salt thereof is included in an amount of 1 to 7 mg when converted to chlorthalidone free base form.
  4. 청구항 1에 있어서, 로사르탄 또는 이의 약제학적 허용 가능한 염은 로사르탄 자유 산 형태로 환산했을 때 7 내지 30 mg의 양으로 포함하는 것인 약제학적 단층정 복합제제. The pharmaceutical single-layer tablet combination formulation according to claim 1, wherein the losartan or a pharmaceutically acceptable salt thereof is included in an amount of 7 to 30 mg when converted into losartan free acid form.
  5. 청구항 1에 있어서, 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 및 로사르탄 또는 이의 약제학적으로 허용가능한 염을 혼합과립부로 포함하는 것인 약제학적 단층정 복합제제.The pharmaceutical monolayer tablet according to claim 1, comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as a mixed granule part. combination drug.
  6. 청구항 1에 있어서, 심혈관계 질환의 예방 또는 치료용 약제학적 단층정 복합제제의 총 중량이 350 mg 이하인 것인 약제학적 단층정 복합제제. The method according to claim 1, wherein the total weight of the pharmaceutical single-layer tablet combination formulation for the prevention or treatment of cardiovascular diseases is 350 mg or less.
  7. 청구항 1에 있어서, 심혈관계 질환의 예방 또는 치료용 약제학적 단층정 복합제제의 총 중량이 70 mg 이상 350 mg 이하인 것인 약제학적 단층정 복합제제. The method according to claim 1, wherein the total weight of the pharmaceutical monolayer tablet combination formulation for the prevention or treatment of cardiovascular diseases is 70 mg or more and 350 mg or less.
  8. 청구항 1에 있어서, 복합제제 중 유효성분으로서 암로디핀 또는 이의 약제학적으로 허용 가능한 염, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염, 및 로사르탄 또는 이의 약제학적으로 허용가능한 염의 총 중량이 15 mg 이상인 것인 약제학적 단층정 복합제제. The method according to claim 1, wherein the total weight of amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof as an active ingredient in the combination formulation is 15 mg or more A pharmaceutical single-layer tablet combination formulation.
  9. 청구항 1에 있어서, 복합제제 총 중량을 기준으로 상기 유효성분은 10% 이상으로 포함되는 것인 약제학적 단층정 복합제제.The pharmaceutical single-layer tablet combination formulation according to claim 1, wherein the active ingredient is included in an amount of 10% or more based on the total weight of the combination formulation.
  10. 청구항 1에 있어서, 복합제제 총 중량을 기준으로 상기 유효성분은 20% 이상으로 포함되는 것인 약제학적 단층정 복합제제.The pharmaceutical single-layer tablet combination formulation according to claim 1, wherein the active ingredient is included in an amount of 20% or more based on the total weight of the combination formulation.
  11. 청구항 1에 있어서, 붕해제를 더 포함하고, 이 때 붕해제의 함량은 복합제제 총 중량을 기준으로 1 내지 15%인 것인 약제학적 단층정 복합제제.The pharmaceutical single-layer tablet combination formulation of claim 1, further comprising a disintegrant, wherein the content of the disintegrant is 1 to 15% based on the total weight of the combination formulation.
  12. 청구항 1에 있어서, 붕해제를 더 포함하고, 이 때 붕해제의 함량은 복합제제 총 중량을 기준으로 4 내지 15%인 것인 약제학적 단층정 복합제제.The pharmaceutical single-layer tablet combination formulation of claim 1, further comprising a disintegrant, wherein the content of the disintegrant is 4 to 15% based on the total weight of the combination formulation.
  13. 청구항 1에 있어서, 붕해제를 더 포함하고, 이 때 붕해제의 함량은 복합제제 총 중량을 기준으로 9 내지 15%인 것인 약제학적 단층정 복합제제.The pharmaceutical single-layer tablet combination formulation of claim 1, further comprising a disintegrant, wherein the content of the disintegrant is 9 to 15% based on the total weight of the combination formulation.
  14. 청구항 1에 있어서, 희석제, 붕해제, 활택제, 및 이들의 조합 중에서 선택되는 약제학적 첨가제를 더 포함하는 것인 약제학적 단층정 복합제제. The pharmaceutical single-layer tablet combination formulation according to claim 1, further comprising a pharmaceutical additive selected from a diluent, a disintegrant, a lubricant, and a combination thereof.
