CN103249415B - Compound formulation comprising Lercanidipine hydrochloride and Valsartan and preparation method thereof - Google Patents

Abstract

The invention relates to a pharmaceutical composition containing lercanidipine hydrochloride and valsartan as active components and a preparation method thereof. The pharmaceutical composition comprising lercanidipine hydrochloride and valsartan of the present invention has excellent effects on preventing and treating cardiovascular diseases and their concurrent diseases, and reduces the side effects of each component. Furthermore, the composition of the present invention comprises lercanidipine hydrochloride and valsartan in isolated form to increase the dissolution rate of both components and reduce side effects.

Description

Composite preparation comprising lercanidipine hydrochloride and valsartan and preparation method thereof

technical field

The invention relates to a pharmaceutical composition containing lercanidipine hydrochloride and valsartan as active components and a preparation method thereof.

Background technique

Hypertension is one of the most common cardiovascular diseases. Persistent high blood pressure damages blood vessels in the kidneys, heart, and brain, which increases the incidence of kidney failure, coronary heart disease, heart failure, and stroke. Hypertension is divided into two types, i.e. essential or primary hypertension and secondary hypertension. The cause of essential hypertension is unknown and occurs without a specific underlying condition. Most (95%) hypertensive patients, especially those over 40 years old, belong to this type. Although no cause of essential hypertension has been found because there is no underlying disease, the problem may lie in genetics, a diet that consumes salty foods, obesity, advanced age, stress, and alcohol and tobacco use. Secondary hypertension arises from a specific predisposing disorder. About 5% of hypertensive patients, relatively young people, are of this type. Secondary hypertension is caused by nephritis, endocrine disorders, and toxemia during pregnancy, etc., and blood pressure decreases with treatment of the inducing disease.

Antihypertensive therapy is not intended to induce disease and relies on blocking the normal physiological mechanisms of blood pressure regulation. Antihypertensive therapy is performed on subclinical patients and it does not directly inconvenience the patient but prevents later onset of symptoms and death by lowering blood pressure.

Antihypertensive agents are generally divided into three classes according to their site of regulation and mechanism of action: diuretics, sympatholytics, and vasodilators, which are subdivided according to their site of action. Diuretics work by increasing the amount of urine to remove water and salt from the body, which lowers blood pressure by reducing the amount of water and salt in the body. The sympathetic nerves work by increasing the rate and intensity of the heartbeat and constricting blood vessels. Sympathetic blockers suppress the action of the sympathetic nerves to lower blood pressure. There are three types of sympathetic blockers: alpha-blockers block the sympathetic nerves that act on blood vessel constriction; beta-blockers block the sympathetic nerves that act on the heartbeat; and central sympathetic blockers block the sympathetic nerves that act on the brain nerve. Vasodilators lower blood pressure by dilating blood vessels. Various vasodilators are known: for example ACE inhibitors, which inhibit the synthesis of the vasoconstrictor angiotensin II, and angiotensin II receptor blockers, which inhibit the action of angiotensin II. Calcium channel blockers inhibit the influx of calcium into cells to lower blood pressure and are also vasodilators because high concentrations of intracellular calcium cause blood vessels to constrict and raise blood pressure.

In cases where an adequate antihypertensive effect cannot be obtained due to severe hypertension, the dose of the antihypertensive agent is usually increased. However, excessively increased doses may cause side effects. In this case, combining drugs with different mechanisms of action instead of increasing the use of drugs can minimize side effects while obtaining sufficient effects.

The advantages of combining drugs are as follows:

First, the antihypertensive effect is synergistically increased by the simultaneous action of drugs with different mechanisms of action. Moreover, the homeostatic compensating effects of one drug are inhibited by the other, resulting in a more potent antihypertensive effect. For example, reflex tachycardia and salt and water retention due to the use of vasodilators can be modulated by the use of beta-blockers and diuretics, respectively, thereby increasing the antihypertensive effect.

Second, by using drugs in combination, sufficient antihypertensive effects can be obtained even at low doses, so that dose-dependent side effects can be reduced. Moreover, side effects caused by pharmacological effects can be blocked and reduced.

