KR20090090748A - Anti-vascular disease treatment containing combination ingredients - Google Patents

Abstract

A therapeutic agent for preventing vascular diseases, which contains a composite is provided to reduce the administering amount of active ingredient by the synergic effect of calcium channel blocker and RAS inhibitor. A therapeutic agent for preventing vascular diseases comprises calcium channel blocker and RAS inhibitor. The calcium channel blocker is amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and lacidipine or its pharmaceutically acceptable salt and derivative. The RAS inhibitor is ramipril or pharmaceutically acceptable salt, and derivative. The composite of calcium channel blocker and RAS inhibitor is table.

Description

A preventing and treating agent of blood-vessel related diseases comprising combination drug}

The present invention relates to a prophylactic and therapeutic agent for vascular diseases, and more particularly, the blood pressure lowering properties, effects and duration of action are remarkable, and further enhanced as compared to the administration of a single substance when administered to the body. The present invention relates to a vascular disease prophylactic agent capable of significantly reducing the dosage.

There are various types of blood pressure lowering agents that have been developed and used to date. These have been used diuretics, sympathetic blockers, ACE inhibitors, calcium antagonists, angiotensin II receptor antagonists, respectively. However, these individual drugs have side effects and are used carefully and strictly after prescription of a specialist.

Such a blood pressure lowering agent can achieve the desired effect by taking a certain amount over a long period of time, when used over a long period of time, as well as an increase in medical costs, the side effects can not be overlooked. Therefore, in order to reduce the side effects due to the continuous administration of the drug can be considered a method of reducing the dose of the drug. However, no effective solution has been proposed.

The present invention has been made to solve the problems of the prior art as described above, the object is that the blood pressure lowering characteristics and effects and duration of action is remarkable compared to the administration of a single substance when administered in the body, and further The present invention provides a therapeutic agent for preventing vascular diseases, which can be enhanced to significantly reduce the dosage of individual active ingredients.

The technical problem as described above is achieved by the following configuration according to the present invention.

(1) vascular disease prevention and treatment comprising calcium channel blocker and RAS inhibitor.

(2) The calcium channel blocker in (1) is amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nirenedipine, lassidipine, lercanidipine, verapamil, galopamil and diltiazem One or more pharmacologically acceptable salts and derivatives thereof selected from the group.

(3) The agent for preventing vascular disease, wherein the calcium channel blocker in (1) is amlodipine or a pharmacologically acceptable salt or derivative thereof.

(4) In the above (1), the calcium channel blocker is a vascular disease preventive treatment, characterized in that amlodipine besylate.

(5) The agent for preventing vascular disease according to any one of (1) to (4), wherein the RAS inhibitor is ramipril or a pharmacologically acceptable salt or derivative thereof.

(6) The vascular disease prophylactic agent according to any one of (1) to (5), wherein the weight ratio of the RAS inhibitor and the calcium channel blocker is 10: 1 to 1:70.

(7) The vascular disease preventive treatment according to any one of (1) to (6), wherein the combination of the calcium channel blocker and the RAS inhibitor is a tablet.

(8) In any one selected from (1) to (7), 0.1% to 5.0% by weight of amlodipine besylate, 0.1% to 5.0% by weight of ramipril, 17% to 60% by weight of corn starch, Avicel PH-101 25% to 42% by weight, alpha-lactose monohydrate 0.05 ~ 37% by weight of vascular disease prevention treatment.

(9) The vascular disease prophylactic agent according to any one of (1) to (8), wherein magnesium stearate is added as a lubricant.

(10) In any one of (1) to (9) above, about 1.67% by weight of amlodipine besylate, about 1.67% by weight of ramipril, about 59% by weight of corn starch, about 26.66% by weight of Avicel PH-101, alpha -About 10% by weight lactose monohydrate and about 1.0% by weight magnesium stearate salt.

According to the above configuration of the present invention, the blood pressure lowering characteristics, effects and duration of action are remarkable and further improved when compared to the administration of a single substance when administered to the body. This can significantly reduce the dosage of the individual active ingredients.

Hereinafter, the content of the present invention will be described in more detail.

The present invention includes a novel vascular disease prophylactic agent combining a calcium channel blocker and a RAS (renin- angiotensin system) inhibitor as an active ingredient.

