KR101168136B1 - Antihypertensive pharmaceutical composition - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing angiotensin-2-receptor and pharmaceutically acceptable salt thereof is provided to reduce side effect and to prevent or treat hypertension. CONSTITUTION: A pharmaceutical composition for reducing blood pressure contains 30mg of fimasartan potassium salt as an angiotensin-2-receptor inhibitor or hydrate thereof and 5 mg of amlodipine besylate as a calcium channel blocker. The pharmaceutical composition is manufactured in the form of oral administration. The pharmaceutical composition for preventing, treating, or relieving hypertension contains fimasartan potassium salt or hydrate thereof and amlodipine besylate.

Description

Antihypertensive pharmaceutical composition

The present invention relates to a pharmaceutical composition for lowering blood pressure.

Hypertension is one of the most common cardiovascular diseases and is usually diagnosed as hypertension when the blood pressure is 140/90 mmHg. In recent years, there has been a rapid increase in the number of adult patients with hypertension, and the development of more effective hypertension therapeutics is required because hypertension may cause acute heart disease or myocardial infarction.

Many clinical trials of antihypertensive agents have shown that lowering blood pressure in hypertensive patients reduces the mortality and morbidity of heart disease or myocardial infarction (Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH, Lancet 1990, 335 (8693): 827-38). Despite the use and application of various types of drugs to treat these medical conditions, proper control of blood pressure is not always achieved (Waeber B, Brunner HR, Am. J. Hypertens 1997. 10 ( 7 Pt 2): 131S-137S).

Among the various applied dosage forms of antihypertensive drugs, using a combination or combination of drugs is one way to achieve the desired therapeutic outcome. On the other hand, the random selection of various classes of antihypertensive agents for inclusion in combination therapy does not necessarily help to reach the desired blood pressure levels in humans and hypertensive mammals (MacGregor GA, Markandu ND, Banks RA, Bayliss). J. Roulston JE, Jones JC, Br Med J (Clin Res Ed), 284 (6317): 693-6).

Thus, there is a clear need for further development of methods of treatment, combinations and pharmaceutical compositions.

Fimasartan is 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl ] Pyrimidin-4 (3H) -one {2-n-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] pyrimidin -4 (3H) -one}, which has the following structural formula and is currently approved as a KANARB as a blood pressure lowering agent of the Angiotensin II Receptor Blocker (ARB) family.

[Pimasaltan]

A randomized, double-blind clinical trial was conducted to compare the blood pressure-lowering effects of fimasartan potassium 60 mg to 120 mg with losartan, a representative compound of ARB, in patients with mild to moderate essential hypertension. The lowering of the DBP change over the baseline was -11.26 ± 7.53mm Hg in the Pimasaltan group and -8.56 ± 7.72mmHg in the Rosaltan group. (A Randomized, Double-blind, Losartan-controlled, Parallel Group Comparison Dose Titration Clinical Study to Evaluate the Antihypertensive Efficacy and Safety of Fimasartan (BR-A-657? K) 60mg ~ 120mg in Patients with Mild to Moderate Essential Hypertension (Phase III)).

Amlodipine (Amlodipine) is a calcium channel blocker (CCB) that blocks calcium ions from entering the cell membranes of the heart and peripheral vestibule smooth muscle, and directly relaxes vascular smooth muscle, resulting in an antihypertensive effect. The exact mechanism of action to relieve amlodipine angina is not fully established, but it has been found to play a role in reducing overall ischemic symptoms by two mechanisms.

First, amlodipine dilates the peripheral arteries, reducing total peripheral vascular resistance (afterload), reducing the burden on the heart, and stabilizing heart rate to reduce the energy consumption and oxygen demand of the myocardium.

Second, amlodipine is thought to dilate the main coronary arteries and other coronary arteries in the ischemic and normal areas. This vasodilation increases oxygen transport in the myocardial ischemic region of patients with coronary artery spasm.

Recently, a combination of amlodipine, which is a calcium channel blocker, and an ARB family of compounds has been actively studied for the treatment of hypertension. However, these combinations sometimes cause side effects such as causing interaction between two drugs and increasing side effects of each drug. do.

Accordingly, the present inventors have completed the present invention as a result of recognizing and solving problems of simple drug complexes of amlodipine and ARB-based compounds.