Third, hypertension is almost asymptomatic and must be regulated for life, so patient compliance with medications determines the outcome of treatment. In this regard, the combination of effective drugs with low side effects can improve quality of life and increase patient compliance.

Recently, complex formulations containing at least two drugs in one pill are commercially available. They are cheap and easy to use. The use of combination preparations can increase patient compliance and prevent or delay target organ damage caused by hypertension.

Contents of the invention

technical problem

In view of the current situation, the present inventors conducted extensive research to develop a new pharmaceutical composition for synergistically increasing antihypertensive effects, reducing side effects, and improving patient compliance. Through these efforts, the present inventors found that such objects can be achieved by using lercanidipine hydrochloride and valsartan in combination, particularly by specific compound preparations containing them, thereby completing the present invention.

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

In particular, the present invention provides a combination preparation comprising lercanidipine hydrochloride and valsartan in an isolated form.

Another object of the present invention is to provide a method for preparing a compound preparation for preventing and treating cardiovascular diseases, the compound preparation comprising lercanidipine hydrochloride and valsartan as active components.

solution

Lercanidipine hydrochloride is a dihydropyridine calcium antagonist and, like other calcium antagonists, inhibits calcium influx into arterial smooth muscle to relax peripheral arterioles and lower blood pressure. Lercanidipine does not cause negative myocardial contraction, but it does cause mild reflex tachycardia. Lercanidipine has a strong affinity for and competitively antagonizes the dihydropyridine subunit of the L-type calcium channel. Calcium channel blockers are considered safe and have been shown to be effective for all types of hypertension. Lercanidipine is a novel dihydropyridine calcium antagonist and has demonstrated potent and long-lasting antihypertensive effects in preclinical trials. Lercanidipine was favorably tolerated at doses of 30 mg or less and lowered blood pressure in a dose-dependent manner. Calcium antagonists are considered renoprotective due to their antihypertensive effects. This possibility has been demonstrated in renal failure and nephrotoxicity induced by chemotherapy, contrast media, cyclosporine, or aminoglycoside antibiotics. Furthermore, calcium antagonists have a renoprotective effect on the kidney donor in kidney transplantation. Lercanidipine is usually used in a dose of 10-20 mg once daily, with a maximum daily dose of about 30 mg. Lercanidipine is rapidly absorbed after oral administration and reaches its maximum plasma concentration within 1.5-3 hours after administration, undergoing extensive first-pass metabolism. Absorption of lercanidipine is highly dependent on food intake and is significantly increased (3-4 fold) by simultaneous food intake. Oral tablets containing 10 or 20 mg lercanidipine are available under the trade name Tablet " is commercially available, and lercanidipine sold by Recordati SpA (Milan, Italy) can be prepared according to the methods disclosed in EP0153016 and US4705797, which are incorporated herein by reference in their entirety. And US-A1-2003/0180355 discloses a treatment for high A method for blood pressure patients, which comprises administering a combination preparation comprising lercanidipine and enalapril as active ingredients.

Valsartan ((S)-N-pentanoyl-N-{[2'-(1H-tetrazol-5-yl)-diphenyl-4-yl]-methyl}-valine) is a An angiotensin II receptor antagonist that lowers blood pressure through vasodilation. Angiotensin II has vasoconstrictor and sodium retention effects. Valsartan is commercially available sheet) and can also be prepared by known methods. For example, the preparation of valsartan is disclosed in US5399578, which is incorporated herein by reference in its entirety. Valsartan is used for the purpose of the present invention in its isolated form or in the form of a suitable salt. In the United States, valsartan is used at an initial dose of 80-160 mg qd and a maximum dose of 320 mg qd. In Korea, valsartan is prescribed to patients with cardiac insufficiency or post-myocardial infarction syndrome at a dose of 160 mgb.id. However, if the patient's blood pressure did not reach the desired value at 160 mg bid, other drugs were substituted for valsartan. Valsartan is usually used in dosages of about 40-320 mg, preferably about 80-320 mg, most preferably about 80-160 mg, in one tablet.

