KR101414814B1 - Complex formulation comprising lercanidipine hydrochloride and valsartan and method for the preparation thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition characterized by containing Lercanidipine HCl and Valsartan as an active ingredient, and a process for producing the same. The lercanidipine hydrochloride and valsartan-containing pharmaceutical composition according to the present invention alleviates side effects of the existing single preparations, and exhibits a preventive and therapeutic effect on the improved cardiovascular diseases and their multiple diseases, and is effective in preventing lercanidipine hydrochloride and valsartan The advantage of increasing the dissolution rate of lercanidipine hydrochloride and valsartan hydrochloride and reducing the side effects.

Description

The present invention relates to a combination preparation comprising lercanidipine hydrochloride and valsartan and a preparation method thereof,

The present invention relates to a pharmaceutical composition characterized by containing Lercanidipine HCl and Valsartan as an active ingredient, and a process for producing the same.

Hypertension is the most common cardiovascular disease, which causes an increase in the blood pressure of the kidneys, heart, and brain to increase the incidence of renal failure, coronary artery disease, heart failure, and stroke. Hypertension is divided into essential hypertension and secondary hypertension. Essential hypertension refers to the case in which the cause of the hypertension is not clearly understood, that is, the blood pressure is high even without a specific cause disease. Most of the hypertensive patients (about 95%) correspond to this, and people in their 40s or older belong to this type. Although there is no causative disease, accurate identification of the cause is difficult, but problems such as genetic predisposition, eating habit, obesity, aging, stress, excessive smoking and drinking can be problems. Secondary hypertension is a condition in which blood pressure is increased secondary to a specific disease. About 5% of patients with hypertension are those who are relatively young. It is mainly caused by nephritis, endocrine abnormality, and addiction to pregnancy, and blood pressure naturally lowers when the causative disease is treated.

Because antihypertensive therapy is not usually a treatment for specific causes, this treatment relies on blocking normal physiological mechanisms that regulate blood pressure. Since antihypertensive therapy is performed in patients with no symptoms, this treatment does not directly alleviate the patient's discomfort, but instead has the advantage of preventing blood disease and death from ever occurring by reducing blood pressure.

The blood pressure lowering agent that lowers blood pressure is divided into three types of diuretics, sympathetic blockers, and vasodilators depending on the main control site and mechanism. A diuretic is a drug that releases water and salts from the body by increasing the amount of urine. Reduce the amount of water and salt in the body to lower blood pressure. The sympathetic nerve increases the number of contractions of the heart, tightens the contraction, and contracts the blood vessels. The drug that reduces the blood pressure is a sympathetic inhibitor. Alpha-blockers that inhibit sympathetic nerves that constrict blood vessels, beta-blockers that suppress sympathetic nerves that constrict the heart, and central sympathetic nervous system inhibitors that act on the brain to suppress sympathetic nerves. Vasodilators are drugs that lower blood pressure by expanding blood vessels. First, there is an ACE inhibitor which inhibits the production of angiotensin II, a vasoconstrictor, and an angiotensin II receptor blocker, which inhibits the action of angiotensin II. In addition, as the calcium in the cells increases, the blood vessels contract and the blood pressure rises. Therefore, the calcium channel blockers that lower the blood pressure by inhibiting the entry of calcium into the cells also belong to the vasodilators.

If the degree of hypertension is so severe that you do not see a sufficient blood pressure lowering effect, the dose of the drug is usually increased. However, if you increase the dosage forcibly, the possibility of side effects increases accordingly. In this case, instead of increasing the amount of one drug, taking a small amount of drugs with different effects is a way to minimize the side effects while showing sufficient effect.

The merits of this combination therapy are

First, it is possible to increase the blood pressure lowering effect by using different drugs and acting simultaneously on various mechanisms. In addition, the homeostatic compensation of one drug is inhibited by other drugs, so that the effect of blood pressure drop more effectively. For example, reflex tachycardia, salt and water retention that can occur when using vasodilators, and reflex tachycardia can increase the effect of blood pressure lowering because the diuretic can control the salt and water retention of the beta-blocker.