[Document 1] KR1989-0011854 1989.08.22., All pages Document 2 WO00 / 16773 1999.09.08., All pages Document 3 KR2001-0013626 2001.02.26., All pages Document 4 KR2001-0079517 2001.08.22., All pages Document 5 KR2001-0090193 2001.10.18., All pages Document 6 KR2004-0032639 2004.04.17., All pages Document 7 KR2010-0048137 2010.05.11., All pages

Yoo SD et.al., Simultaneous determination of fimasartan, a novel antihypertensive agent, and its active metabolite in rat plasma by liquid chromatography-tandem mass spectrometry, Biomed Chromatogr. 2011 Jan 26. doi: 10.1002 / bmc. 1592.Epub ahead of print (Date: 2011.07.28) Yu KS, et.al., Effect of multiple doses of fimasartan, an angiotensin II receptor antagonist, on the steady-state pharmacokinetics of digoxin in healthy volunteers. Int J Clin Pharmacol Ther. 2011 May; 49 (5): 321-7 10. Yu KS et.al., The Effect of the Newly Developed Angiotensin Receptor II Antagonist Fimasartan on the Pharmacokinetics of Atorvastatin in relation to OATP1B1 in Healthy Male Volunteers. J Cardiovasc Pharmacol. 2011 Jul 14.Epub ahead of print (Date: 2011.07.28)

It is an object of the present invention to provide a pharmaceutical composition for lowering blood pressure, which is effective for preventing, alleviating and treating hypertension, as well as for preventing, alleviating or treating complications caused by hypertension and / or hyperlipidemia.

The present invention provides an angiotensin-2-receptor blocker as fimasartan, pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof; And a blood pressure lowering pharmaceutical composition comprising amlodipine, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof as a calcium channel blocker.

Fimasartan, pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof in the present invention may be crystalline or amorphous, and the present invention includes their crystalline and / or amorphous forms.

In the present invention, amlodipine, isomers thereof, pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof may be crystalline or amorphous, and the present invention includes their crystalline and / or amorphous forms.

In the present invention, pharmaceutically acceptable salts generally mean inorganic acid salts, organic acid salts, and metal salts used by pharmaceutical manufacturers to prepare medicines. As the "organic acid," hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, and the like may be used. "Organic acid" includes citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholine Ethanesulfonic acid, camphorsulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, kalucturonic acid, emboic acid, glutamic acid, aspartic acid, adipate salt, camsylate salt or besylate salt And "metal" includes sodium, potassium, calcium, magnesium, and the like.

In the present invention, it is preferable that the angiotensin-2-receptor blocker is fimasartan potassium salt, hydrochloride, calcium salt, sulfate, adipate salt, camsylate salt or besylate salt, and fimasartan potassium salt or fimasartan trihydrate potassium salt Even more preferred. These are commercially available and can be manufactured by known methods (for example, Korean Patent Registration Nos. 0354654 and 0521980).

In the present invention, it is preferred that the calcium channel blocker is amlodipine besylate salt, sulfate, camsylate salt, hydrochloride, potassium salt, calcium salt or adipate salt, and even more preferred are amlodipine besylate salts, which are commercially available. And may be prepared by a known method (eg, US Pat. No. 4652909).

In the present invention, the solvent in the "solvate" means a conventional organic solvent used to prepare an organic compound, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1 Acetates, acetone, acetic acid, anisole, tetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, dimethyl sulfoxide, pentane, heptane, and the like. The solvates of the present invention are not limited.

In the present invention, "hydrate" and "solvate" may be contained in a 0.25 to 10 molar ratio with respect to 1 mole of fimasartan or amlodipine, for example 0.5 mole, 1 mole, 1.5 mole, 2 mole, 2.5 mole, 3 moles, 5 moles, etc., but the present invention is not limited thereto.

The composition of the present invention may contain 0.5 to 240 mg of angiotensin-2-receptor blocker, preferably 50 to 180 mg, still more preferably 60 to 120 mg.

In addition, the composition of the present invention may contain 0.1 to 20 mg of calcium channel blocker, preferably 5 to 15 mg, and even more preferably 5 to 10 mg.

On the other hand, commercially available high doses (ie, pharmaceutically acceptable high doses per dose) for these drugs in pharmaceutical compositions are up to 240 mg of maximatantan and up to 240 mg based on, for example, an average adult weighing about 60 kg. It is known to be less than 20mg.