The present inventors conducted various experiments with lercanidipine hydrochloride and valsartan having the above-mentioned mechanism of action and the maximum daily dose to confirm that the combined use of these drugs has a synergistic effect on the prevention and treatment of cardiovascular diseases compared to single use , reduce side effects caused by monotherapy and improve patient compliance. Therefore, the pharmaceutical composition comprising lercanidipine hydrochloride and valsartan can be used to effectively prevent and treat cardiovascular diseases. Examples of cardiovascular diseases include, but are not limited to, angina pectoris, hypertension, arterial spasm, arrhythmia, cardiac hypertrophy, cerebral infarction, congestive heart failure, myocardial infarction, and the like.

However, a composite formulation comprising lercanidipine hydrochloride and valsartan prepared by simply mixing the two drugs may have certain problems caused by differences in their inherent physical properties.

The first problem is the difference in their pKa values. The pKa value of lercanidipine hydrochloride is about 6.83, while the pKa value of valsartan is about 3.92. Thus, lercanidipine hydrochloride has increased solubility at pH 4.0 or lower, while valsartan has increased solubility at pH 4.0 or higher. Such pKa differences between two drugs affect the solubility of each drug.

The second problem is the gelling of valsartan. Valsartan starts to gel at a pH of 4.0 or lower due to its low solubility, and dissolves very slowly. Such delayed dissolution delays the absorption of valsartan in the small intestine. In addition, the gelation of valsartan can delay the dissolution of lercanidipine hydrochloride. This problem may adversely affect the absorption of lercanidipine hydrochloride, which is rapidly disintegrated and absorbed in the gastrointestinal tract. Therefore, gelation of valsartan at low pH in co-formulations must be avoided.

The third problem is the low dissolution of the compound formulation. In preliminary experiments with a co-formulation prepared by wet granulation of a mixture of lercanidipine hydrochloride and valsartan, the co-formulation showed low dissolution due to the interaction between the two components. Such low dissolution seriously affects the absorption and bioavailability of both components. Reduced bioavailability is expected to also reduce the efficacy of co-formulations. Therefore, improved preparation methods are needed to prevent this problem.

A fourth problem is the variance in disintegration time among commercially available single drug formulations, which makes it difficult to maintain the inherent dissolution profile of each drug by using conventional formulation methods.

In order to overcome the above problems, the present inventors designed a compound formulation comprising lercanidipine hydrochloride and valsartan, which physically separates the two components to minimize the contact area and chance of contact. According to the present invention, the composite preparation can provide excellent dissolution rates of lercanidipine hydrochloride and valsartan.

beneficial effect

The pharmaceutical composition comprising lercanidipine hydrochloride and valsartan of the present invention has excellent effects for preventing and treating cardiovascular diseases and complex diseases thereof, and reduces side effects of each component due to different effects A synergistic combination of the two components of the mechanism. In addition, the present invention provides a combined preparation comprising lercanidipine hydrochloride and valsartan in an isolated form, whereby the problems caused by a simple mixture of lercanidipine hydrochloride and valsartan can be overcome, and both components can be increased dissolution rate.

Description of drawings

1 is a graph showing the results of the dissolution test of lercanidipine for the composite preparations of Examples 1-4 compared with Comparative Example 1. FIG.

2 is a graph showing the results of the dissolution test of lercanidipine for the composite formulations of Examples 5-8 compared with Comparative Example 1. FIG.

Fig. 3 is a graph showing the results of the dissolution test of lercanidipine for the composite formulations of Examples 1-4 compared with Examples 9-12.

4 is a graph showing the results of the dissolution test of lercanidipine in comparison with Example 1 and Example 13 of the composite formulation.

5 is a graph showing the results of the dissolution test of lercanidipine for the composite formulation of Example 1 compared with the formulations of Comparative Examples 2 and 3. FIG.

Fig. 6 is a graph showing the following: according to Test Example 8, after coadministration of lercanidipine hydrochloride 2 mg/kg (Z) and valsartan 16 mg/kg (V), changes in systolic blood pressure (BP) over time ( %)( ^*** p<0.001 (vs. control), ^## p<0.01 (vs. valsartan)).

