KR20040100696A - Novel Amlodipine Gentisate and Method for the Preparation Thereof - Google Patents

Abstract

PURPOSE: Amlodipine gentisate and a method for the preparation thereof are provided, which is stable by using nontoxic substance such as gentisic acid, and which amlodipine gentisate is constantly released regardless of pH and stomach movement, so that it can be useful for treatment of heart disease or hypertension of a patient having stomach disorder. CONSTITUTION: The amlodipine gentisate represented by formula (1) is provided. The method for preparing the amlodipine gentisate of formula (1) comprises amlodipine base of formula (2) with gentisic acid of formula (3) in organic solvent. A pharmaceutical composition for treating heart disease or hypertension contains the amlodipine gentisate of formula (1) as an effective component.

Description

Novel Amlodipine Gentisate and Method for the Preparation Thereof

The present invention relates to a novel salt of amlodipine which is expected to improve the bioavailability, a preparation method thereof, and a pharmaceutical composition thereof. More specifically, the present invention has the following formula (1) The present invention relates to a novel amlodipine gentiate salt, and also to a method of preparing a novel crystalline amlodipine gentiate salt represented by the following Chemical Formula 1 by reacting an amlodipine compound represented by the following Chemical Formula 2 with the gentianic acid represented by the following Chemical Formula 3 in an organic solvent The present invention relates to a pharmaceutical composition for treating cardiovascular diseases or hypertension, which contains amlodipine gentisate salt as an active ingredient and has various dosage forms.

[Formula 1]

[Formula 2]

[Formula 3]

Amlodipine (3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5 represented by Formula 2 -Pyridinedicarboxylate) is a long-acting calcium channel blocker in the human body and is useful for the treatment of cardiovascular diseases and hypertension.

In general, hypertension is a disease that requires proper prevention and treatment at the same time to maintain blood pressure normally, and should constantly take antihypertensive drugs. Therefore, it is important that drugs administered to patients with hypertension always have certain pharmacological effects regardless of age and other diseases.

However, hypertensive patients are mainly composed of elderly people after middle age, weak gastrointestinal motor function, often accompanied by other diseases, and also have disorders in gastrointestinal motor function, such as patients with hypoxia or anoxic disease or gastrointestinal resection. In the case of administering hypertension drugs to hypertension patients, the absorption of the drug is significantly lower than that of normal people, and even if the drug is administered, it is very difficult to set the dosage of the drug due to the variation between individuals in bioavailability.

In general, when the drug is orally administered, as the gastrointestinal absorption of the drug increases, the expression intensity and bioavailability of the drug increase together, and the drug dissolution rate in the gastrointestinal tract during the absorption process in vivo may be a rate step. That is, when an abnormality occurs in the gastrointestinal tract and the motor function decreases or the pH in the gastrointestinal tract increases, most drugs have a lower dissolution rate, so that the absorption is lowered and thus the expression and bioavailability of the drug are decreased. Deviation also increases.

In particular, the elderly patients, who occupy most of the hypertension patients are deteriorated body function due to poor absorption of drugs, it is necessary to treat the hypertension drugs in any condition to reduce the deviation of absorption and bioavailability.

Therefore, hypertension treatment agent can reduce fluctuation of absorption rate and decrease variation of bioavailability among individuals by showing constant dissolution rate regardless of exercise function or pH environment of gastrointestinal tract.

Amlodipine, which is currently widely used as a therapeutic agent for hypertension, is prepared and administered in the form of pharmaceutically acceptable acids and salts because of the disadvantage of poor stability of the compound.

EP Published Patent Application No. 89167 describes pharmaceutically acceptable salts of amlodipine as hydrochloride, hydrobromide, sulfate, phosphate or acid phosphates, acetates, malates, fumarates, lactates, tartrates, citrates and gluconates. Although salts are shown, even in the maleate salts, which are presented in the most preferred pharmaceutical form among these salts, the solubility is very high but there is a problem of degradation in aqueous solution after several weeks.