Throughout this specification, "pharmaceutical composition" means a single unit dosage form, such as a tablet, capsule or injection, which is taken or administered at one time, as well as a plurality of units administered in two or more times, unless expressly stated otherwise. It is understood that dosage forms can also be broadly referred to. For example, "fimasartan, pharmaceutically acceptable salts thereof, solvates or hydrates thereof as angiotensin-2-receptor blockers; and amlodipine, isomers thereof, pharmaceutically acceptable salts thereof, as calcium channel blockers "Solvate or pharmaceutical composition comprising a hydrate thereof" refers to a single unit dosage form comprising these two active ingredients together, as well as two unit dosage forms each containing one active ingredient. It is interpreted as being possible. That is, when these two unit dosage forms are administered simultaneously or at intervals of no more than a certain time, the effective amounts of the two active ingredients included in each of these unit dosage forms are present in the body together and cause synergy. Encompassing unit dosage forms, "fimasartan, pharmaceutically acceptable salts thereof, solvates or hydrates thereof as angiotensin-2-receptor blockers; and amlodipine, isomers thereof, pharmaceutically acceptable as calcium channel blockers; Salts, solvates thereof, or hydrates thereof; and the like.

The composition of the present invention may be prepared by containing one or more pharmaceutically acceptable carriers in addition to the above components for administration. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary, as antioxidants, buffers And other conventional additives such as bacteriostatic agents can be added.

In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Furthermore, it may be preferably formulated according to each disease or component by a suitable method in the art or using the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA.

The composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex, health status, The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease. The composition of the present invention may be administered once to several times a day.

The compositions of the present invention may be injectable formulations, such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules or tablets, or formulations for oral administration, more preferably for oral administration, even more monolithic. desirable.

In addition, the composition of the present invention can be used for the prevention, alleviation or treatment of hypertension, heart failure, coronary heart disease, ischemic heart disease, ischemic peripheral circulatory disease, hypertensive renal failure, stroke or atherosclerosis due to the elevated blood pressure lowering effect.

Accordingly, the present invention provides an angiotensin-2-receptor blocker with fimasartan, pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof; And hypertension, heart failure, coronary heart disease, ischemic heart disease, ischemic peripheral circulatory disease, hypertensive renal failure, stroke or as a calcium channel blocker, including amlodipine, isomers thereof, pharmaceutically acceptable salts thereof, solvates or hydrates thereof. Provided are pharmaceutical compositions for the prevention, alleviation or treatment of atherosclerosis.

In addition, the present invention provides an angiotensin-2-receptor blocker, fimasartan, pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof; And high blood pressure, heart failure, coronary heart disease, ischemic heart disease, ischemic peripheral circulatory disease, hypertensive renal failure, including an effective amount of amlodipine, isomers thereof, pharmaceutically acceptable salts thereof, solvates or hydrates thereof as calcium channel blockers; Provided is a method for preventing, alleviating or treating such a disease by administering to a mammal, including a human, in need of prevention, alleviation or treatment of stroke or atherosclerosis.

 The present invention also relates to fimasartan as an angiotensin-2-receptor blocker for the preparation of a pharmaceutical for the prevention, alleviation or treatment of hypertension, heart failure, coronary heart disease, ischemic heart disease, ischemic peripheral circulatory disease, hypertensive renal failure, stroke or atherosclerosis. , Pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof; And an effective amount of amlodipine, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof as a calcium channel blocker.

The compositions of the present invention exhibit an elevated blood pressure lowering effect than a simple sum of the blood pressure lowering values of the same dose of each active ingredient. Therefore, since the composition of the present invention can be used in a lower amount or dosage than the amount of each active ingredient, it is possible to more effectively treat or prevent hypertension and the like while reducing side effects caused by overuse of each active ingredient.

Hereinafter, examples and experimental examples are presented to help understand the present invention. The following Examples and Experimental Examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited thereto.

< Experimental Example > Confirm the blood pressure lowering effect of the composition of the present invention

In this study, blood pressure, heart rate and heart rate were measured in oral administration for four weeks of oral administration of the test drug pimasartan trihydrate potassium, rozatan potassium salt, valsartan, and amlodipine besylate salt in combination with amlodipine besylate salt. By measuring weight change, we tried to identify the coercive effect of long-term administration of each drug, to confirm the effective and stable blood pressure maintenance, and to identify the difference between single and complex administrations. And to evaluate.