Fig. 7 is a graph showing the following: according to Test Example 8, after co-administration of lercanidipine hydrochloride 2 mg/kg (Z) and valsartan 16 mg/kg (V), the mean BP change (%) over time ( ^*** p<0.001 (vs. control), ^## p<0.01 (vs. valsartan)).

Fig. 8 is a graph showing the following: According to Test Example 8, after coadministration of lercanidipine hydrochloride 2 mg/kg (Z) and valsartan 16 mg/kg (V), changes in diastolic BP over time (%) ( ^*** p<0.001 (vs. control), ^## p<0.01 (vs. valsartan)).

Fig. 9 is a graph showing the time-dependent changes in heart rate (%) after combined administration of lercanidipine hydrochloride 2 mg/kg (Z) and valsartan 16 mg/kg (V) according to Test Example 8 ( ^{* **} p<0.001 (vs. control), ^## p<0.01 (vs. valsartan)).

detailed description

As a preferred embodiment of the present invention, the composite formulation comprising lercanidipine hydrochloride and valsartan in isolated form is prepared by granulating lercanidipine hydrochloride and valsartan separately.

The method for preparing compound preparation of the present invention may further comprise the steps:

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

(b) wet granulating a mixture of valsartan and a pharmaceutically acceptable excipient, and drying the granules; and

(c) mixing the dried granules prepared in steps (a) and (b).

For example, the composite preparation of the present invention is prepared by separately preparing lercanidipine hydrochloride granules and valsartan granules, mixing the two granules, and then compressing the mixture into tablets. Compared with the composite preparation of Comparative Example 1, the composite preparation of Examples 1-4 prepared according to the above-mentioned method shows the dissolution of lercanidipine hydrochloride improvement without affecting the dissolution of valsartan, and the composite preparation of Comparative Example 1 passed Prepared by wet granulation of an unisolated mixture of lercanidipine hydrochloride and valsartan (see Figure 1).

Another specific embodiment of the present invention provides a bilayer tablet of a composite preparation, which comprises lercanidipine hydrochloride and valsartan. Using a bi-layer tablet press, as described in Examples 5-8 below, a bi-layer tablet can be formed by compressing valsartan granules into the first tablet layer and then lercanidipine hydrochloride granules into the second tablet layer to prepare. The bilayer tablet of the present invention exhibited the same excellent dissolution of lercanidipine hydrochloride as in Examples 1-4 (see Figure 2).

In another embodiment of the present invention, the bilayer tablet may comprise a separation layer between the lercanidipine hydrochloride layer and the valsartan layer, whereby a three-layer tablet may be obtained. The separating layer may, for example, consist of microcrystalline cellulose.

Another embodiment of the present invention provides a composite preparation comprising lercanidipine hydrochloride and valsartan in an isolated form, wherein a tablet consisting of valsartan is coated with lercanidipine hydrochloride. Such a formulation can be prepared by dissolving or dispersing lercanidipine hydrochloride and excipients in a coating solvent to prepare a coating composition, and coating a tablet consisting of valsartan with the coating composition. Examples of excipients include polyvinylpyrrolidone, and ethanol can be used as a coating solvent. If desired, another barrier layer can be placed between the valsartan tablet and the lercanidipine hydrochloride coating.

The compound preparation of the present invention may contain 4-32 parts by weight, preferably 4-16 parts by weight of valsartan per 1 part by weight of lercanidipine hydrochloride. If the amount of valsartan is less than 4 parts by weight per 1 part by weight of lercanidipine hydrochloride, the desired effect cannot be obtained. On the other hand, the inclusion of more than 32 parts by weight of valsartan per 1 part by weight of lercanidipine hydrochloride is not permitted.

The composition for preventing and treating cardiovascular diseases of the present invention may contain pharmaceutically acceptable carriers or excipients in the lercanidipine hydrochloride granules and valsartan granules, respectively. Examples of pharmaceutically acceptable carriers or excipients include microcrystalline cellulose, lactose, low-substituted hydroxypropyl cellulose, disintegrants such as croscarmellose sodium, crospovidone, and carboxymethyl starch sodium) and granulation binders (such as polyvinylpyrrolidone and hydroxypropylcellulose). Additionally, lubricants such as colloidal silicon dioxide, hydrated silicon dioxide, magnesium stearate, sodium stearyl fumarate may be included Glyceryl behenate Calcium stearate, stearic acid and talc.

