KR20100043732A - Pharmaceutical composition - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing telmisartan and cilnidipine is provided to suppress damage or enlargement of blood vessel. CONSTITUTION: A pharmaceutical composition for reducing blood pressure contains effective amount of telmisartan and cilnidipine. The pharmaceutical composition contains 5-80 mg of telmisartan and 1.25-20 mg of cilnidipine in a weight ratio of 64 : 1-1 : 4. The pharmaceutical composition for reducing blood pressure is manufactured in the form of oral formulation.

Description

Pharmaceutical composition {PHARMACEUTICAL COMPOSITION}

The present invention relates to pharmaceutical compositions. More specifically, the present invention relates to pharmaceutical compositions that can exhibit better blood pressure lowering effects through the synergistic action of the two active ingredients and can be used in novel applications that effectively inhibit blood vessel damage and hypertrophy.

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, the number of adult patients with hypertension, such as high blood pressure is rapidly increasing, and in particular, the damage caused by such high blood pressure can lead to acute heart disease or myocardial infarction, etc., there is a continuous need for the development of more effective hypertension therapy.

Meanwhile, the antihypertensive drugs developed so far are based on their mechanism of action, such as Angiotensin II Receptor Blocker (ARB), Angiotensin-Converting Enzyme Inhibitor (ACEI) or Calcium Chanel Blocker (CCB). ) May be divided into drugs. Among these, drugs belonging to the ARB or CCB, etc. exhibits a better blood pressure lowering effect, and thus are used at a higher frequency in recent years.

However, these drugs also have a limit on the blood pressure lowering effect, and in particular, when each of these drugs is administered in a certain amount or more may have a number of side effects. Therefore, in recent years, various attempts have been made to obtain better blood pressure lowering effects by using a combination or combination of two or more drugs or a combination treatment method.

In particular, since the side effects associated with each drug are directly related to the content or dosage of each single drug, two or more of these drugs may be combined or combined to reduce the content or dosage of each single drug, Attempts to obtain better blood pressure lowering effects by the synergistic action of drugs are being made very actively.

For example, US Patent Publication No. US20040198789 discloses a blood pressure lowering pharmaceutical composition combining lercanidipine, which is a type of CCB, and valsartan, irbesartan, or olmesartan, which is a type of ARB. In addition, there has been disclosed a blood pressure lowering complex composition or a combination treatment method thereof in which various blood pressure lowering drugs are combined or combined.

However, even with this conventional technique, it is difficult to sufficiently reduce the content or dosage of each of these single drugs, which may cause side effects, or the synergistic action between drugs contained in the above combination composition, etc., is insufficient, so that the limit on the effect of lowering blood pressure is limited. It is a reality.

Atherosclerosis, such as atherosclerosis; Aneurysms or varicose veins, such as aortic aneurysms or dissections, aneurysms of other arteries, varicose veins of the legs, or varicose veins of other sites; Various vascular diseases such as peripheral vascular disease, arterial embolism, arterial thrombosis, venous embolism, venous thrombosis, stenosis of arteries, stenosis of veins, phlebitis, thrombophlebitis, portal thrombosis or capillary diseases; Cerebral infarction due to thrombus, embolism, occlusion or stenosis of cerebral artery or cerebral artery, cerebral infarction due to cerebral vein thrombosis; This disease is known to be caused by damage to blood vessels due to stress on blood vessels, or pathological enlargement of blood vessels (Korshunov VA, Schwarz SM, Berk BC. Vascular remodeling: hemodynamic and biochemical mechanisms underlying Glagov's phenomenon.Arterioscler Thromb Vasc Biol. 2007; 27: 1722-1728; Marjo MPC Donners, Sylvia Heeneman, Mat JAP Daemen.Models of atherosclerosis and transplant ateriosclerosis: the quest for the best.Drug Discovery Today.2004; 1 (3); 257-263 et al. ).

However, a drug that can effectively suppress damage to the gastric vessels or pathological enlargement of the vessels, or to effectively treat or prevent various diseases caused by the above, has not been proposed or developed.