Calcium channel blockers used in the present invention are selected from the group of amlodipine, felodipine, nicardidipine, nifedipine, nimodipine, nisoldipine, nirenedipine, lassidipine, lercanidipine, verapamil, gallopamil and diltiazem. It can be selected from one or pharmacologically acceptable salts thereof and derivatives thereof. Preferably the calcium channel blocker is amlodipine, more preferably amlodipine besylate.

Amlodipine besylate represented by Chemical Formula 1 used in the present invention is a general name of benzenesulfonate salt of amlodipine represented by the following Chemical Formula 2, and the chemical name is 3-ethyl-methyl-2- [2-aminoethoxymethyl] -4. -[2-chlorophenyl] -6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulfonate, potent in the form of dihydropyridine-dicarboxylate, which is active over a long period of time Calcium channel blocker.

(1) (2)

In general, the pKa value of amlodipine is 8.6. This means that the ratio of the number of charged amlodipine molecules to the uncharged amlodipine molecules in the solution at pH 8.6 is 1: 1. In general, charged molecules have higher solubility in water than uncharged molecules. The solubility of amlodipine in distilled water at pH 7 is 75.3 μg / ml. In a solution at pH 7, the solubility of amlodipine is lowered because the number of charged amlodipine molecules is greater than the number of uncharged amlodipine molecules, and as the pH value of the solution increases, the proportion of uncharged amlodipine molecules increases.

Other ingredients that make up the formulations of the invention include RAS inhibitors.

Suitable RAS inhibitors for the purposes of the present invention are in particular angiotensin II antagonists, more preferably angiotensin converting enzyme (ACE) inhibitors. Examples of such ACE inhibitors are captopril, enalapril, enalapril, ramipril, quinapril, perindopril, risinopril, venazepril, posinopril, alasepril, silazapril, silazapril Lat, delapril, spirapril, trandolapril and zofenopril. Of these, ramipril is particularly preferred.

Some of the angiotensin converting enzyme inhibitors described above may be reduced by food after taking. In the case of captopril, quinapril and trandolapril, the decrease in absorption is a large one, so it is recommended to take 1 hour before meals, whereas in the case of enalapril, ricinopril, and ramipril, the change in absorption is caused by food. There is little or no big difference. Excretion is mainly done through the kidneys, so the half-life is extended in patients with renal impairment. For the above reason, ramipril may have the highest utility as a combination formulation with amlodipine, not as a single formulation.

The molecule corresponding to ramipril has five chiral centers and can therefore exist in the form of 32 different enantiomers, of which (1S, 5S, 7S) -8-[(2S) -2-[(1S) -1 Preferred is an enantiomer named ethoxycarbonyl-3-phenyl-propyl] amino] propanoyl] -8-azabicyclo [3.3.0] octane-7-carboxylic acid. This compound is ramipril of the following formula (3).

(3)

The pKa values of ramipril are 3.7 (CO ₂ H) and 5.5 (NH ⁺ ). This means that the ramipril molecule has a positive charge in a solution with a pH value of 3.7 or less, a neutral charge in a solution with a pH value of 3.7 or more and a value of 5.5 or less, and a negative charge in a solution with a pH value of 5.5 or more. In general, charged molecules have higher solubility in water than uncharged molecules. The solubility of ramipril in distilled water at pH 7 is 3.5 μg / ml. In a solution at pH 7, the number of charged ramipril molecules is greater than the number of uncharged ramipril molecules, and as the pH value of the solution is increased, the ratio of charged ramipril molecules increases, so the solubility of ramipril increases.

The composition ratio of the RAS inhibitor to the calcium channel blocker in the vascular disease preventive treatment according to the present invention is about 10: 1 to 1:70 by weight. It is preferably 5: 1 to 1:60, more preferably 3: 1 to 1: 3. 1: 1 was used as an embodiment of the present invention.

Such co-formulations have significant blood pressure lowering properties, effects, and duration of action compared to the administration of a single substance when administered to the body, and further enhance the effect. Accordingly, the dosage of the individual active ingredients can be significantly reduced, which means that side effects can be reduced more during administration.

Ramipril is rapidly hydrolyzed through hepatic metabolism after absorption to become an active metabolite, ramiprilat. When used in combination with amlodipine, ramiprilat reduced cardiac muscle oxygen consumption by 15% or more compared with ramiprilat and amlodipine alone, which was found to be effective in treating heart failure and hypertension.