In the present invention, the lercanidipine hydrochloride granules may comprise 4-10 parts by weight of pharmaceutically acceptable excipients per 1 part by weight of lercanidipine hydrochloride; and the valsartan granules may comprise 1- 2 parts by weight of pharmaceutically acceptable excipients. Such ratios apply to all formulations of the invention, including isolated particles. If the formulation has a ratio outside the above range, too small or too large tablet may be produced, and its dissolution may be delayed or increased.

Particular attention should be paid to the ratio of disintegrants used in the present invention. The recommended dosage of conventional superdisintegrants such as croscarmellose sodium, crospovidone and sodium starch glycolate is 0.5-8.0wt% based on the total amount of excipients. However, in the present invention, an overdose of superdisintegrant of 5-20 wt% was used to prevent gelation and exhibited an inherent dissolution behavior. Conventional formulations coated with an overdose of superdisintegrants have problems in that coating is difficult due to rapid wetting and that the coating layer breaks during storage. However, it was confirmed that the present invention does not have such a problem.

Examples of coating agents that can be used in the film coating layer include conventional coating agents such as hydroxypropylmethylcellulose, series, series, but not limited to this.

The invention is explained in more detail by the following examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example

Examples 1-4: Preparation of isolated particles

[Table 1]

The lercanidipine hydrochloride granules and valsartan granules having the above composition were wet granulated with distilled water, dried and ground into 25 meshes. The two granules are mixed and compressed into a composite tablet, which is then film-coated. Selling Colorcon as PVP II was used as a film coating material, and film coating was performed in the same manner in all of the following Examples and Comparative Examples. The mixture was mixed for 5 minutes or longer to fully wet the super-integrating agent added during wet granulation. Such intensive mixing time increases the porosity of the granules, aids disintegration time to prevent gelling. In the examples below, wet granulation was performed as described above.

Embodiment 5-8: Preparation of composite bilayer tablet

[Table 2]

The lercanidipine hydrochloride granules and valsartan granules having the above composition were wet granulated with distilled water, dried and ground into 25 meshes. The two sets of granules were compressed into a bilayer solid form, whereby the bilayer solid form was film coated.

Embodiment 9-12: Preparation of composite three-layer tablet

[table 3]

The lercanidipine hydrochloride granules and valsartan granules having the above composition were wet granulated with distilled water, dried and ground into 25 meshes. Valsartan granules were added to make the first tablet portion, a barrier layer was added to make the second tablet portion, and lercanidipine hydrochloride granules were added to make the third tablet portion. Composite three-layer tablets are obtained and film-coated.

Example 13: Preparation of tablet coated with lercanidipine hydrochloride layer

[Table 4]

The valsartan granules having the above composition were compressed into tablets and then introduced into a coating machine. Lercanidipine hydrochloride and polyvinylpyrrolidone were dissolved and dispersed in ethanol to prepare a coating layer. Valsartan tablets were coated by spraying the coating layer onto them, followed by film coating.

Comparative Example 1: Preparation of tablets from a mixture of unisolated lercanidipine hydrochloride and valsartan

[table 5]

The same amount of lercanidipine hydrochloride, valsartan and excipients as in Example 1 were mixed together, wet granulated, and then compressed into tablets. The tablets thus obtained are film-coated.

Comparative Example 2: Tablets obtained from a simple mixture of commercially available granules

[Table 6]

Preparation with commercially available lercanidipine hydrochloride tablets) and valsartan Tablets) granules of the same composition, which are simply mixed and compressed into tablets, which are then film-coated.

Comparative Example 3: Commercially available formulation of lercanidipine hydrochloride

[Table 7]

According to the commercially available lercanidipine hydrochloride Tablets) were prepared in the same prescription and method.