Second, combination therapy can result in sufficient blood pressure lowering effects even at low doses, thus reducing dose-dependent side effects. In addition, side effects caused by pharmacological action can be blocked to reduce side effects.

Third, hypertension should be controlled for lifetime but there is almost no subjective symptom. Therefore, it is said that maintaining compliance with the patient 's medication influences the success or failure of treatment. It is effective, has few side effects, and can improve the quality of life Combination therapy can increase compliance.

In recent years, complex drugs made by mixing two or more drugs with one egg are commercially available. Therefore, if they are used well, they can be easily medicated and their value is lowered to further improve compliance, delay the damage of target organs due to hypertension Can be prevented.

Under these circumstances, the present inventors intensively conducted research to develop a novel composition which improves therapeutic effect, alleviates side effects, and improves compliance by causing two or more hypertensive therapeutic agents having different action mechanisms to act synergistically with each other As a result, it has been found that the use of known lercanidipine hydrochloride and valsartan in combination can achieve this purpose, and in particular, a combination preparation having a specific structure containing them can be preferably used for this purpose. Thereby completing the invention.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cardiovascular diseases, which comprises lercanidipine hydrochloride and valsartan as active ingredients having different action mechanisms.

In particular, the present invention provides a combination preparation comprising lercanidipine hydrochloride and valsartan, wherein lercanidipine hydrochloride and valsartan are contained separately.

It is still another object of the present invention to provide a method for producing a combination preparation for prevention or treatment of cardiovascular diseases containing lercanidipine hydrochloride and valsartan as an active ingredient.

Lercanidipine HCl is a dihydropyridine calcium antagonist. Like other calcium antagonists, it also inhibits calcium entry into arterial smooth muscle cells and relaxes the peripheral arterioles, reducing blood pressure. Lercanidipine does not cause negative myocardial contractions, but only mild reflex tachycardia. This has a high affinity for the dihydropyridine subunit of the L-type calcium channel and competitively antagonizes it. Calcium channel antagonists are considered safe and have proven effective against all types of hypertension. Lercanidipine is a new type of calcium antagonist of the dihydropyridine class, which has been shown to have potent hypotensive effects and long duration of action in preclinical studies. Lercanidipine is well tolerated at doses of 30 mg or less and causes blood pressure to drop in a dose-dependent manner. Calcium antagonists are considered as a kidney protectant due to their antihypertensive action. This possibility has been demonstrated in renal failure and toxicity caused by cancer chemotherapy, radiological contrast agents, cyclosporine or aminoglycoside antibiotics. Calcium antagonists may also have protective effects on donor kidneys during kidney transplantation. Lercanidipine is usually used in a dose of 10 mg to 20 mg once daily, with a maximum dose of about 30 mg per day. Lercanidipine is rapidly absorbed after oral administration, and the maximum plasma level appears after 1.5 to 3 hours of administration, but it is subject to extensive saturating first pass metabolism. Absorption is highly dependent on food intake, so simultaneous ingestion of food increases the uptake significantly (3 to 4 times). For oral administration, allergic Carney dipin is formulated as a tablet containing, 10mg or 20mg tablet currently under the trade name janidip ^® sold. Lercanidipine is commercially available from Recordati SpA (Milan, Italy) and may be prepared as described in EP 153016 and US 4,705,797, the entire contents of which are incorporated herein by reference. In addition, US-A1-2003 / 0180355 discloses a method of treating hypertension patients, comprising administering a combination preparation comprising lercanidipine and enalapril, the active ingredients.

((S) -N-valeryl-N - {[2 '-( 1H-tetrazol-5-yl) Is an angiotensin II receptor blocker that functions to lower blood pressure through vasodilation. This may be commercially available (other rekjeong ^®) And may be produced according to known methods. For example, the preparation of valsartan is described in U.S. Patent No. 5,399,578, the entire contents of which are incorporated herein by reference. Valsartan can be used for purposes of the present invention in any suitable salt form as well as the free form. Valsartan is an antihypertensive drug in the United States with an initial dose of 80-160 mg qd and can be prescribed up to 320 mg qd. In Korea, 160 mg bid is prescribed to patients after heart failure or myocardial infarction, but substitution is made with other drugs if 160 mg qd does not reach target blood pressure. Valsartan is typically used in an amount in the range of from about 40 mg to about 320 mg, preferably from about 80 mg to about 320 mg, and most preferably in an amount of about 80 mg or about 160 mg in the tablet.