(1) test materials and methods

① Experiment animal

The male SHR was supplied from Charles River Japan (CRJ) for 8 weeks of age (230-250 g), and the test period was applied until 18-19 weeks (340-380 g) of average blood pressure of 160-170 mmHg. . Animals in good condition were selected by careful observation through the pre-test period, and 8 animals were used for each test group (n = 8). The animals were checked for blood pressure increase using the indirect blood pressure measurement device (CODA-6). Only applied to the test group. At this time, subjects outside the normal SHR blood pressure range (measured as mean blood pressure below 140mmHg or above 220mmHg) were excluded from the test.

② Drug group  Setup and Dosing Method

The final dose of the drug administered to the experimental rats in this study was set to an appropriate dose that can have a significant coercive effect through basic and preliminary tests. In the preliminary test, a dose that can set a low, medium, and high dose for each drug, and the blood pressure of the hypertensive rat before the test resulted in a significant drop in blood pressure of about 20 to 50 mmHg after drug administration (clinical dose is equivalent to 20 to 25%) Dose) was selected as the appropriate dose of the single dose group. On the other hand, in the combination-administered group, the results of the literature review set a dose capable of exhibiting only coercive action in a stable state without toxicity in 4 weeks of administration. All doses refer to the doses used in the trials performed and the doses and drug administration groups used in the final study were as follows.

As the ARB compound, lozatan potassium salt, valsartan and fimasartan trihydrate potassium salt were purchased from Zhejiang Huahai Pharmaceutical, respectively. The rozatan potassium salt was set to 10 mg / kg in the L group, the valsartan 10 mg / kg to the V group, and in the case of fimasartan trihydrate potassium salt, 3 mg / kg to the F1 group and 10 mg / kg to the F2 group. .

Amlodipine besylate salt (self-synthesis, US Pat. No. 4,727,909) was used as a calcium channel blocker, and 0.5 mg / kg of amlodipine besylate salt was set to the A1 group, and a 1.6 mg / kg dose was set to the A2 group. The test substance and the comparative drug were both suspended with 0.5% CMC-Na (carboxymethylcellulose sodium salt; Sigma) and 0.5% CMC was administered as a control.

③ Test method

-Administration : At the time of administration, the temperature of the preparation was adjusted to 35 ° C., followed by forced oral administration using gastride at a dose of 5 mL / kg.

Blood pressure measurement : Rat's blood pressure is calibrated to the rat and warmed for 13 minutes at a temperature of 40 ℃ (based on temperature of 37 ℃ in fixation frame) in the heating device to make the tail blood vessel aging, and through a pair of cuffs connected to the tail. CODA-6 was used to measure blood pressure with the software of the main body. Indirect blood pressure measurement through CODA-6 (Kent Scientific Corporation) enables long-term blood pressure measurement tests that require repeated doses that cannot be performed by direct blood pressure measurement using arterial cannulation such as physiograph and power lab. It was made. The blood pressure was measured once daily for one week after the end of the final administration in order to confirm the loss pattern according to the dose of the drug and the recovery to the original blood pressure.

The change in blood pressure was confirmed by the change in mean blood pressure (MAP), and the results of this period, systolic blood pressure, heart rate, and weight change were referred to the test results.

(2) result processing and statistical analysis

Statistical analysis of the measurements obtained in this experiment was carried out using SPSS, a statistical processing program, in the range of significance level between the control group and the dose group (p <0.001, 0.01, 0.05). Compared.

In the 4-week repeated dose study, the weight gain was mild in all groups, including the control group. At the beginning of the test, there was a tendency to decrease, but after the mid-test, body weight was confirmed. This was not a direct effect of the drug, but rather a symptom that accompanied with stress such as warming and correction during indirect blood pressure measurement.

The type and drug dose of the administered drug of each drug-administered group and the blood pressure drop obtained in each drug-administered group, that is, the degree of blood pressure drop for 4 weeks according to the drug administration were calculated based on the pre-administration blood pressure. The values are shown in [Table 1].

The degree of coercive force (mmHg) as a result of 4 weeks of continuous administration compared to pre-administration blood pressure Drug administration group
(Drug type and dose) Average Standard error Example 1 (F1 + A1) -55 2.255 Example 2 (F2 + A2) -75 2.536 Comparative Example 1 (F1) -35 1.375 Comparative Example 2 (F2) -50 2.135 Comparative Example 3 (L) -20 1.256 Comparative Example 4 (V) -32 2.862 Comparative Example 5 (A1) -13 1.105 Comparative Example 6 (A2) -20 1.325 Comparative Example 7 (L + A2) -32 2.268 Comparative Example 8 (V + A2) -46 2.675

As can be seen from the above [Table 1], Comparative Example 1 compared to Comparative Example 3 and Comparative Example 4 clinical clinical dose (the clinical normal dose of fimasartan trihydrate potassium salt = 60 mg, clinical normal dose of rozatan potassium salt = 50 mg, Valsartan clinical normal dose = 80 mg), even though the dose was administered in a small dose compared to the superior blood pressure lowering effect was confirmed.