Accordingly, the present invention is to provide a pharmaceutical composition for lowering blood pressure, which exhibits an excellent blood pressure lowering effect while the content of each active ingredient is relatively small through the synergistic action of two active ingredients. In addition, the present invention is to provide a pharmaceutical composition that can more effectively treat or prevent vascular damage or pathological enlargement of blood vessels and various diseases caused by the synergistic action of the two active ingredients.

The present invention provides a pharmaceutical composition for lowering blood pressure, comprising an effective amount of telmisartan and silnidipine. Such pharmaceutical compositions may comprise only telmisartan and silnidipine as active ingredients and no other active ingredients exhibiting blood pressure lowering action.

The present invention also provides a pharmaceutical composition for inhibiting blood vessel damage or pathological enlargement of blood vessels comprising an effective amount of telmisartan and silnidipine.

Hereinafter, a pharmaceutical composition for lowering blood pressure and a pharmaceutical composition for inhibiting blood vessel damage or pathological enlargement of blood vessels according to specific embodiments of the present invention will be described.

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 unless otherwise stated, a plurality of units administered in two or more times. It is understood that dosage forms can also be broadly referred to. For example, "pharmaceutical composition comprising telmisartan and silnidipine" 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 to be understood that may also refer to together. That is, if 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 contained in each of these unit dosage forms are present in the body together and cause synergy. It may be referred to as falling within the scope of the above "pharmaceutical composition comprising telmisartan and silnidipine" encompassing unit dosage forms.

On the other hand, according to one embodiment of the invention, there is provided a pharmaceutical composition for lowering blood pressure comprising an effective amount of telmisartan and silnidipine. As a result of the experiments of the present inventors, surprisingly, by combining or combining the two active ingredients of telmisartan and silnidipine, they can synergistically exhibit an excellent blood pressure lowering effect at the same content than the use of each active ingredient. It turns out that. Therefore, by using the pharmaceutical composition according to the embodiment of the present invention, while reducing the content of each active ingredient can exhibit substantially the same or better blood pressure lowering effect, while reducing the side effects of overuse of each active ingredient It can effectively treat or prevent hypertension.

Such an antihypertensive pharmaceutical composition may include only telmisartan and silnidipine as active ingredients having an antihypertensive effect, and no other active ingredient exhibiting an antihypertensive action. As a result of the experiments of the present inventors, by using only these two active ingredients in combination or in combination, the excellent synergism of these two active ingredients allows a single agent or a third agent containing the same amount or the same dosage of each single active ingredient. It has been found that it can show an excellent blood pressure lowering effect compared to other combinations containing the active ingredient.

In addition, the blood pressure lowering pharmaceutical composition preferably contains 5 to 80 mg of telmisartan and 1.25 to 20 mg of silnidipine. More specifically, the pharmaceutical composition comprising each active ingredient in this amount may be in a single dosage form which is administered or taken one day or one time.

The active ingredients telmisartan and cilnidipine included in the above pharmaceutical composition are known antihypertensive drugs belonging to ARB and CCB, respectively, and are commercially available high doses (ie, pharmaceutically acceptable high doses per dose) on a general adult basis. These are known to be 80 mg and 20 mg, respectively.

By the way, the pharmaceutical composition for lowering blood pressure according to the embodiment of the present invention, due to the excellent synergistic effect of combining or combining these two active ingredients, even if each of these active ingredients are used in a content of less than a commercially available high dose (particularly It has been found that even if one or more of these active ingredients are used in an amount of less than one-half of a commercial high dose, they may exhibit a blood pressure lowering effect similar to or greater than that of each active ingredient at a commercial high dose. Therefore, by using the blood pressure lowering pharmaceutical composition comprising these two active ingredients, it is possible to reduce the content or dosage of each active ingredient and to exhibit the same or better blood pressure lowering effect, and thus to effectively treat hypertension and the like. It can contribute greatly.

In addition, the pharmaceutical composition for lowering blood pressure may include 10 to 20 mg of telmisartan and 1.25 to 20 mg of silnidipine. In addition, the pharmaceutical composition for lowering blood pressure may include telmisartan: silnidipine in a weight ratio of 64: 1 to 1: 4, and more preferably in a weight ratio of 8: 1 to 1: 2.