The present inventors have conducted various experiments on lercanidipine hydrochloride and valsartan hydrochloride, which exhibit the above-mentioned mechanism of action and the maximum daily dose, and when they are used in combination, they act synergistically to each other, And it is confirmed that there is an advantage of improving the compliance of the patients and reducing the side effects of the drugs used respectively. Accordingly, the pharmaceutical composition of the present invention containing lercanidipine hydrochloride and valsartan can be effectively used for prevention or treatment of cardiovascular diseases. Examples of cardiovascular diseases include, but are not limited to, angina, hypertension, arterial spasm, cardiac arrhythmia, cardiomyopathy, cerebral infarction, congestive heart failure, and myocardial infarction.

However, the combination preparation of the present invention containing lercanidipine hydrochloride and valsartan may cause some problems in the case of simple compounding of lercanidipine hydrochloride and valsartan due to differences in inherent physical properties thereof .

The first problem is the difference in the pKa value of each component. The pKa of lercanidipine hydrochloride is about 6.83, and the pKa of valsartan is about 3.92. Therefore, lercanidipine hydrochloride has a high solubility at pH below 4.0 and solubility at pH 4.0 or higher as opposed to valsartan. This difference in pKa value affects the solubility of each component.

The second problem is the gelation of valsartan. Valsartan has a low solubility at pH 4.0 or lower, and gelation proceeds and dissolves very slowly. This dissolution delay phenomenon causes a problem of delaying the absorption in the small intestine of valsartan. In addition, the gelation of valsartan may lead to a problem of lowering to the elution of lercanidipine hydrochloride. This phenomenon can have a significant impact on the absorption of lercanidipine hydrochloride, which is rapidly disintegrated in the gastrointestinal tract. Therefore, it is necessary to develop a preparation that does not gel valsartan even under low pH conditions.

The third problem is that when the combination preparation of lercanidipine hydrochloride and valsartan is performed by wet granulation simultaneously, the dissolution rate of the drug is lowered due to the interaction of the two components, Which greatly influences the absorption and bioavailability of the two drugs. A new formulation approach is needed to improve the drug efficacy of the combination preparation due to the change in bioavailability.

The fourth problem is that it is difficult to achieve the purpose of maintaining the inherent dissolution pattern with a common formulation method because there is a difference in disintegration time of the single commercially available products.

In order to overcome the above-mentioned problems, the inventors of the present invention have devised a complex formulation which physically separates lercanidipine hydrochloride and valsartan to minimize contact area and opportunity. Thus, the combined preparation provided can provide an excellent dissolution rate for each of lercanidipine hydrochloride and valsartan.

The pharmaceutical composition containing lercanidipine hydrochloride and valsartan hydrochloride according to the present invention alleviates the adverse effects of the existing single agent by synergistic combination of drugs having different mechanism of action and at the same time prevents the improvement of the cardiovascular diseases and their complex diseases And therapeutic effects. In addition, according to the present invention, a combination preparation comprising lercanidipine hydrochloride and valsartan is advantageous in that the dissolution rate is improved by overcoming the problems associated with the combination of lercanidipine hydrochloride and valsartan.