The composition of the preparations according to the invention can be administered orally in the form of tablets, lacquered tablets, sugar coated tablets, hard and soft capsules, solutions, emulsions or suspensions. Formulations of this type can also be administered parenterally. It may also be administered rectally, for example in the form of suppositories, or parenterally in the form of injections.

The active ingredients may be formulated in a form containing all of the active ingredients in the form of such oral or parenteral dosage forms as above, or may be administered separately in a special combination of single substances which may be administered together or sequentially.

To prepare tablets, lacquered tablets, sugar coated tablets, and capsules, pharmaceutically inert, inorganic or organic excipients may be added for the formulation of the present invention. Such excipients include lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof. Suitable excipients for the capsules include vegetable oils, waxes, fats, semisolid or liquid polyols. Suitable siblings for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar glucose and the like. Suitable excipients for injection include water, alcohols, glycerol, vegetable oils. Suitable excipients for suppositories include natural or hardened oils, waxes, fats, semi-liquid or liquid polyols.

The formulations according to the invention may also further contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, coloring agents, flavoring agents, osmotic agents, buffers, coatings and / or antioxidants as necessary.

Specific examples of the formulation that can be prescribed according to the present invention include amlodipine besylate 0.1% by weight to 5.0% by weight, ramipril 0.1% by weight to 5.0% by weight, and the remaining vascular disease prevention therapeutics containing the necessary excipients.

Examples of preferred formulations include 0.1% to 5.0% by weight of amlodipine besylate, 0.1% to 5.0% by weight of ramipril, 17% to 60% by weight of corn starch, 25% to 42% by weight of Avicel PH-101, alpha -Lactose monohydrate 0.05 ~ 37% by weight of vascular disease prevention treatment.

Hereinafter, the content of the present invention will be described in more detail with reference to Examples. However, these examples are merely to help the understanding of the present invention is not limited to the scope of the present invention.

<Example 1-3>

Tablets were prepared according to the components and composition ratios described in Table 1 below.

Amlodipine besylate, ramipril, corn starch, Avicel PH-101 and alpha-lactose monohydrate were wet-granulated with distilled water, dried and sieved to obtain granules having a diameter of 200 to 500 µm, and magnesium stearate salts. After mixing, the mixture was compressed into tablets of 300 mg each using a tableting machine.

TABLE 1

Raw material Content per tablet (mg) Example 1 Example 2 Example 3 Amlodipine Besylate 5 5 5 Ramipril 5 5 5 Corn starch 137 52 177 Avicel PH-101 80 125 80 Alpha-lactose monohydrate 70 110 30 Magnesium Stearate 3 3 3 Distilled water 140 140 140 Total (excluding distilled water) 300 300 300

Tablets prepared according to the present invention was confirmed that the drug in the combination formulation is not denatured by external moisture even without performing a separate coating process.

<Example 4-6>

According to the same procedure as in Example 1 to prepare a tablet according to the composition of Table 2.

TABLE 2

Raw material Content per tablet (mg) Example 4 Example 5 Example 6 Amlodipine Besylate 0.3 9 15 Ramipril 0.3 9 15 Corn starch 146.4 52 157 Avicel PH-101 80 117 80 Alpha-lactose monohydrate 70 110 30 Magnesium Stearate 3 3 3 Distilled water 140 140 140 Total (excluding distilled water) 300 300 300

Tablets prepared according to the present invention was confirmed that the drug in the combination formulation is not denatured by the external moisture even without performing a separate coating process.

Experimental Example 1 Dissolution Test

The following tests were conducted to demonstrate the salient properties of the formulations according to the inventive examples.

The tablets prepared in accordance with the present invention were collected in a reverse phase high performance liquid by separating a sample for 12 hours while rotating at 50 rpm in accordance with the dissolution test paddle method of the Korean Pharmacopoeia in 900 mL HCl-NaCl aqueous solution pH 1.2 and 900 mL phosphate buffer pH 6.8. The dissolution rate of each drug was determined by chromatography (RP-HPLC) system.

1 is a graph showing the dissolution rate of the combination tablet of Example 3 in 900 mL HCl-NaCl aqueous solution pH 1.2. In the results of Figure 1 after 5 minutes after the start of elution it was confirmed that the dissolution rate of amlodipine and ramipril are all 60% or more.