As also supported by the following examples, Interaction Index (Ronald J. Tallarida., The interaction index: a measure of drug synergism.Pain. 2002. 98.) assesses the synergistic effects of the two active ingredients. 163-168; Lee JJ, Kong M, Ayers GD, Lotan R. Interaction index and different methods for determining drug interaction in combination therapy.See Journal of Biopharmaceutical Statistics, 2007.17: 461-480, etc. , The preferred content range and content ratio of the two active ingredients, that is, the content range of 10 to 20mg of telmisartan and 1.25 to 20mg of silnidipine and the weight ratio of telmisartan: silinidipine to 8: 1 to 1: 2 In the case of satisfying the two active ingredients, these two active ingredients may produce a better synergy, so that the pharmaceutical composition for lowering blood pressure may exhibit a better blood pressure lowering effect under the same content or the same dose of each active ingredient. This turned out to be. On the contrary, when the content of the active ingredients is outside the range or the content ratio, the synergistic action of these active ingredients is not sufficient, so that it is difficult to sufficiently reduce the content of each active ingredient, or the blood pressure lowering effect using the pharmaceutical composition for lowering blood pressure is sufficient. It may not be.

For reference, the Interaction index is an index known in the art that is a criterion for determining whether an effect of a drug caused by a combination of drugs is a synergistic, additive or antagonistic effect. Each drug has a characteristic potency and efficacy according to its characteristics, and this effect and efficacy results in a characteristic dose-effect response. If one drug shows the same effect at a lower dose compared to the other drug, it is a potent drug, and if one drug has the greatest effect regardless of the dose, the drug is a high potency drug. That is, the potency or efficacy per dose seen in each drug may be characteristically different from each other. Because of this characteristic dose-effect response, the effects of each drug when combined with a drug cannot simply be obtained by a simple sum of the effects of each single drug in the combined dose. Therefore, the Interaction index is proposed to evaluate all drug interactions, including all of these complex factors. It is known that such an interaction index can be calculated by the following equation:

Interaction index = a / A + b / B

Where A is the dose of drug 1 alone showing effect X, B is the dose of drug 2 alone showing effect X, and a and b are doses of drugs 1 and 2 showing effect X when used in combination. An interaction index of> 1 indicates an antagonistic effect, = 1 means an additive effect, and <1 indicates a synergistic effect.

However, by calculating the Interaction index, the pharmaceutical composition for lowering blood pressure according to an embodiment of the present invention has two active ingredients, telmisartan and silnidipine, in particular, in the above-described preferred content range and content ratio, excellent rise It was found that the action, and accordingly, it was found that the pharmaceutical composition for lowering blood pressure may exhibit a better blood pressure lowering effect under the same content or at the same dose of each active ingredient.

On the other hand, in view of the excellent synergistic effect of these two active ingredients, the pharmaceutical composition for lowering blood pressure is more preferred in each of the two active ingredients of telmisartan and silnidipine in the following amounts:

1) 80 mg of telmisartan and 5 mg of silnidipine, 2) 40 mg of telmisartan and 10 mg of silnidipine, 3) 20 mg of telmisartan and 2.5 to 20 mg of silnidipine, 4) 10 mg of telmisartan and silni 1.25-20 mg of dipine (most preferably 1.25-5 mg of silnidipine) or 5) 5 mg of telmisartan and 5 mg of silnidipine.

That is, as a result of the experiments of the present inventors, when the pharmaceutical composition for lowering blood pressure includes two active ingredients in the above-mentioned amounts of 1) to 5), these two active ingredients are most effective. It has been found that the synergistic effect is such that the blood pressure lowering pharmaceutical composition can exhibit the best blood pressure lowering effect under the same content or at the same dose of each active ingredient. Accordingly, the pharmaceutical composition for lowering blood pressure containing each active ingredient in such a content shows an excellent blood pressure lowering effect by an excellent synergistic effect of these active ingredients, while the content of each active ingredient decreases, thereby greatly reducing the risk of side effects. Can be.

Meanwhile, as described above, the blood pressure lowering pharmaceutical composition according to one embodiment of the present invention may be formulated into various formulations for oral or parenteral administration, and these formulations may be obtained by methods and configurations apparent to those skilled in the art. have. However, the pharmaceutical composition is preferably formulated in an oral dosage form for oral administration, such as capsules or tablets, as in the conventional blood pressure lowering pharmaceutical composition.