Korean Patent Publication No. 1995-0007228 discloses a benzenesulfonate salt of amlodipine (hereinafter abbreviated as besylate salt) and has a number of advantages over other salts of known amlodipine, resulting in excellent formulation properties. It is known to be suitable for the preparation of pharmaceutical formulations having

However, amlodipine besylate salts have high solubility and dissolution rate under acidic conditions, such as gastric juice (pH 1.2), but tend to decrease in solubility and dissolution rate with increasing pH (serum (pH 6.8)) (see FIGS. 4 and 5). The dissolution rate is lowered when the number of rotations decreases during the dissolution test (see FIGS. 11 and 13). Therefore, the dissolution rate and the biomarker are taken by hypertensive patients who have undergone gastrectomy, hypotensive / anoxic hypertension patients or hypertension patients whose gastrointestinal motility is reduced There is a problem that the utilization rate is lowered.

Amlodipine besylate salts also use benzenesulfonic acid, which is problematic in the manufacture of corrosive to skin and eyes and respiratory toxicity by inhalation (US Toxicology Program, US National Toxicology Program, http: //ntp-server.niehs). .nih.gov /) Safety issues have been raised in terms of worker and environmental toxicity during the synthesis process.

In order to reduce such toxicity, Korean Patent Publication No. 2002-0076561 shows an example of using camphorsulfonic acid instead of benzenesulfonic acid, but it does not provide experimental evidence that a constant dissolution rate appears even when the gastrointestinal motor function is reduced.

Therefore, even if a certain effective amount is administered in hypertensive patients with reduced gastrointestinal motor function or hypertensive patients who have undergone hypoxia / anoxia or gastrointestinal resection, they may have the same hypertension treatment effect as normal people, and in terms of worker and environmental toxicity during the manufacturing process There is an urgent need for a therapeutic agent for hypertension with safety.

Accordingly, the present inventors have long researched to solve the above problems, and as a result, the novel amlodipine 2,5-produced using 2,5-dihydroxybenzoic acid (hereinafter, abbreviated as 'genticic acid') having relatively low toxicity. Dihydroxybenzoate salt (hereinafter abbreviated as 'gentisate salt') ensures safety in terms of worker and environmental toxicity during the manufacturing process and shows that the dissolution test shows almost constant dissolution rate regardless of rotation speed and pH variation. In addition, the present invention has been completed by designing a pharmaceutical formulation containing amlodipine gentisate salt as an active ingredient, not limited to tablets, and by using soft capsules to exhibit the same dissolution pattern in the entire gastrointestinal pH region.

Therefore, the present invention can exhibit a hypertensive treatment effect equivalent to that of a normal person in a certain effective amount even in hypertensive patients such as elderly people with reduced gastrointestinal motor function or hypertensive patients who have undergone hypoxia / anoxia or gastrointestinal resection, It is an object of the present invention to provide a novel crystalline genitate salt of amlodipine, a method for preparing the same, and a pharmaceutical formulation thereof.

1 is X-ray diffraction data of the amlodipine gentesate salt of the present invention.

Figure 2 is the nuclear magnetic resonance spectroscopy data of the amlodipine gentiate salt of the present invention.

3 is infrared spectral data of the amlodipine gentisate salt of the present invention.

Figure 4 is an elution profile at pH 2.0, 75 rpm of the amlodipine gentiate salt tablet and amlodipine besylate salt tablet of the present invention.

Figure 5 is an elution profile at pH 6.8, 75 rpm of the amlodipine gentiate salt tablet and amlodipine besylate salt tablet of the present invention.

Figure 6 is an elution profile at pH 6.8 (containing 1% polysorbate 80), 75 rpm, of the amlodipine gentesate salt tablet and amlodipine besylate salt tablet of the present invention.

Figure 7 is an elution profile at pH 6.8, 75 rpm of the amlodipine gentiseate salt soft capsule of the present invention and amlodipine besylate salt tablets.

Figure 8 is an elution profile at pH 4.0, 50 rpm of the amlodipine gentiate salt tablet and amlodipine besylate salt tablet of the present invention.

FIG. 9 is an elution profile at pH 4.0 (containing 1% polysorbate80), 50 rpm, of the amlodipine genisate salt and amlodipine besylate salt tablets of the present invention.