Test example 1: the dissolution test of the lercanidipine hydrochloride of the preparation of embodiment 1-4

For the composite tablets of Examples 1-4 prepared from the isolated granules and the composite tablet of Comparative Example 1 prepared from the non-isolated mixture, dissolution tests were performed and compared under the following conditions.

<Dissolution conditions>

Eluent: pH1.2 (900mL)

Instrument: USP pulp method, 50rpm

Temperature: 37°C

<analysis conditions>

Column: Stainless steel column with an inner diameter of about 4.6 mm and a length of 15 cm filled with 5 μm octadecylsilyl silica gel for liquid chromatography

Mobile phase: acetonitrile/pH3.0 sodium perchlorate buffer (60/40)

Flow rate: about 1.0mL/min

Detector: UV spectrophotometer (wavelength 240nm)

<result>

As demonstrated in Figure 1, compared with the tablet of Comparative Example 1, the lercanidipine hydrochloride-valsartan composite tablets of Examples 1-4 prepared from spacer granules showed a higher level of dissolution rate at the initial stage .

Test example 2: the dissolution test of the lercanidipine hydrochloride of the preparation of embodiment 5-8

For the composite bilayer tablets of Examples 5-8 prepared from the isolated granules and the wet composite tablet of Comparative Example 1 prepared from the unisolated mixture, dissolution tests were performed under the same conditions as Test Example 1 and compared.

As demonstrated in FIG. 2 , compared with the tablet of Comparative Example 1, the lercanidipine hydrochloride-valsartan composite tablets of Examples 5-8 prepared from spacer granules exhibited a higher level of dissolution rate.

Test example 3: the dissolution test of the lercanidipine hydrochloride of the preparation of embodiment 9-12

For the composite three-layer tablets of Examples 9-12 prepared from spacer granules and the wet composite tablets of Examples 1-4 prepared from spacer granules, the dissolution test was performed under the same conditions as Test Example 1 and compared.

As demonstrated in Figure 3, composite trilayer tablets prepared from spacer granules exhibited similar dissolution rates to wet composite tablets prepared from spacer granules.

Test example 4: the dissolution test of the lercanidipine hydrochloride of the preparation of embodiment 13

For the barrier-coated tablet of Example 13 and the wet composite tablet of Example 1, the dissolution test was carried out under the same conditions as Test Example 1 and compared.

As demonstrated in Figure 4, the barrier coated tablets exhibited similar dissolution rates as the wet compounded tablets.

Test Example 5: Comparative Dissolution Test of Formulations of Example 1 and Comparative Examples 2 and 3

For the composite tablet of Example 1 prepared from isolated granules, the tablet of Comparative Example 2 obtained from a simple mixture of commercial granules, and the commercial preparation of Comparative Example 3, the dissolution test was performed under the same conditions as in Test Example 1 and Compare.

As demonstrated in FIG. 5 , the composite tablet of Example 1 exhibited the same dissolution pattern of lercanidipine hydrochloride as that of the commercial formulation of lercanidipine hydrochloride of Comparative Example 3. On the other hand, the tablet of Comparative Example 2 obtained by simply mixing commercially available lercanidipine hydrochloride granules and valsartan granules and compressing them into tablets showed very low dissolution of lercanidipine hydrochloride, This appears to be due to gelling of the valsartan.

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

The following tests were performed to evaluate the efficacy and safety of the combination therapy of lercanidipine hydrochloride and valsartan compared to administration of each component alone to patients with essential hypertension.

The subjects were 20-75-year-old patients with essential hypertension who exhibited a blood pressure of 90 mmHg≤DBP (diastolic blood pressure)≤109 mmHg when measured at week 0 after administration of placebo for 2 weeks. In order to eliminate the interference effect of the previously used antihypertensive drugs and improve drug compliance, the test patients used placebo in a single-blind manner during the 2-week run-in period after the 0-1 week drug holiday. After the subjects were randomized with equal probability into a total of 4 groups consisting of 1 placebo group, 4 monotherapy groups and 4 combination therapy groups, they were assigned according to the group, measurement point and dosing period in the table below Drugs were administered in a double-blind manner. In this case, commercially available Tablet 10mg is used as lercanidipine hydrochloride, and is commercially available Tablets 80mg are used as valsartan.