In addition, Examples 1 and 2 of the combination of pimasartan and amlodipine of the composition of the present invention showed a greater blood pressure lowering effect than a simple sum of the blood pressure lowering effects administered alone. For example, Examples of -13mmHg when administered alone with amlodipine besylate (Comparative Example 5) and -35mmHg when administered with 3mg / Kg of potassium masaltan trihydrate potassium salt (Comparative Example 1), but the combination of both In the case of 1, -55mmHg showed a higher blood pressure lowering effect than the sum of the two blood pressure lowering effects, which is significant even when the standard error is considered. In addition, in the case of Example 2, which is -20mmHg when administered alone with amlodipine besylate (Comparative Example 6) and -50mmHg when administered with 10mg / Kg of potassium salt of trimasartan trihydrate alone (Comparative Example 2), At -75mmHg, the blood pressure drop effect was higher than the sum of the simple values of the two blood pressure drop effects. This effect is expected when compared with the above results that the combination of the other ARB compound with amlodipine shows a lower blood pressure drop than the simple sum of the blood pressure drop values of each single component of the combination (Comparative Examples 7 and 8). It is confirmed that it is not a significant effect.

Therefore, the composition of the present invention exhibits an elevated blood pressure lowering effect than the single blood pressure lowering effect of each active ingredient (synergy effect), thereby reducing the risk of side effects due to overuse of each active ingredient by reducing the content of each active ingredient. In addition, it is possible to alleviate the inconvenience of taking the medicine of the patient according to the combination therapy of each active ingredient.

< Manufacturing example > Preparation of the composition (tablet) of the present invention

The composition of the present invention was prepared as a tablet containing the components and their contents as described in the following [Table 2], which is shown in Preparation Examples 1 to 4.

ingredient Preparation Example 1
(mg / 1 tablet) Preparation Example 2
(mg / 1 tablet) Preparation Example 3
(mg / 1 tablet) Preparation Example 4
(mg / 1 tablet) Fimasartan Trihydrate Potassium Salt 66.01 132.02 66.01 132.02 Amlodipine Besylate Salt 6.99 6.99 13.98 13.98 Corn starch 46 98.99 39.01 92 Microcrystalline cellulose 16 32 16 32 Crospovidone 10 20 10 20 Hydroxypropyl
cellulose 3.5 7 3.5 7 Magnesium stearate 1.5 3 1.5 3 1 tablet gross weight
(mg) 150 300 150 300

<Production method of the tablet>

Fimasaltan trihydrate potassium salt, amlodipine besylate salt, corn starch, microcrystalline cellulose, crospovidone were added to a high speed mixer and mixed. Separately, hydroxypropyl cellulose and an appropriate amount of purified water were mixed to make a binder solution, and then put into a high speed mixer containing premixed powder to prepare granules, and dried in a drier. The dried granules were sieved with No. 20 sieve, and then magnesium stearate was added and mixed to obtain a final mixture. The final mixture was compressed using a rotary tablet press to prepare each tablet corresponding to Preparation Examples 1-4.

Claims (15)

30 mg of fimasartan potassium salt or a hydrate thereof as angiotensin-2-receptor blocker and
A pharmaceutical composition for lowering blood pressure comprising 5 mg of amlodipine besylate salt as a calcium channel blocker. delete delete The pharmaceutical composition for lowering blood pressure according to claim 1, wherein the angiotensin-2-receptor blocker is fimasartan trihydrate potassium salt. delete delete delete delete delete delete delete The pharmaceutical composition for lowering blood pressure according to claim 1, wherein the pharmaceutical composition is an oral dosage form. The pharmaceutical composition for lowering blood pressure according to claim 12, wherein the dosage form is a single tablet. 30 mg of fimasartan potassium salt or a hydrate thereof as angiotensin-2-receptor blocker and
Comprising 5 mg of amlodipine besylate salt as a calcium channel blocker,
Pharmaceutical compositions for the prevention, alleviation or treatment of hypertension. delete