FIG. 10 is an elution profile at pH 6.8 (containing 1% polysorbate80), 50 rpm, of the amlodipine genisate salt and amlodipine besylate salt tablets of the present invention.

Fig. 11 is an elution profile at pH 4.0, 50 rpm of the amlodipine gentisate salt soft capsule of the present invention and amlodipine besylate salt tablets.

Fig. 12 is an elution profile at pH 6.8, 50 rpm of the amlodipine gentisate salt soft capsule of the present invention and amlodipine besylate salt tablets.

FIG. 13 compares elution profiles according to rotational speed at pH 6.8 (containing 1% polysorbate 80) of amlodipine besylate salt tablets.

FIG. 14 compares the dissolution profiles according to the rotational speed at pH 6.8 (containing 1% polysorbate 80) of the amlodipine gentiate salt tablet of the present invention.

Figure 15 is a comparison of the dissolution profile according to the rotational speed at pH 6.8 of the amlodipine gentase salt soft capsule of the present invention.

In order to achieve the above object, the present invention provides a novel amlodipine gentiate salt that can exhibit a nearly constant dissolution rate regardless of the motility or pH fluctuations of the gastrointestinal tract.

In addition, the present invention provides a method for producing a novel crystalline acid addition salt of amlodipine which ensures safety in terms of worker and environmental toxicity during the manufacturing process by essentially using a relatively low toxicity gentic acid.

In addition, the present invention is effective in treating amlodipine gentisate salt which can exhibit the same pharmacological effect as a normal person when a certain effective amount is administered to hypertensive patients such as elderly people with reduced gastrointestinal motor function or hypertensive patients who have undergone hypoxia / anoxia or gastrointestinal resection. Provided are pharmaceutical compositions for treating cardiovascular diseases and hypertension of various pharmaceutical formulations.

Hereinafter, the present invention will be described in detail.

The amlodipine gentisate salt can be prepared according to the following process.

First, the amlodipine and the gentic acid are dissolved in an organic solvent, and then, the gentic acid solution is added to the amlodipine solution to prepare a mixture, and the solid obtained by stirring the mixture is filtered, washed, and dried to obtain a crystalline acid addition salt.

The organic solvent is selected from methanol, ethanol, isopropanol, acetonitrile, or a mixed solution thereof with water. In particular, when ethanol is used as a solvent, the concentration of amlodipine in the reaction solution is 5 in ethanol. It is preferable to use 20 to 20% by weight, more preferably 10 to 15% by weight of ethanol. Gentic acid may preferably be used in an amount of 0.1 to 5.0 equivalents, more preferably 1.0 to 1.2 equivalents relative to amlodipine.

Gentiic acid used in the preparation of the amlodipine salt of the present invention is one of the components of Gentiana Scabarae Radix , a high- density hygiene drug ( National Institute of Biopharmaceuticals, Modern Pharmacy, Hakchangsa , 1995), Gentiic acid is the US National Toxicology Program) and acute toxicity by the literature (http://ntp-server.niehs.nih.gov/, PH Stahl, CG Wermuth (Eds.), Handbook of Pharmaceutical Salts, WILEY-VCH, 2002) Half the lethal doses of oral and intraperitoneal administration in rats of the same species were three times safer than those of benzenesulfonic acid. It can be seen that it is a safe substance having a relatively low toxicity compared to phonic acid.

Exam conditions Benzene sulfonic acid CAS No. 98-11-3 Gentiic acid CAS No. 490-79-9 Rat Oral LD ₅₀ (mg / kg) 890 - Rat abdominal cavity LD ₅₀ (mg / kg) - 3,000 Mouse Oral LD ₅₀ (mg / kg) - 4,500 Mouse Vein LD ₅₀ (mg / kg) - 374 Wild Bird Oral LD ₅₀ (mg / kg) 75 -

Therefore, the present invention can produce a novel crystalline acid addition salt of amlodipine which ensures safety in terms of worker and environmental toxicity during the manufacturing process by essentially using a relatively low toxicity of gentic acid.