Fig. 1 is a graph comparing results of leucandin hydrochloride dissolution tests on the combination preparation of Examples 1 to 4 and the preparation of Comparative Example 1 according to the present invention.
FIG. 2 is a graph comparing results of leucandyin hydrochloride dissolution tests on the combination preparation of Examples 5 to 8 and the preparation of Comparative Example 1 according to the present invention.
Fig. 3 shows the results of the leucandin hydrochloride dissolution test of the combination preparation of Examples 1 to 4 and the combination preparation of Examples 9 to 12 in comparison.
Fig. 4 is a graph comparing results of lercanidipine hydrochloride dissolution test on the combined preparation of Example 1 and Example 13; Fig.
FIG. 5 is a graph comparing results of lercanidipine hydrochloride dissolution tests on the combination preparation of Example 1 and the preparations of Comparative Examples 2 and 3 according to the present invention.
Figure 6 shows the change in systolic blood pressure over time after concomitant administration of 2 mg / kg (Z) + valsartan 16 mg / kg (V) of lercanidipine hydrochloride according to Test Example 8 ( ^{**) *} P <0.001 (vs control), ^## P <0.01 (vs valsartan)).
7 shows the change in mean blood pressure (%) after combination administration of lercanidipine hydrochloride 2 mg / kg (Z) + valsartan 16 mg / kg (V) according to Test Example 8 ( ^{**) *} P <0.001 (vs control), ^## P <0.01 (vs valsartan)).
Figure 8 shows changes in diastolic blood pressure over time after concomitant administration of 2 mg / kg (Z) + valsartan 16 mg / kg (V) of lercanidipine hydrochloride according to Test Example 8 ( ^{**) *} P <0.001 (vs control), ^## P <0.01 (vs valsartan)).
9 shows the changes in heart rate (%) after combination administration of lercanidipine hydrochloride 2 mg / kg (Z) + valsartan 16 mg / kg (V) according to Test Example 8 ( ^*** P < 0.001 (vs control), ^## P < 0.01 (valsartan)).

In one preferred embodiment of the present invention, in order to prepare a combination preparation in which lercanidipine hydrochloride and valsartan are separated from each other, lercanidipine hydrochloride and valsartan are each granulated to prepare a lercanidipine-valsartan hydrochloride complex preparation Respectively.

The combination preparation

(a) wet granulating and drying a mixture of lercanidipine hydrochloride and a pharmaceutically acceptable excipient;

(b) wet granulating and drying a mixture of valsartan and a pharmaceutically acceptable excipient; And

(c) mixing the dry granules of the valsartan granules of step (b) with the dried granules of lercanidipine hydrochloride of step (a).

For example, a complex tablet can be prepared by preparing lercanidipine hydrochloride granules and valsartan granules separately, and mixing the two granules to be tableted. Compared with the combination preparation of Comparative Example 1, which was a tablet prepared by wet granulation of a non-separated mixture of lercanidipine hydrochloride and valsartan, the combined preparation of Examples 1 to 4 thus prepared had an effect on the dissolution rate of valsartan And further shows the dissolution rate of lercanidipine hydrochloride (see Fig. 1).

In another specific embodiment, the present invention provides a composite bilayer of lercanidipine hydrochloride and valsartan. As described in Examples 5 to 8 below, the granules of valsartan granules are compressed into primary granules by using a two-layer tablet machine, and granules of lercanidipine hydrochloride granules are granulated by secondary granules to obtain composite granules. Composite Double Layer Degree According to the Present Invention The excellent leucandinin hydrochloride dissolution rate (see FIG. 2) is similar to the combined preparation of Examples 1 to 4.

In a further embodiment, the composite bilayer tablet may further comprise a separating layer between the contact surfaces of the lauranide hydrochloride layer and valsartan layer. That is, a composite three-layer tablet having an additional separation layer can be produced. As a constituent component of the separation layer, for example, microcrystalline cellulose can be used.

In another embodiment, the combination preparation of the present invention in which lercanidipine hydrochloride and valsartan are separated may be tablets coated with lercanidipine hydrochloride in a tablet made of valsartan. Such preparations can be prepared by dissolving or dispersing lercanidipine hydrochloride together with excipients in a coating solvent and coating the tablets with valsartan. As the excipient, for example, polyvinyl pyrrolidone can be used, and as the coating solvent, ethanol can be used. At this time, if necessary, another separation layer may be provided between the valsartan purified portion and the lercanidipine hydrochloride coated portion.

In the preparation of the combination preparation according to the present invention, lercanidipine hydrochloride and valsartan as active ingredients are mixed with 4 to 32 parts by weight, preferably 4 to 16 parts by weight of valsartan, based on 1 part by weight of lercanidipine hydrochloride, . If the amount of valsartan is less than 4 parts by weight based on 1 part by weight of lercanidipine hydrochloride, a desired effect can not be obtained, and more than 32 parts by weight is not allowed.