[Table 8]

At each measurement point, according to the blood pressure monitoring guidelines provided by the Korean Society of Hypertension, the blood pressure of the subjects was measured to calculate the changes in DBP and SBP (systolic blood pressure) relative to the baseline after 8 weeks (8 weeks value after - baseline). The effect of the combination therapy was compared to the effect of the monotherapy to assess superiority.

130 patients meeting the criteria of 100mmHg≤DBP≤109mmHg were tested at Visit 3 (Day 0) and the results are summarized in Table 9 below. It confirmed that compared with patients using placebo or monotherapy, patients using lercanidipine hydrochloride 20 mg + valsartan 80 mg combination therapy showed significant superiority in both DBP and SBP changes.

In Table 9 below, "Diff." indicates the difference in blood pressure change with monotherapy compared to combination therapy (i.e., blood pressure change with monotherapy - blood pressure change with combination therapy), and the two-sided 95% CI is the two-sided 95% confidence interval , which means that when the lower limit of the confidence interval is greater than 0, the difference can be considered significant. The terms used hereinafter have the same meaning.

[Table 9]

Moreover, for the 368 patients whose blood pressure was measured in the trough period (22 to 26 hours after administration) at visit 3 (day 0) and met the criteria of 90mmHg≤DBP≤109mmHg, at visit 5 (day 56) when testing. The results confirmed that patients treated with lercanidipine hydrochloride 10mg + valsartan 160mg or lercanidipine hydrochloride 20mg + valsartan 160mg showed statistically significant superiority in DBP and SBP changes compared with placebo or monotherapy. sex. In the case of patients treated with the combination therapy of lercanidipine hydrochloride 20mg + valsartan 80mg, it was demonstrated that they performed superiorly in DBP and SBP changes relative to patients treated with placebo or monotherapy with lercanidipine hydrochloride 20mg alone Sex (see Table 10-12).

[Table 10]

[Table 11]

[Table 12]

Test Example 7: Clinical effect of combination therapy of lercanidipine hydrochloride and valsartan

The following tests were performed to evaluate the efficacy and safety of the combination therapy of lercanidipine hydrochloride and valsartan compared to administration of each component alone to patients with essential hypertension.

The subjects were 20-75-year-old patients suffering from essential hypertension who exhibited a blood pressure of 95 mmHg≤DBP≤114 mmHg when measured at week 0 after administration of placebo for 2-4 weeks. In order to eliminate the interference effect of the previously used antihypertensive drugs and improve drug compliance, the test patients used the placebo in a single-blind manner during the 2-4 week run-in period after the 1-week drug holiday. After the subjects were randomized with equal probability into a total of 4 groups consisting of 1 placebo group, 2 monotherapy groups and 1 combination therapy group, they were assigned according to the group, measurement point and dosing period in the table below Drugs were administered in a double-blind manner. In this case, commercially available Tablet 10mg is used as lercanidipine hydrochloride, and is commercially available Tablets 80mg are used as valsartan.

[Table 13]

At each measurement point, the blood pressure of the test patients was measured according to the blood pressure monitoring guidelines provided by the Korean Hypertension Society to calculate the changes in DBP and SBP from the baseline after 8 weeks (value after 8 weeks-baseline). The effect of the combination therapy was compared to the effect of the monotherapy to assess superiority.

193 patients meeting the criteria of 95mmHg≤DBP≤114mmHg were tested at Visit 3 (Day 0) and the results are summarized in Table 14 below. It demonstrated that patients treated with the combination therapy of lercanidipine hydrochloride 10 mg + valsartan 80 mg showed statistically significant superiority in both DBP and SBP changes compared to patients treated with placebo. It also demonstrated that patients treated with combination therapy of lercanidipine hydrochloride 10 mg + valsartan 80 mg showed a statistically significant superiority in SBP change compared to patients treated with monotherapy of lercanidipine hydrochloride 10 mg.