In addition, the blood pressure lowering pharmaceutical composition according to an embodiment of the present invention may further include a diluent or excipient such as fillers, extenders, binders, wetting agents, disintegrating agents or surfactants generally used according to the form of each formulation. .

In addition, the pharmaceutical composition according to the embodiment of the present invention is apparent to those skilled in the art based on the weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of the disease of the patient. Can be determined. For example, the pharmaceutical composition comprising 5 to 80 mg of telmisartan and 1.25 to 20 mg of silnidipine may be administered or taken as an oral formulation once to several times per day. However, it will be apparent to those skilled in the art that the dosage or dosage of each active ingredient should be such that it does not cause side effects, including an excessively high content of each active ingredient.

The pharmaceutical composition for lowering blood pressure according to an embodiment of the present invention, due to the excellent synergistic action of the two active ingredients, may contain an equal or better blood pressure lowering effect while including each active ingredient in a reduced content. Therefore, while significantly reducing the risk of side effects due to the high content of each active ingredient, it can exhibit an excellent blood pressure-lowering effect, such as high blood pressure or related diseases, such as heart failure, chronic stable angina or heteroangular angina It can be very preferably used for the treatment or prevention of heart disease, ischemic heart disease, ischemic peripheral circulatory disease, hypertensive renal failure, stroke or atherosclerosis.

On the other hand, as a result of the experiments of the present inventors, the pharmaceutical composition containing telmisartan and silinidipine described above effectively inhibits damage of blood vessels or enlargement of pathological vessels due to stress applied to blood vessels, thereby preventing damage or pathological damage of the blood vessels. It has been found that it can also be effectively used to treat or prevent diseases caused by enlargement of blood vessels.

According to another embodiment of the present invention, there is provided a pharmaceutical composition for inhibiting vascular damage or pathological enlargement of blood vessels comprising an effective amount of telmisartan and silnidipine.

In particular, such pharmaceutical compositions, due to the excellent synergistic action of the two active ingredients of telmisartan and silnidipine, are very effective against damage or pathological enlargement of the blood vessels even when using each of these active ingredients alone. It has been found that it can be suppressed.

Accordingly, the pharmaceutical composition may be used for various diseases caused by damage or pathological enlargement of the blood vessels (Korshunov VA, Schwarz SM, Berk BC. Vascular remodeling: hemodynamic and biochemical mechanisms underlying Glagov's phenomenon.Arterioscler Thromb Vasc Biol. 2007; 27: 1722 -1728; Marjo MPC Donners, Sylvia Heeneman, Mat JAP Daemen.Models of atherosclerosis and transplant ateriosclerosis: the quest for the best.Drug Discovery Today.2004; 1 (3); 257-263 et al.), For example, Atherosclerosis such as atherosclerosis; Aneurysms or varicose veins, such as aortic aneurysms or dissections, aneurysms of other arteries, varicose veins of the legs, or varicose veins of other sites; Various vascular diseases such as peripheral vascular disease, arterial embolism, arterial thrombosis, venous embolism, venous thrombosis, stenosis of arteries, stenosis of veins, phlebitis, thrombophlebitis, portal thrombosis or capillary diseases; Cerebral infarction due to thrombus, embolism, occlusion or stenosis of cerebral artery or cerebral artery, cerebral infarction due to cerebral vein thrombosis; It can be preferably applied to treat or prevent various diseases such as.

On the other hand, the pharmaceutical composition according to another embodiment of the present invention may have a configuration similar to that of the blood pressure lowering pharmaceutical composition according to one embodiment of the invention, except that the pharmaceutical use is different.

For example, the pharmaceutical composition may include 5 to 80 mg of telmisartan and 1.25 to 20 mg of silnidipine, and may include telmisartan: silnidipine in a weight ratio of 64: 1 to 1: 4.

In addition, the pharmaceutical compositions may be formulated in oral administration or dosage form such as capsules or tablets, and these capsules or tablets may be obtained by applying conventional excipients and methods according to the respective formulation form.

In addition, the pharmaceutical composition may be determined by the person skilled in the art in consideration of the weight, age, sex, health status, diet, administration time, administration method, excretion rate and severity of the disease, etc. For example, the pharmaceutical composition comprising 5 to 80 mg of telmisartan and 1.25 to 20 mg of silnidipine may be administered or taken as an oral formulation once to several times per day.