The composition for preventing or treating cardiovascular diseases of the present invention may further comprise a pharmaceutically acceptable carrier or excipient in the granules of lercanidipine hydrochloride and granules of valsartan, respectively. Pharmaceutically acceptable carriers or excipients include, for example, microcrystalline cellulose, lactose, low substituted hydroxypropylcellulose, disintegrants (e.g., croscarmellose sodium, crospovidone, sodium starch glycolate) (For example, polyvinylpyrrolidone, hydroxypropylcellulose) can be mentioned. In addition, lubricants such as colloidal silicon dioxide, hydrous silicon dioxide, magnesium stearate, sodium stearyl fumarate (trade name: Pruv), glyceryl behenate (trade name: compritol 888), calcium stearate, stearic acid and talc may be included.

In the present invention, the lercanidipine hydrochloride granules may comprise from 4 to 10 parts by weight of a pharmaceutically acceptable excipient per 1 part by weight of lercanidipine hydrochloride, wherein the granules of valsartan comprise 1 to 2 parts by weight of a pharmaceutically acceptable excipient per 1 part by weight of valsartan Section. These quantitative ratios apply to all formulations of the invention, including isolated granules. If the ratio is exceeded, the tablets may become too small or too large and the elution may be delayed or accelerated.

In particular, it is necessary to pay attention to the ratio of the disintegrant among the excipients used according to the present invention. Croscamellose sodium, crospovidone, sodium starch glycolate and the like, which are commonly used super-disintegrants, are generally recommended to be used in an amount of about 0.5 to 8.0% by weight based on the total weight of the excipient. However, the super-disintegrant is used in an amount of about 5 to 20% by weight based on the total weight of the excipient in order to prevent gelation and to exhibit inherent dissolution behavior due to the characteristics of the present invention. If such an excessive amount of super disintegrant is used, it is difficult to coat due to rapid wetting in a general coating formulation, and there may occur a problem that a coating film is blown during storage. However, in the present invention, it is confirmed that this problem does not occur.

Examples of the coating agent that can be used for the film coating layer include conventional coating agents such as hydroxypropyl methylcellulose, Opadry series, Eudragit series, and the like, but are not limited thereto.

Hereinafter, the present invention will be described in detail with reference to examples. However, the examples are illustrative of the present invention, and the scope of the present invention is not limited in any sense.

Example  1 to 4: Preparation of isolated granules

[Table 1]

Granules of lercanidipine hydrochloride and granules of valsartan of the above composition were wet-granulated using purified water, dried, and sized to 25 mesh. The two granules were mixed and then tableted to obtain a complex tablet and film-coated. As the film coating machine, Opaquid 2 of the pvp series of Colorcon was used, and film coating was carried out in the same manner in all Examples and Comparative Examples below. The coalescence time was sufficient for 5 minutes or more so that the super-disintegrant added at wet granulation could be sufficiently wetted. Such a sufficient coalescence time increases the porosity of the granules, thereby exhibiting a property of promoting disintegration time, thereby preventing gelation. In the following examples, all of the wet granulation processes were carried out in the same manner as described above.

Example  5 to 8: Manufacture of composite double layer definition

[Table 2]

Granules of lercanidipine hydrochloride and granules of valsartan of the above composition were wet-granulated using purified water, dried, and sized to 25 mesh. The valsartan granulate and the lercanidipine hydrochloride granules were squeezed into a bilayer solid dosage form and the formed bilayer solid dosage form was film coated.

Example  9 to 12: Compound Three-layer definition  Produce

[Table 3]

Granules of lercanidipine hydrochloride and granules of valsartan of the above composition were wet-granulated using purified water, dried, and sized to 25 mesh. The granules of valsartan were added and the first purified portion was tableted, the separation layer was added, the second purified portion was compressed, and then the third purified portion was compressed by adding lercanidipine hydrochloride granules. Composite three-layered tablets were obtained and film coated.

Example  13: The lercanidipine hydrochloride layer  Preparation of Coated Tablets

[Table 4]

The granules of valsartan of the above composition were tabletted to obtain tablets, which were then introduced into a coater. A coating layer in which lercanidipine hydrochloride and polyvinylpyrrolidone were dissolved and suspended in ethanol was sprayed onto valsartan tablets to be coated and then film-coated.