Amlodipine gentisate salt of Formula 1 prepared by the present invention is a crystalline acid addition salt having a crystalline form through X-ray diffraction analysis (see FIG. 1) and its structure can be qualitatively confirmed through NMR spectral analysis. have.

According to the present invention, the pharmaceutical formulation of amlodipine gentiate salt can be diversified without being limited to tablets, and in particular, the dissolution rate according to pH fluctuation can be almost constant due to the formulation of soft capsules.

In fact, although the bioavailability of amlodipine besylate salt tablets is known to be large, the individual difference is large, 64-90%, but the amlodipine gentisate salt of the present invention and its pharmaceutical preparations have almost constant dissolution rate regardless of gastrointestinal motor function in the pH region of the gastrointestinal tract. It can reduce the variation between individuals of bioavailability.

Therefore, the amlodipine gentiate salt of the present invention and its pharmaceutical preparations can treat hypertension equivalent to those of normal persons with a constant effective amount of administration even in hypertensive patients with reduced gastrointestinal motor function, hypertensive patients undergoing gastrointestinal resection, and hypoxic / anoxic hypertension patients. Can be effective.

The following examples embody the invention, but the invention is not limited to these examples.

Example 1 Preparation of Amlodipine Gentiate Salt

To a 50 ml ethanol solution in which 8.18 g (0.02 mole) of amlodipine base is dissolved, slowly add 10 ml of ethanol solution of 3.39 g (0.022 mole) of gentidic acid. After the mixture was stirred at room temperature for 4 hours, the resulting off-white solid was filtered, washed with 25 ml of ethanol and 10 ml of cold methanol, and then dried under vacuum at 50 degrees to obtain 9.9 g of off-white crystals. 87.9%).

m.p .: 162 to 166 degrees

1 H NMR (400 MHz, DMSO- d ₆ ) (ppm): 8.48 (b, 1H), 8.42 (s, 1H), 8.03 (br, 3H), 7.32 ~ 7.08 (m, 5H), 6.58 (d, 1H) , 6.43 (d, 1H), 5.28 (s, 1H), 4.71 ~ 4.54 (dd, 2H), 3.95 (q, 2H), 3.65 (m, 2H), 3.49 (s, 3H), 3.08 (m, 2H ), 2.29 (s, 3 H), 1.09 (t, 3 H).

IR (KBr): 3374, 3148, 2990, 2947, 2901, 1669, 1668, 1644, 1482, 1246, 1209, 1111, 1041, 837, 781, 757 cm ^-1 .

Example 2 Preparation of Amlodipine Gentiate Salt Tablets

As shown in Table 1 below, tablets were prepared with their respective ingredients and contents. Specifically, the amlodipine gentisate salt was apologized to 80 mesh and then excipients, disintegrants and glidants were mixed and compressed into tablets by direct spinning.

TABLE 1

Composition Content (mg / tablet) Remarks Amlodipine Gentiate Salt 6.885 5 mg / tablet as amlodipine Calcium Hydrogen Phosphate 63 Microcrystalline cellulose 124.115 Avicel PH101 Croscarmellose sodium 4 Primellose Magnesium Stearate 2 Tablet weight 200 mg / tablet

Example 3 Preparation of Amlodipine Gentiate Salt Soft Capsule

As shown in Table 2 below, a soft capsule was prepared in each component and content. Specifically, after mixing the polysorbate 80, propylene carbonate and polyethylene glycol 400- propylene glycol (100: 4) mixture, the contents are prepared after mixing by adding amlodipine gentiate salt and poloxamer 407 in a 100 degree water bath, A soft capsule was prepared by the phosphorus method.

TABLE 2

Composition Content (mg / tablet) Remarks Amlodipine Gentiate Salt 6.885 5 mg / tablet as amlodipine Polysorbate 80 5 Avicel PH101 Propylene carbonate 3 Primellose Polyethylene 400 / propylene glycol mixture 6 PEG400: PG = 100: 4 Poloxamer 407 3 Soft capsule weight 23.885 mg / capsule

Experimental Example 1 Solubility Test

In general, when the drug is administered orally to the human body, solubility of 1 mg / ml or more must be maintained in the digestive organs to favor the absorption of the drug. In addition, salts that provide a solution with a pH close to the pH of the blood (pH 7.4) upon dissolution are readily miscible in vivo. Accordingly, the solubility and pH at saturation of the amlodipine gentiate salt of the present invention prepared in Example 1 were measured and compared with the conventional amlodipine besylate salt.