[Table 14]

Test Example 8: Effect of combination therapy of lercanidipine hydrochloride and valsartan in rats

A 13-week-old male SHR (spontaneously hypertensive rat, Orient) was adapted and domesticated for one week while maintaining a temperature range of 22-24°C and a humidity range of 50-70%, with a light-dark cycle of 12 hours. Standard diet food and water were provided ad libitum.

On the day before the administration, the blood pressure and heart rate of the test animals were measured using a BP-2000 blood pressure analysis system (Visitech). After the measurement, the animals were fasted for approximately 12 hours, during which time water was provided ad libitum. Each test drug was orally administered to fasted test animals in a volume of 5 ml/kg. The same volume of vehicle was orally administered to the negative control group. The test drugs lercanidipine hydrochloride and valsartan were used after being dissolved in 20% 2-hydroxypropyl-β-cyclodextrin (HPCD). To increase solubility, add 0.5 ml of 1N HCl to lercanidipine hydrochloride and 0.5 ml of 0.05% NaOH to valsartan, then dissolve completely. The test group (one of which is a combination therapy group (N=10), administered 2mg/kg of lercanidipine hydrochloride and 16mg/kg of valsartan; the other is a monotherapy group (N=10), administered 16mg/kg of valsartan) compared with the control group for changes in blood pressure and heart rate, and then statistically calculated. Statistical calculations were performed with one-way ANOVA to analyze significant differences between the test group and the control group and between the combination therapy group and the monotherapy group.

From the results of Fig. 6-9, it can be seen that the combination therapy group of lercanidipine hydrochloride administered with 2mg/kg and valsartan of 16mg/kg is compared with the monotherapy group and the matched group of valsartan administered with 16mg/kg , showed a significant decrease in blood pressure and an increase in heart rate after 1 hour of administration in SHR. On the other hand, the monotherapy group administered 16 mg/kg of valsartan showed no significant reduction in blood pressure or increase in heart rate compared to the control group.

Claims (5)

1. a kind of method for preparing medicinal composition for preventing and treating cardiovascular diseases, it comprises the following steps：

(a) when Lercanidipine hydrochloride and pharmaceutically acceptable excipient being mixed, and mixing 5 minutes or be longer the mixture Between, wherein the excipient is by following material composition：Microcrystalline cellulose, lactose, granulation binders polyvinylpyrrolidone, lubrication Agent and the Ac-Di-Sol as superdisintegrant；

(b) wet granulation is carried out to the mixture obtained in step (a), by thus obtained particle drying and is ground to 25 mesh；

(c) Valsartan and pharmaceutically acceptable excipient are mixed, and the mixture is mixed to the time of 5 minutes or longer, its Described in excipient by following material composition：Microcrystalline cellulose, low-substituted hydroxypropyl cellulose, granulation binders hydroxy propyl cellulose Element, lubricant and Ac-Di-Sol and Crospovidone as superdisintegrant；

(d) wet granulation is carried out to the mixture obtained in step (c), by thus obtained particle drying and is ground to 25 mesh； And

(e) particle by the drying prepared in step (b) and (d) mixes；

Total amount wherein based on the pharmaceutically acceptable excipient, the combined amount of the superdisintegrant is 5-20 weight %.

2. the method for claim 1 wherein the Lercanidipine hydrochloride particle includes every 1 parts by weight Lercanidipine hydrochloride 4-10 weights Measure the pharmaceutically acceptable excipient of part.

3. the pharmacy that every 1 parts by weight Valsartan 1-2 parts by weight are included the method for claim 1 wherein the valsartan particles can The excipient of receiving.

4. 10mg Lercanidipine hydrochloride and 80mg Valsartan are included the method for claim 1 wherein described pharmaceutical composition Combination, the 10mg combination of Valsartan of Lercanidipine hydrochloride and 160mg, 20mg Lercanidipine hydrochloride and 80mg figured silk fabrics it is husky The combination of the Valsartan of smooth combination or 20mg Lercanidipine hydrochloride and 160mg.

5. the method for claim 1 wherein the angiocardiopathy is selected from at least one of the following group：Angina pectoris, high blood Pressure, arteriospasm, arrhythmia cordis, cardiomegaly, congestive heart failure and myocardial infarction.