Comparative Example  One: Lercanidipine hydrochloride  And Valsartan  Preparation of Unseparated Mixed Wet Tablets

[Table 5]

The same amounts of lercanidipine hydrochloride, valsartan and excipients as in Example 1 were mixed together, wet granulated, and then tableted. The tablets were film coated.

Comparative Example  2: Commercial product  Simple mixed tablet of granules

[Table 6]

After preparing the commercially available hydrochloric acid Carney dipin allergic agents (janidip information ^®) and valsartan formulation (L rekjeong ^®) a mixture of the same composition after a simple purification appointed other to prepare a granulate with the coated film.

Comparative Example  3: Lercanidipine hydrochloride Commercial product

[Table 7]

Commercially available acid Carney dipin allergic agents (janidip information ^®) &Lt; tb &gt;&lt; TABLE &gt;

Test Example  One: Example  1 to 4 &lt; / RTI &gt; Lercanidipine hydrochloride  Dissolution test

The composite tablets prepared in Examples 1 to 4 and the unmixed mixture wet composite tablets prepared in Comparative Example 1 were subjected to a dissolution test under the following conditions and compared.

&Lt; Dissolution condition >

Eluent: pH 1.2 (900 mL)

Apparatus: USP paddle method, 50 rpm

Temperature: 37 ° C

<Analysis condition>

Column: A column filled with octadecylsilylated silica gel for liquid chromatography of 5 mu m in a stainless steel tube having an inner diameter of about 4.6 mm and a length of 15 cm

Mobile phase: Acetonitrile / pH 3.0 Sodium Perchlorate Buffer (60/40)

Flow rate: about 1.0 mL / min

Detector: ultraviolet absorption spectrophotometer (measuring wavelength 240 nm)

<Result>

As confirmed by FIG. 1, the dissolution rates of the preparations according to Examples 1 to 4, which were lercanidipine-valsartan hydrochloride complex preparations made from the separated granules, were initially high compared to the preparations of Comparative Example 1. [

Test Example  2: Preparation of the preparation according to Examples 5 to 8 Lercanidipine hydrochloride  Dissolution test

Separation granules of Examples 5 to 8 and Comparative Example 1 were subjected to a dissolution test under the same conditions as in Test Example 1,

As confirmed by FIG. 2, the dissolution rates of the preparations according to Examples 5 to 8, which were lercanidipine-valsartan hydrochloride complex preparations prepared with the separated granules, were higher than those of the preparations of Comparative Example 1.

Test Example  3: Example  9-12 &lt; / RTI &gt; Lercanidipine hydrochloride  Dissolution test

The wet-mixed tablets of Examples 1 to 4 prepared from the composite three-layered tablets and the separated granules of Examples 9 to 12 prepared from the separated granules were tested for dissolution under the same conditions as in Test Example 1 and compared.

As can be seen in FIG. 3, the dissolution rates of the combined three-layered tablets prepared with the separated granules and the wet-shaped tablets prepared with the separated granules showed similar results.

Test Example  4: Example  13 Lercanidipine hydrochloride  Dissolution test

Separation-coated tablets obtained in Example 13 and wet-mixed tablets obtained in Example 1 were subjected to a dissolution test under the same conditions as in Test Example 1 and compared.

As evidenced by FIG. 4, the dissolution rates of the separate coating tablets and the wet complex tablets were similar.

Test Example  5: Example  One, Comparative Example  2 and Comparative Example  Comparative elution test of preparation according to 3

Dissolution tests were carried out on the complex tablets of Example 1 prepared as the separated granules, the simple mixed tablet of the commercial preparations of Comparative Example 2, and the commercial preparations of Comparative Example 3 under the same conditions as in Test Example 1 and compared.

As shown in FIG. 5, the complex tablet of Example 1 according to the present invention exhibits the same lercanidine hydrochloride dissolution pattern as the lercanidipine hydrochloride commercial formulation of Comparative Example 3, while the commercially available lercanidipine hydrochloride granules The preparation of Comparative Example 2, which was tableted by simple mixing of valsartan granules, showed very low elution of lercanidipine hydrochloride, which appears to be the result of gassing of valsartan.