As described above, according to the present invention, due to the excellent synergism of telmisartan and silnidipine, even under the content or dosage of each single active ingredient, a better blood pressure lowering effect or inhibition of blood vessel damage or pathological hypertrophy Pharmaceutical compositions may be provided that produce the effect.

Thus, such pharmaceutical compositions contain each single active ingredient in a reduced amount, thereby reducing the risk of adverse effects of overuse of each active ingredient, while providing better pharmaceutical activity under the content or dosage of each single active ingredient. Can be represented.

Therefore, the pharmaceutical composition can be very preferably used for treating or preventing various diseases due to hypertension or related diseases or damage or pathological enlargement of blood vessels.

Hereinafter, preferred preparation examples and experimental examples are provided to help the understanding of the present invention, but the following examples are merely to illustrate the present invention, and the scope of the present invention is not limited to the following examples.

Experimental Example 1 Blood Pressure Drop Test

(1) test model and method

Tests were conducted on SHR (Spontaneously hypertensive rat, SHR / NCrlCrlj; Pinto YM, Paul M, Ganten D., Lessons from rat models of hypertension: from Goldblatt to genetic engineering. Cardiovasc. Res. 1998 Jul; 39 1): 77-88; Lilach O. Lerman, Alejandro R. Chade, Vincenzo Sica and Claudio Napoli, Animal models of hypertension: an overview.J. Lab. Clin.Med. 2005 Sep; 146 (3): 160-73 Dataquest IV telemetry system (Data Sciences International, USA; Anderson NH, Devlin AM, Graham D, Morton JJ, Hamilton CA, Reid JL, Schork NJ, Dominiczak AF., Telemetry for cardiovascular monitoring in a pharmacological) study: new approaches to data analysis.Hypertension.1999 Jan; 33 (1 Pt 2): 248-55; Deveney AM, Kjellström A, Forsberg T, Jackson DM., A pharmacological validation of radiotelemetry in conscious, freely moving rats J Pharmacol Toxicol Methods. 1998 Aug; 40 (2): 71-9 et al.) To measure systolic, diastolic and heart rate. It was performed by the method. The specific method is as follows.

1 to 2 weeks after the acquisition of the stabilized SHR anesthesia (Pentobarbital Sodium, 50 ~ 60 mg / kg BW), the abdominal center of the rat was incised by inserting the catheter of the sensor into the abdominal aorta and confirmed the bleeding and sutured. After the surgery, antibiotics (Penicillin G Procaine 30,000 IU, Penicillin G Sodium 10,000 IU) were administered intramuscularly to suppress infection by surgery. The recovery period of the animals was set for about 2-3 weeks after the insertion operation. After recovery, the blood pressure (contraction systolic criterion) of each subject was checked by a telemetry system (DataquestTM ARTTM Version 3.1), and the stabilized 3-day blood pressure average value was set as the baseline value. Drug administration was started for individuals in the range of ≦ ± 5 mmHg by comparing the mean values from 00 to 08:59. Blood pressure and heart rate were measured by systolic blood pressure (SBP), diastolic BP (DBP), mean of arterial pressure (MAP) It was measured by collecting data on the HR (Hart Rate). Drug doses were administered once daily to animals in a random, blinded cross-over model, and the number of individuals administered was 8 or more, as shown in the following drug administration group.

(2) Setting and administration method of drug administration group

The dose and drug administration group of the drug administered to the experimental rat were set as follows.

Telmisartan was converted to T5 group by converting 80 mg of human commercially available dose into T5 group, T4 group was 1/2 dose of T5 group, T3 group was 1/2 dose of T4 group, T2 group. Is set to 1/2 the dose of T3 group, T1 to the 1/2 dose of T2 group.

In the same manner, silinidipine was converted into a C5 group by converting a commercially available high dose of 20 mg into a dose for rats, and the C4 group was 1/2 dose of C5 group, C3 group was 1/2 dose of C4 group, The C2 group was set to 1/2 dose of the C3 group and the C1 group to 1/2 dose of the C2 group.