Figure 2 is a graph showing the dissolution rate of the combination tablet of Example 3 in 900 mL phosphate buffer pH 6.8. In the results of FIG. 2, 5 minutes after the start of the dissolution, the dissolution rates of amlodipine and ramipril were confirmed to be less than 25%.

According to the results of FIGS. 1 and 2, amlodipine and ramipril elute faster under acidic conditions than under neutral conditions, which results in rapid dissolution and absorption in the gastrointestinal tract when taking the tablets of the examples. In addition, when the patient takes the tablet, the drug is eluted in the oral cavity before swallowing into the stomach through the esophagus, so that the patient does not feel uncomfortable.

Experimental Example 2 In vitro Administration

Nine-week-old male spontaneous hypertension rats SHR / Hos (n = 32) were purchased and subjected to pure quarantine for two weeks in a nursery at constant temperature and humidity (23 ± 3 ° C, 50 ± 10%) and used for testing. The tablets obtained in Example 1-3 were dissolved in distilled water and then freely ingested for 4 weeks so that 80 mg of the drug per 100 g of body weight could be administered. Blood pressure was measured by systolic blood pressure of spontaneously hypertensive rats using a non-vascular autonomous blood pressure measurement device. The control group was used as the only prescription group of amlodipine besylate, and 100 mg of the drug was administered per 100 g of body weight, and the results were calculated and compared according to the following equation.

Each measured value after intake-measured value before intake = amount of change (△ mmHg)

As a result of comparing the control with 4 weeks after the start of ingestion, it was confirmed that the same or superior effect was shown in the blood pressure suppression effect as shown in Table 3 below.

TABLE 3

Control group (n = 8) Example 1 (n = 8) Example 2 (n = 8) Example 3 (n = 8) Change amount (△ mmHg) -13.8 -12.7 -13.5 -14.6

These results suggest that the multi-prescription according to the present invention can significantly reduce the dosage while exerting the same level of efficacy as using a single agent.

As described above, the present invention has been described with reference to the preferred embodiments, but those skilled in the art can variously modify the present invention without departing from the spirit and scope of the present invention as set forth in the claims below. It will be appreciated that it can be changed.

1 is a graph showing the dissolution rate of the combination tablet of Example 3 in 900 mL HCl-NaCl aqueous solution pH 1.2.

Figure 2 is a graph showing the dissolution rate of the combination tablet of Example 3 in 900 mL phosphate buffer pH 6.8.

Claims (10)

Vascular disease prevention and treatment comprising calcium channel blocker and RAS inhibitor. The method of claim 1, wherein the calcium channel blocker is selected from the group of amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nirenedipine, lassidipine, lercanidipine, verapamil, gallofamil and diltiazem. One or more pharmacologically acceptable salts and derivatives thereof are selected. The method of claim 1, wherein the calcium channel blocker is amlodipine or a pharmacologically acceptable salt or derivative thereof. According to claim 1, wherein the calcium channel blocker is vascular disease prevention treatment, characterized in that amlodipine besylate. The therapeutic agent for preventing vascular diseases according to any one of claims 1 to 4, wherein the RAS inhibitor is ramipril or a pharmacologically acceptable salt or derivative thereof. The vascular disease preventive treatment according to any one of claims 1 to 4, wherein the weight ratio of the RAS inhibitor and the calcium channel blocker is 10: 1 to 1:70. The method of any one of claims 1 to 4, wherein the combination of the calcium channel blocker and the RAS inhibitor is a tablet. The method according to any one of claims 1 to 4, 0.1% to 5.0% by weight of amlodipine besylate, 0.1% to 5.0% by weight of ramipril, 17% to 60% by weight of corn starch, Avicel PH-101 25% to 42% by weight of alpha-lactose monohydrate 0.05 ~ 37% by weight of vascular disease prevention treatment. The therapeutic agent for preventing vascular diseases according to any one of claims 1 to 4, wherein magnesium stearate is added as a lubricant. The method of claim 9, wherein about 1.67% by weight of amlodipine besylate, about 1.67% by weight of ramipril, about 59% by weight of corn starch, about 26.66% by weight of Avicel PH-101, about 10% by weight of alpha-lactose monohydrate and magnesium stearate About 1.0% by weight of vascular disease prevention treatment.

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