Test Example 6: Clinical effect by combination administration of lercanidipine hydrochloride and valsartan

To evaluate the efficacy and safety of lercanidipine hydrochloride and valsartan in patients with essential hypertension in combination with each single agent, the following experiment was conducted.

Patients with essential hypertension who were between 20 and 75 years of age and whose blood pressure was 90 mmHg ≤ DBP (diastolic blood pressure) ≤ 109 mmHg at week 0 after 2 weeks of placebo. In order to eliminate the interference effect with the previously used hypertensive drugs and to increase the drug compliance, subjects were allowed to take a placebo for 0 ~ 1 week and a single blind for 2 weeks run-in period. Subjects were randomly assigned to placebo group, single group 4 group, and combined group 4, and subjects were assigned the same probability. Then, according to the following table, the dose combination group, the measurement period and the administration period were set to double- . At this time, hydrochloric acid was used as allergic Carney dipin janidip the commercially available tablet ^® 10 mg, was used for the other rekjeong ^® 80 mg is being marketed valsartan.

[Table 8]

The subject's blood pressure was measured according to the Hypertension Association's blood pressure monitor guidelines for each measurement point, and the change in DBP and systolic blood pressure (systolic blood pressure) (8 weeks-baseline value) was calculated 8 weeks after the baseline value. The superiority was evaluated against the effect of administration.

As a result of the test on 130 patients who met the criteria of 100 mmHg ≤ DBP ≤ 109 mmHg at the time of measurement 3 (0 day), as shown in Table 9 below, the patients who received lercanidipine hydrochloride 20 mg + valsartan 80 mg Both DBP changes and SBP changes in combination with placebo and monotherapy were statistically significant.

In Table 9, Diff indicates the difference in blood pressure change (single-agent administration-change in blood pressure at the time of administration of the combined agent) during the administration of the single agent. Two-side 95% CI was 95% confidence interval Meaning that there is a significant difference when they are large, and so on.

[Table 9]

In addition, patients who met blood pressure at trough time (22 to 26 hours after drug administration) at measurement 5 (56 days) and at 90 mmHg ≤ DBP ≤ 109 mmHg at measurement 3 (0 day) In patients who received lercanidipine hydrochloride 10 mg plus valsartan 160 mg and lercanidipine 20 mg plus valsartan 160 mg, changes in DBP and SBP were statistically significant in both placebo and single agent combinations The difference was proven to be superior, and for patients receiving 20 mg lercanidipine hydrochloride + 80 mg valsartan, both DBP changes and SBP changes were superior only to placebo and lercanidipine hydrochloride 20 mg monotherapy (see Tables 10-12) ).

[Table 10]

[Table 11]

[Table 12]

Test Example  7: With lercanidipine hydrochloride Valsartan  Clinical effect according to concomitant administration

To evaluate the efficacy and safety of lercanidipine hydrochloride and valsartan in patients with essential hypertension in combination with each single agent, the following experiment was conducted.

Patients with essential hypertension who were between 20 and 75 years of age and who had a blood pressure of 95 mmHg ≤ DBP ≤ 114 mmHg at week 0 after 2 to 4 weeks of placebo. In order to eliminate the effects of interference with previously used hypertensive drugs and to increase drug compliance, subjects were allowed to take placebo for one week and a single blind spot for 2 to 4 weeks of run-in. Subjects were randomly assigned to four groups of placebo, single-agent, and single-agent groups at the same probability. Then, according to the following Table 13, dose combination group, measurement period and administration period were set, Respectively. At this time, hydrochloric acid was used as allergic Carney dipin janidip the commercially available tablet ^® 10 mg, was used for the other rekjeong ^® 80 mg is being marketed valsartan.

[Table 13]

The subjects' blood pressure was measured according to the guidelines of the Hypertension Association Blood Pressure Monitor for each measurement point, and the changes in DBP and SBP (8 weeks-baseline value) after 8 weeks compared to baseline were calculated and the superiority Respectively.