The conversion of human doses to rats is based on body surface area: animal dose (in mg / kg) = HED (human equivalent dose, in mg / kg, based on 60 kg) / BSA-CF (body surface area dose) Guidance for Industry and Reviewers-Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers: Table 3) (see Conversion of Animal Doses to Human Equivalent Doses (HED) Based on Body Surface Area, etc.) Calculated.

(3) Result processing and statistical analysis

All results collected from the Telemetry System during the test were treated with AOC (Area Over the Curve, mmHgxhour), using OriginPro Version 7.5 SP6 (OriginLab Corp., USA). At this time, the AOC is based on the area for 24 hours of the hourly blood pressure measurement result graph before drug administration, and the area for 24 hours on the hourly blood pressure measurement result graph after drug administration is calculated as a result, and the difference between these results and the standard Defined by value. This is to evaluate the degree of blood pressure lowering effect for 24 hours according to drug administration in each administration group.

In addition, all test results are expressed in Mean and Standard Error Mean (SEM), and the Interaction index (Ronald J. Tallarida., The interaction index: a measure of drug synergism.Pain. Lee JJ, Kong M, Ayers GD, Lotan R. Interaction index and different methods for determining drug interaction in combination therapy.Refer to Journal of Biopharmaceutical Statistics, 2007.17: 461-480, et al. 2002.98: 163-168; The synergistic effect of co-administration was evaluated and commercialized program of PharmTools PRO Version 1.1 (McCary Group, USA; Ronald J. Tallarida.Drug synergism and dose-effect data analysis. Chapman & Hall / CRC, 2000, etc.). Was evaluated using.

The types and drug doses of the administered drugs of each drug-administered group calculated as a result of the measurement are shown in Tables 1 and 2 below, together with the AOC results obtained from each drug-administered group (that is, the degree of blood pressure drop during 24 hours following drug administration) Table 1) and Interaction index results (see Table 2) measured to assess the synergistic effects of these drugs in the two drug administration groups are shown in Tables 1 and 2 below.

TABLE 1

AOC Result (mm Hg x Hour) Drug administration group (drug type and dose) Average Standard error Example 1 (T5 C3) 647.96 63.147 Example 2 (T4 C4) 495.58 75.305 Example 3 (T3 C5) 444.02 33.830 Example 4 (T3 C4) 383.87 61.809 Example 5 (T3 C3) 401.75 30.356 Example 6 (T3 C2) 370.02 61.510 Example 7 (T2 C5) 366.73 82.480 Example 8 (T2 C3) 293.82 54.806 Example 9 (T2 C2) 313.48 29.827 Example 10 (T2 C1) 275.96 60.735 Example 11 (T1 C3) 246.49 47.666 Comparative Example 1 (T5) 497.92 37.806 Comparative Example 2 (T4) 478.88 52.332 Comparative Example 3 (T3) 305.46 31.170 Comparative Example 4 (T2) 226.16 25.035 Comparative Example 5 (T1) 153.15 15.425 Comparative Example 6 (C5) 210.04 53.213 Comparative Example 7 (C4) 121.17 61.142 Comparative Example 8 (C3) 104.73 45.327 Comparative Example 9 (C2) 80.68 47.615 Comparative Example 10 (C1) 67.95 30.361

TABLE 2

Synergistic assessment Drug administration group (drug type and dose) Interaction index Synergism Average Standard error Example 1 (T5 C3) 0.393 0.116 O Example 2 (T4 C4) 0.602 0.109 O Example 3 (T3 C5) 0.444 0.067 O Example 4 (T3 C4) 0.691 0.086 O Example 5 (T3 C3) 0.602 0.078 O Example 6 (T3 C2) 0.759 0.090 O Example 7 (T2 C5) 0.411 0.072 O Example 8 (T2 C3) 0.689 0.090 O Example 9 (T2 C2) 0.582 0.067 O Example 10 (T2 C1) 0.764 0.093 O Example 11 (T1 C3) 0.539 0.109 O

* If the mean ± standard error of the interaction index is less than 1, there is a synergism of the two active ingredients.

Referring to Table 1, Example 1 vs Comparative Example 1, Example 2 vs Comparative Example 2, Examples 3 to 6 vs Comparative Example 3, Examples 7 to 10 vs Comparative Example 4 and Example 11 vs Comparative Example 5 Through comparison, it was confirmed that when telmisartan and silnidipine were administered in combination or in combination, a better blood pressure lowering effect was observed at the same dose of telmisartan compared to telmisartan alone.