  15. 청구항 14에 있어서, 상기 희석제는 미결정 셀룰로오스, 전분, 전호화전분, 제2인산칼슘(DCP), 락토오스, 저치환도 히드록시프로필셀룰로오스 및 이들의 조합 중에서 선택되는 어느 하나인 것인 약제학적 단층정 복합제제. The pharmaceutical single-layer tablet according to claim 14, wherein the diluent is any one selected from microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate (DCP), lactose, low-substituted hydroxypropyl cellulose, and combinations thereof. combination drug.
  16. 청구항 14에 있어서, 상기 붕해제는 크로스포비돈, 크로스카르멜로즈 나트륨, 전분 글리콘산 나트륨, 전분, 전호화전분 또는 이들의 조합 중에서 선택되는 어느 하나인 것인 약제학적 단층정 복합제제. The pharmaceutical single-layer tablet combination formulation of claim 14, wherein the disintegrant is any one selected from crospovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch, or a combination thereof.
  17. 청구항 14에 있어서, 상기 활택제는 스테아르산 마그네슘, 팔미트산, 활석(탈크), 스테아르산 마그네슘, 스테아르산 아연, 스테아르산 칼슘 또는 이들의 조합 중에서 선택되는 어느 하나인 것인 약제학적 단층정 복합제제. The pharmaceutical single-layer tablet complex according to claim 14, wherein the lubricant is any one selected from magnesium stearate, palmitic acid, talc (talc), magnesium stearate, zinc stearate, calcium stearate, or a combination thereof. formulation.
  18. 청구항 1에 있어서, 희석제로 미결정 셀룰로오스 및 저치환도 히드록시프로필셀룰로오스를 더 포함하고, 이 때 미결정 셀룰로오스 대 저치환도 히드록시프로필셀룰로오스의 중량비는 2:1 내지 1:1인 것인 약제학적 단층정 복합제제.The pharmaceutical monolayer according to claim 1, further comprising microcrystalline cellulose and low-substituted hydroxypropyl cellulose as a diluent, wherein the weight ratio of microcrystalline cellulose to low-substituted hydroxypropyl cellulose is 2:1 to 1:1. Tablet combination formulation.
  19. 청구항 1에 있어서, 상기 복합제제는 경구의약품 용출규격 설정 가이드라인에 따라 용출시험시, 30분 이내에 암로디핀의 용출률이 80% 이상인 것인 약제학적 단층정 복합제제. The pharmaceutical single-layer tablet combination formulation of claim 1, wherein the dissolution rate of amlodipine is 80% or more within 30 minutes when the dissolution test is performed according to the guidelines for setting dissolution standards for oral pharmaceuticals.
  20. 청구항 1에 있어서, 상기 복합제제는 경구의약품 용출규격 설정 가이드라인에 따라 용출시험시, 30분 이내에 클로르탈리돈의 용출률이 80 % 이상인 것인 약제학적 단층정 복합제제. The pharmaceutical single-layer tablet combination formulation of claim 1, wherein the dissolution rate of chlorthalidone within 30 minutes of the combination formulation is 80% or more during a dissolution test according to the guidelines for setting dissolution standards for oral pharmaceuticals.
  21. 청구항 1에 있어서, 상기 복합제제는 경구의약품 용출규격 설정 가이드라인에 따라 용출시험시, 30분 이내에 로사르탄의 용출률이 80 % 이상인 것인 약제학적 단층정 복합제제.The pharmaceutical single-layer tablet combination formulation of claim 1, wherein the dissolution rate of losartan within 30 minutes is 80% or more in the dissolution test according to the guidelines for setting dissolution standards for oral drugs.
PCT/KR2021/006285 2020-06-09 2021-05-20 Complex pharmaceutical preparation, for preventing or treating cardiovascular disease, comprising amlodipine, losartan and chlorthalidone in single-layer tablet WO2021251644A1 (en)

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KR20150034120A (en) * 2014-10-15 2015-04-02 대봉엘에스 주식회사 Direct-compressible pharmaceutical composition comprising amlodipine and losartan, and tablet using the same
KR20180049510A (en) * 2016-11-03 2018-05-11 한미약품 주식회사 Pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone
KR20190043076A (en) * 2017-10-17 2019-04-25 한미약품 주식회사 Pharmaceutical composition comprising amlodipine, losartan and rosuvastatin for prevention and treatment of cardiovascular diseases accompanied by diabetes and formulated combination including the same

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