As a result of the test for 193 patients satisfying the criteria of 95 mmHg ≤ DBP ≤ 114 mmHg at the time of measurement 3 (0 day), as shown in Table 14, in the case of patients receiving lercanidipine hydrochloride 10 mg + valsartan 80 mg Both the DBP change and the SBP change were statistically significant superior to placebo. In addition, patients receiving lercanidipine 10 mg plus valsartan 80 mg demonstrated a statistically significant superiority in SBP changes compared to patients receiving lercanidipine 10 mg monotherapy.

[Table 14]

Test Example  8: With lercanidipine hydrochloride Valsartan  Concomitant administration In rats  effect

A 13-week-old male SHR (Spontaneous Hypertensive Rat, Orient) was bred for 1 week at a temperature of 22 to 24 ° C and a humidity of 50 to 70% while maintaining a light cycle. Standard diets and negative water were freely consumed.

Test animals were measured for blood pressure and heart rate one day before the administration of the drug using a BP-2000 blood pressure analyzing system (Visitech). After the measurement, it was fasted for about 12 hours. Negative numbers were freely available. Each test substance was orally administered to the fasted test animal at a volume of 5 ml / kg and the same volume of the medium was orally administered to the negative control group. Lercanidipine hydrochloride and valsartan were dissolved in 20% 2-hydroxypropyl-beta-cyclodextrin (HPCD). To increase solubility, 0.5 ml of 1N HCl was added to lercanidipine hydrochloride and 0.05% NaOH 0.5 ml was added to dissolve completely. The changes of blood pressure and heart rate were measured in 2 mg / kg of lercanidipine hydrochloride and 16 mg / kg of valsartan (N = 10) and 16 mg / kg of valsartan alone (N = 10) And statistical analysis was performed. Statistical analysis was performed by one-way ANOVA, and the significance of the test group, the control group, the combination group and the single group was analyzed.

As shown in FIGS. 6 to 9, in the SHR group, 2 mg / kg of lercanidipine hydrochloride and 16 mg / kg of valsartan were given a significant blood pressure lowering than 1 mg of valsartan 16 mg / kg alone and the control group And heart rate increase effect were confirmed. In the group of valsartan 16 mg / kg alone, there was no significant decrease in blood pressure and heart rate compared to the control group.

Claims (13)

delete A pharmaceutical combination for the prevention or treatment of cardiovascular diseases comprising lercanidipine HCl and valsartan as active ingredients,
Wherein separately wet granulated lercanidipine hydrochloride and valsartan are present separately from each other. delete 3. The combination preparation according to claim 2, further comprising a pharmaceutically acceptable excipient in the lercanidipine hydrochloride granule part and the valsartan granule part. 5. The combination preparation according to claim 4, comprising 4 to 10 parts by weight of a pharmaceutically acceptable excipient per 1 part by weight of lercanidipine hydrochloride in the lercanidipine hydrochloride granule part. 5. The combination preparation of claim 4 comprising 1 to 2 parts by weight of a pharmaceutically acceptable excipient per 1 part by weight of valsartan in the valsartan granule part. The pharmaceutical composition according to claim 4, which comprises 10 mg of lercanidipine per tablet + 80 mg of valsartan, 10 mg of lercanidipine hydrochloride + 160 mg of valsartan, 20 mg of lercanidipine hydrochloride + 80 mg of valsartan or 20 mg of lercanidipine hydrochloride + valsartan 160 mg. &lt; / RTI &gt; 3. The combination preparation according to claim 2, wherein separately wet granulated lercanidipine hydrochloride and valsartan are contained in separate layers, respectively. 9. The combination preparation according to claim 8, further comprising a separation layer between the lercanidifin hydrochloride layer and valsartan layer. delete delete 3. The combination preparation according to claim 2, for the prophylaxis or treatment of angina pectoris, hypertension, arterial spasm, heart arrhythmia, cardiomyopathy, cerebral infarction, congestive heart failure and myocardial infarction. (a) wet granulating and drying a mixture of lercanidipine hydrochloride and a pharmaceutically acceptable excipient;
(b) wet granulating and drying a mixture of valsartan and a pharmaceutically acceptable excipient; And
(c) mixing the lercanidipine granule hydrochloride of step (a) and the valsartan granule of step (b) separately in the wet granulation so as to be in a separated state. &Lt; / RTI &gt;

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