Experimental method was measured the solubility according to the method described in the Korean Pharmacopoeia (7 revision).

After dissolving each compound in distilled water, the supernatant was analyzed by liquid chromatography to measure solubility. The results are shown in Table 3.

TABLE 3

salt Solubility (mg / ml) PH at saturation Amlodipine Gentiate 2.02 5.89 Amlodipine Besylate 2.14 5.44

As a result of measuring solubility and pH at saturation, both amlodipine gentiate and amlodipine besylate showed solubility of about 2 mg / ml or more. It is considered that the solubility of the two salts is almost equivalent considering the molecular weight of amlodipine gentiate (molecular weight: 563.01) and amlodipine besylate (molecular weight: 559.06). In addition, pH at saturation was similar in both salts.

Experimental Example 2 Acute Toxicity Study of Oral Administration of Amlodipine Gentiate

Amlodipine besylate salt and amlodipine gentiate salt were suspended in 1% carboxymethylcellulose solution and 6-week-old male ICR mice were acutely administered with oral administration of 10 mg / kg to 50 mg / kg body weight per unit weight. Toxicity was investigated. Mice were fasted overnight the day before administration, and then administered directly into the stomach using an oral injection needle and observed at least once daily for two weeks. The results were not statistically significant (p = 0.24, Fisher's exact test), but the half-doses (44.95 mg / kg) of the amlodipine bentate salt were higher than the half-doses (31.45 mg / kg) of the amlodipine besylate salt, resulting in an improvement in safety. It seems to have been.

Experimental Example 3 Dissolution Test Evaluation 1

In order to compare the dissolution rate of each of the amlodipine gentiate salt tablets of Example 2 and conventional amlodipine besylate salt tablets under pH conditions, dissolution test evaluation was performed as follows.

Experimental Method

With 6 tablets of each formulation, 10, 20, 30, and 60 minutes of samples were taken by dissolution test in 500 ml of eluate under the following conditions. The sample was centrifuged to obtain an analytical sample, and then amlodipine was analyzed using high-speed chromatograph (HPLC).

Eluent: pH 2.0, pH 6.8, pH 6.8 + Polysorbate 80 (1%)

Eluent temperature: 37 degrees

RPM: 75 rpm

HPLC conditions

Column: Inertsil ODS-2 (4.6 × 150 mm)

Mobile phase: Ethanol: 0.03 M potassium dihydrogen phosphate solution = 6: 4

Detector: UV Absorbance Spectrophotometer (237 nm)

Flow rate: 1.5 ml / min

The dissolution rate / time data of amlodipine for the two formulations at each pH condition was obtained, and the dissolution profiles for the two formulations are shown in FIGS. 4, 5 and 6.

As shown in Figures 4, 5 and 6, the amlodipine salt has a high dissolution rate under acidic conditions such as pH 2.0, but the dissolution rate decreases as the pH rises to 6.8. In addition, in order to reflect the environment of the intestinal fluid containing the surfactant in vivo, the dissolution rate of both formulations increases when 1% of the polysorbate 80 surfactant is added to the pH 6.8 solution. As can be seen from this result, amlodipine has a lower bioavailability due to a lower dissolution rate when the pH in the stomach increases, the dissolution rate can be increased at a high pH by the surfactant.

Experimental Example 4 Dissolution Test Evaluation 2

The dissolution test evaluation was performed as follows to compare the dissolution rate under the high pH conditions of the amlodipine gentiate salt soft capsule of Example 3 and the conventional amlodipine besylate salt tablet.

Experimental Method

Amlodipine was analyzed in the same manner as Experimental Example 3 by carrying out the dissolution test under the following conditions in 500 ml of the eluate with each of the six formulations.