Similarly, Example 3, 7 vs Comparative Example 6, Example 2, 4 vs Comparative Example 7, Example 1, 5, 8, 11 vs Comparative Example 8, Example 6, 9 vs Comparative Example 9 and Example Compared to 10 vs Comparative Example 10, when telmisartan and cilnidipine were administered in combination or in combination, a better blood pressure lowering effect was observed at the same dose of silnidipine as compared to when silnidipine was administered alone. It is confirmed.

In particular, referring to Table 2, when telmisartan and silnidipine are administered in combination or in combination, most of the active ingredients have an Interaction index of less than 1, and the two active ingredients are elevated. It is confirmed that the blood pressure lowering effect can be better than that simply predicted by the combination of each of the active ingredients which is better.

Therefore, according to the use of a pharmaceutical composition comprising a combination or combination of the two active ingredients, it is confirmed that a superior blood pressure lowering effect can be exhibited by the excellent synergism of these active ingredients, accordingly, It is also confirmed that the content can be further reduced to significantly reduce the risk of side effects due to overuse of each active ingredient.

Experimental Example 2: Test of the Inhibitory Effect of Vascular Injury and Pathological Hypertrophy

(1) test model and method

Tests were performed using C57BL / 6 mouse (9-10 week-old, 25-30 g), Cuff-placement protocol (Masatsugu Horiuchi, Tai-Xing Cui, Zhen Li, Jian-Mei Li, Hironori Nakagami and Masaru Iwai. Fluvastatin Enhances the Inhibitory Effects of a Selective Angiotensin II Type 1 Receptor Blocker, Valsartan, on Vascular Neointimal Formation. Circulation. 2003; 107: 106-112, etc.). The specific method is as follows.

With the incision of the femoral part of the mouse, the femoral vein is separated from the surrounding tissue, and a longitudinally incised polyethylene tube (2-mm long PE-0; inner diameter, 0.86 mm; outer diameter, 1.27 mm; Becton-Dickinson) Wrapped around the artery, the incision was closed again. This method is a cuff-placement protocol, and is an experimental model in which the intima of blood vessels due to blood vessel damage is enlarged pathologically. After 7 days, DNA synthesis in the intima was measured using bromodeoxyuridine (BrdU) to accurately measure the vascular endothelial hypertrophy. Bromodeoxyuridine (BrdU) was administered subcutaneously by 100 mg / kg, intraperitoneally by 30 mg / kg 18 hours before lethality, and intraperitoneally by 30 mg / kg 12 hours before administration. After the death due to excessive anesthesia of the animals, arteries in which the cuff was installed were collected and fixed through tissue treatment. Sections of fixed tissues were prepared and stained with hematoxylin. The number of stained nuclei and the total nuclei from the final tissue sections were measured and used for the results.

(2) setting and administration method of drug administration group

The dose and drug administration group of the drug administered to the experimental rat were set as follows.

Telmisartan was converted to the T group by converting 80 mg of a commercial high dose of human into a dose for rats. Was set. In addition, the T + C group was set to co-administer telmisartan and silnidipine at each dose converted above.

The conversion of human doses to rats is based on body surface area: animal dose (in mg / kg) = HED (human equivalent dose, in mg / kg, based on 60 kg) / BSA-CF (body surface area dose) Guidance for Industry and Reviewers-Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers: Table 3) (see Conversion of Animal Doses to Human Equivalent Doses (HED) Based on Body Surface Area, etc.) Calculated.

(3) result processing and statistical analysis

Test results were measured in% by BrdU index (= BrdU-positive nuclei / total nuclei) and expressed as mean (Mean) and standard error (Standard Error Mean, SEM).

The type and drug dose of the administered drug of each drug-administered group calculated as a result of the measurement are shown in Table 3 below, and the BrdU index results obtained in each drug-administered group are shown in Table 3 below.

[Table 3]

BrdU Index (%) DNA synthesis inhibition rate (% Cuff control) Drug administration group Average Standard error No cuff 1.10 0.06 Cuff control 21.40 0.26 - C 20.27 0.20 5.30 T 17.03 0.12 20.40 T + C 13.10 0.26 38.79

Referring to Table 3, it is confirmed that when telmisartan and silinidipine are administered in combination or in combination, DNA can be pathologically synthesized by stress applied to blood vessels, thereby effectively inhibiting pathological hypertrophy. .