Eluent: pH 6.8

Eluent temperature: 37 degrees

RPM: 7 5 rpm

Dissolution rate / time data of amlodipine for both formulations was obtained and the dissolution profile for this is shown in FIG. 7.

As shown in Figure 7, under the high pH (pH 6.8) conditions amlodipine gentiate salt softcapsule dissolution rate was superior to amlodipine besylate salt tablets. As can be seen from this result, the amlodipine gentiate salt soft capsule agent can exhibit a constant dissolution rate with little effect of pH. Therefore, the bioavailability can be increased in hypoxic / anoxic patients with high gastric pH or in patients with hypertension who have undergone gastrointestinal resection, with a constant dissolution rate regardless of pH fluctuations in the gastrointestinal tract.

Experimental Example 5 Dissolution Test Evaluation 3

Dissolution test evaluation was performed as follows to compare the dissolution rate under the low rotation speed (50 rpm) conditions of the amlodipine gentiate salt tablet of Example 2 and the conventional amlodipine besylate salt tablet.

Experimental Method

Amlodipine was analyzed in the same manner as Experimental Example 3, with six tablets of each formulation, and a dissolution test under the following conditions in 500 ml of the eluate.

Eluent: pH 4.0, pH 4.0 + polysorbate 80 (1%), pH 6.8 + polysorbate 80 (1%)

Eluent temperature: 37 degrees

RPM: 50 rpm

Dissolution rate / time data of amlodipine for both formulations was obtained and their dissolution profiles are shown in FIGS. 8, 9, 10, 13 and 14.

As shown in FIGS. 8, 9, 10, 13, and 14, the amlodipine gentisate salt tablets had better dissolution rates than the amlodipine besylate salt tablets under low rotational speed (50 rpm), and the dissolution rate differences between rpms were different. Was small. As can be seen from this result, the amlodipine gentiate salt tablet can exhibit a constant dissolution rate without being affected by the rotational speed. Therefore, the bioavailability can be increased in hypertensive patients with reduced gastrointestinal motor function and hypertensive patients undergoing gastrointestinal resection, and the variation between individual patients can be reduced.

Experimental Example 6 Dissolution Test Evaluation 4

The dissolution test evaluation was performed as follows to compare the dissolution rate under the low rotation speed (50 rpm) conditions of the amlodipine gentiate salt soft capsule of Example 3 and the conventional amlodipine besylate salt tablet.

Experimental Method

Amlodipine was analyzed in the same manner as Experimental Example 3 by carrying out the dissolution test under the following conditions in 500 ml of the eluate with each of the six formulations.

Eluent: pH 4.0, pH 6.8

Eluent temperature: 37 degrees

RPM: 50 rpm

Dissolution rate / time data of amlodipine for both formulations was obtained and the dissolution profiles for them are shown in FIGS. 11, 12 and 15.

As shown in FIGS. 11, 12, and 15, the amlodipine gentiate salt soft capsules under the low rotational speed (50 rpm) conditions had better dissolution rates than the amlodipine besylate salt tablets, and showed little difference in dissolution rates between rpms. As can be seen from this result, the amlodipine gentiate salt soft capsule agent can exhibit a constant dissolution rate without being affected by the rotational speed. Therefore, the bioavailability can be increased in hypertensive patients with reduced gastrointestinal motor function and hypertensive patients undergoing gastrointestinal resection, and the variation between individual patients can be reduced.

In addition, according to the results of Experimental Examples 5 and 6, since the amlodipine gentiate salt soft capsule agent shows almost constant dissolution rate regardless of pH and rotation speed, the dissolution rate is constant regardless of the gastrointestinal motility function in the pH region before the gastrointestinal tract in vivo. It is an excellent agent that can increase the bioavailability and reduce the variation among individuals.

Experimental Example 7 Pharmacokinetic Test in Gastrointestinal Movement Disorder Model

Amlodipine besylate and amlodipine gentiate salts were orally administered to 10-week-old male rats undergoing vagus nerve cutting at a dose of 10 mg / kg per unit weight in a microcapsule for rats and evaluated for pharmacokinetics (n = 5). . Rats underwent vagus nerve cutting 7 days before the test, and were directly administered to the stomach using microcapsule oral injector (Natsume, Japan) on the day of the test and 1, 2, 3, 4, 6, 8, 10, 24 hours. Pharmacokinetics were evaluated by taking 0.5 ml of blood. As a result, the highest concentration of 40.6 ng / ml (AUC = 470 nghr / ml) was reached after 5.6 hours in normal rats treated with amlodipine besylate salt, but 8.4 hours in drug-treated rats treated with vagus nerve cutting. When the vagus nerve cutting was reached after reaching the highest concentration of 28.1 ng / ml (AUC = 352 nghr / ml), the absorption of the drug was delayed and the absorption rate was 70% compared to that of normal animals. Was observed. On the other hand, normal rats treated with amlodipine gentiate salt reached a maximum concentration of 42.8 ug / ml (AUC = 496 nghr / ml) after 5.2 hours of drug administration. The delay of absorption was observed in some animals after reaching the ug / ml (AUC = 462 nghr / ml), but the absorption rate was almost equal. These results are consistent with the results observed in the dissolution test described above, and it is considered that the dissolution rate of amlodipine besylate salt is decreased in the animals whose vagus nerve is disconnected and the gastric motility and gastric acid secretion are not smooth. On the other hand, in the case of amlodipine gentiate salts, the dissolution rate did not decrease even when the secretion of gastric acid was not smooth, so that the blood concentration could be maintained similar to that of normal animals. These results suggest that amlodipine gentiate salt may have the same antihypertensive effect as a normal person even with a certain effective dose even in hypertensive patients with reduced gastrointestinal motor function, patients with hypertension who underwent gastrectomy, and hypoxic / anoxic hypertension. do.

Drug / Item Amlodipine Besylate Normal Rat Vagus Nerve Cutting Rat Amlodipine Gentiate Normal Rat Vagus Nerve Cutting Rat Cmax (ng / ml) 40.6 28.1 ^a 42.8 39.2 Tmax (hr) 5.6 8.4 ^a 5.2 6 ^b AUC (nghr / ml) 470 352 ^a 496 462

a: Item that statistically significant was observed compared with normal rats when amlodipine besylate was administered (Student t-test, P <0.05),

b: Statistical significance was observed in normal rats when amlodipine gentiate was administered (Student t-test, P <0.05)

The amlodipine gentiate salt according to the preparation method of the present invention is a crystalline acid addition salt suitable for the preparation of pharmaceutical formulations, and the preparation process is carried out using gentiic acid having a relatively low toxicity compared to the amlodipine besylate salt prepared using benzenesulfonic acid. It is possible to prepare a new crystalline acid addition salt of amlodipine which is safe in terms of worker and environmental toxicity, and also the dissolution rate according to pH fluctuation is small and shows almost constant dissolution rate regardless of the rotational speed, so that the gastrointestinal tract in vivo It can show almost constant dissolution rate regardless of gastrointestinal motility in the entire pH range, thereby increasing bioavailability and reducing variation among individuals. Therefore, even in hypertensive patients with reduced gastrointestinal motor function, hypertensive patients undergoing gastrointestinal resection, or hypoxic / anoxic hypertension patients, a certain effective amount may be used to exhibit a hypertension treatment effect equivalent to that of normal people.

Claims (5)

Amlodipine gentisate salt having the structure of Formula 1. [Formula 1] A method for preparing the amlodipine gentiate salt according to claim 1 by reacting an amlodipine base of Formula 2 with the genitic acid of Formula 3 in an organic solvent. [Formula 2] [Formula 3] A pharmaceutical composition for treating heart disease or hypertension, comprising the amlodipine gentiate salt of Formula 1 as an active ingredient. The pharmaceutical composition for treating heart disease or hypertension according to claim 3, wherein a constant dissolution rate is expected even when administered to hypertensive patients with reduced gastrointestinal motor function, hypertension patients undergoing gastrointestinal resection, or hypoxic / anoxic hypertension. The pharmaceutical composition for treating heart disease or hypertension according to claim 3, wherein the formulation is in the form of tablets, hard capsules, soft capsules, granules, sachets.