Particularly, when the telmisartan and the silnidipine are administered in combination or in combination, these two active ingredients exhibit a very good synergistic effect and show a significantly superior inhibitory effect even when each of these active ingredients is administered alone. It is confirmed that it can.

Therefore, by using a pharmaceutical composition comprising a combination or combination of the two active ingredients, it is confirmed that the excellent synergistic action of these active ingredients can effectively inhibit blood vessel damage or pathological enlargement, and accordingly It has been found that it can be very preferably used to treat or prevent related diseases such as atherosclerosis or vascular stenosis.

Preparation Example: Preparation of pharmaceutical composition (tablet) comprising telmisartan and silnidipine

To prepare a tablet having the composition of Table 4. First, the silnidipine granules containing lactose monohydrate and the telmisartan spray dried granules containing sorbitol were mixed, and then magnesium stearate and other excipients were added and compressed into tablets.

TABLE 4

ingredient mg / tablet Telmisartan 40 Silnidipine 10 Lactose monohydrate 197 NaOH 3.36 Meglumine 12 Povidone 52 Sorbitol 184 Magnesium stearate 7.5

Claims (18)

A blood pressure lowering pharmaceutical composition comprising an effective amount of telmisartan and silnidipine. A blood pressure lowering pharmaceutical composition comprising only telmisartan and silnidipine as active ingredients. The pharmaceutical composition for lowering blood pressure according to claim 1, comprising 5 to 80 mg of telmisartan and 1.25 to 20 mg of silnidipine. The pharmaceutical composition for lowering blood pressure according to claim 1, comprising 10 to 20 mg of telmisartan and 1.25 to 20 mg of silnidipine. The pharmaceutical composition for lowering blood pressure according to claim 1, comprising telmisartan: silnidipine in a weight ratio of 64: 1 to 1: 4. The pharmaceutical composition for lowering blood pressure according to claim 1, comprising telmisartan: silnidipine in a weight ratio of 8: 1 to 1: 2. The pharmaceutical composition for lowering blood pressure according to claim 1, comprising 80 mg of telmisartan and 5 mg of silnidipine. The pharmaceutical composition for lowering blood pressure according to claim 1, comprising 40 mg of telmisartan and 10 mg of silnidipine. The pharmaceutical composition for lowering blood pressure according to claim 1, comprising 20 mg of telmisartan and 2.5 to 20 mg of silnidipine. The pharmaceutical composition for lowering blood pressure according to claim 1, comprising 10 mg of telmisartan and 1.25 to 20 mg of silnidipine. The pharmaceutical composition for lowering blood pressure according to claim 1, comprising 5 mg of telmisartan and 5 mg of silnidipine. The pharmaceutical composition for lowering blood pressure according to claim 1, formulated in an oral dosage form, The pharmaceutical composition for lowering blood pressure according to claim 1, which is used for the treatment or prevention of hypertension, heart failure, coronary heart disease, ischemic heart disease, ischemic peripheral circulatory disease, hypertensive renal failure, stroke or atherosclerosis. Pharmaceutical composition for inhibiting vascular damage or pathological hypertrophy of blood vessels comprising an effective amount of telmisartan and silnidipine. A pharmaceutical composition according to claim 14 comprising 5 to 80 mg of telmisartan and 1.25 to 20 mg of silnidipine. The pharmaceutical composition of claim 14 comprising telmisartan: silnidipine in a weight ratio of 64: 1 to 1: 4. The pharmaceutical composition according to claim 14, formulated orally. 15. The disease according to claim 14, wherein atherosclerosis, aneurysms, varicose veins, peripheral vascular disease, arterial embolism, arterial thrombosis, venous embolism, venous thrombosis, stenosis of the arteries, vein stenosis, phlebitis, thrombophlebitis, portal thrombosis, capillary disease, A pharmaceutical composition for use in the treatment or prevention of cerebral infarction due to thrombus, embolism, occlusion or stenosis of cerebral artery or cerebral artery, or cerebral infarction due to cerebral vein thrombosis.