KR20050041284A - Amlodipine malonate, and process for preparing it - Google Patents

Abstract

The present invention relates to amlodipine malonate salts and a method for preparing the same, and more particularly, to crystalline acid addition salts prepared by reacting amlodipine and malonic acid, having excellent physicochemical properties such as solubility, stability, non-hygroscopicity, and anti-adhesion properties. The present invention relates to an amlodipine malonate salt represented by the following formula (1), which is effective as a therapeutic agent for cardiovascular diseases including hypertension because of its low toxicity, and a method for preparing the same.

Description

Amlodipine malonate salt and preparation method thereof {Amlodipine malonate, and process for preparing it}

The present invention relates to amlodipine malonate salts and a method for preparing the same, and more particularly, to crystalline acid addition salts prepared by reacting amlodipine and malonic acid, having excellent physicochemical properties such as solubility, stability, non-hygroscopicity, and anti-adhesion properties. The present invention relates to an amlodipine malonate salt represented by the following formula (1), which is effective as a therapeutic agent for cardiovascular diseases including hypertension because of its low toxicity, and a method for preparing the same.

[Formula 1]

Amlodipine is 3-ethyl-5-methyl-2- (2-aminoethoxy-methyl) -4- (2-chlorophenyl) -6-methyl-1,4-dihydro-3,5-pyridine It has the chemical name of dicarboxylate, is used as a calcium-channel blocker for the treatment of ischemic heart disease and hypertension, and is known as a useful and efficient substance that exhibits activity over a long period of time.

Amlodipine was first reported as one of the novel 1,4-dihydropyridines in EP 89,167. In the above-mentioned European Patent Publication No. 89,167, acid addition salts are exemplified as pharmaceutically acceptable salts of 1,4-dihydropyridine, and pharmaceutically acceptable acid addition salts are non-toxic containing pharmaceutically acceptable anions. Hydrochloride, hydrobromide, sulfate, phosphate or acid phosphate, acetate, malate, fumarate, lactate, tartrate, citrate and gluconate salts are described as formed from acids forming acid addition salts, among which The rate is described as the most preferred.

Pharmaceutically, amlodipine is useful in free form, but due to its low stability, it is administered in the form of acid addition salts with pharmaceutically acceptable acids.

Korean Patent Registration No. 90,479 discloses (1) excellent solubility in preparing in the form of a pharmaceutically acceptable salt; (2) good stability; (3) nonhygroscopic; (4) states that four physicochemical criteria such as processability as tablet formulations should be met. It is very difficult to meet all four of the above conditions as a pharmaceutically acceptable acid addition salt, and in fact even the malate salt, which has been presented in the most preferred pharmaceutical form, is degraded after several weeks in solution and found to have stability problems. lost.

In Korean Patent No. 91,020, a benzene sulfonate salt (hereinafter abbreviated as besylate salt) is presented as an acid addition salt showing excellent stability. Amlodipine besylate salts have a number of advantages over known salts of amlodipine and have been found to have excellent formulation properties that make the preparation of pharmaceutical formulations of amlodipine suitable. However, since the amlodipine besylate salt uses benzene sulfonic acid, which is a toxic compound, the safety problem has been raised.

Accordingly, the present inventors have used amlodipine malonate, a novel crystalline acid addition salt of amlodipine, which satisfies all physicochemical conditions of pharmaceutically acceptable salts using malonic acid, which is less toxic than benzene sulfonic acid. The present invention has been completed by preparing the salt.

Accordingly, it is an object of the present invention to provide an amlodipine malonate salt which has low toxicity and meets all of the physicochemical conditions of the pharmaceutically acceptable salt.

Another object of the present invention is to provide a method for preparing amlodipine malonate salt using malonic acid having a relatively low toxicity compared to benzene sulfonic acid.

In addition, the present invention provides a pharmaceutical composition for treating cardiovascular diseases comprising amlodipine malonate salt which satisfies all the physicochemical conditions of the pharmaceutically acceptable salt with low toxicity prepared by the method. There is another purpose.

The present invention is characterized by the amlodipine malonate salt represented by the following formula (1) which is effective in treating cardiovascular diseases due to its excellent solubility, stability, non-hygroscopicity and processability as a tablet formulation.

[Formula 1]

In addition, the amlodipine malonate salt represented by Formula 1 includes all of the salts of each isomer of amlodipine or a mixture of these isomers.

On the other hand, the present invention includes a method for preparing the amlodipine malonate salt represented by the formula (1), the preparation method is represented by the following formula 2 and amlodipine represented by the following formula 2 in the organic solvent, as shown in the following scheme 1 It consists of making by making malonic acid react.

When subdividing the production method of the present invention represented by the reaction scheme 1 for each process,

1) dissolving amlodipine in an organic solvent;

2) dissolving malonic acid in an organic solvent, and then adding it to the amlodipine reaction solution to prepare a mixture; And

3) filtering, washing and drying the solid obtained by stirring the mixture to form a crystalline acid addition salt.

Crystalline acid addition salt of amlodipine according to the present invention is prepared by adding malonic acid in the amlodipine-containing solution represented by the formula (2), and will be described in detail for each preparation step as follows.

In the first step of the preparation process, it is important to control the concentration of amlodipine in the reaction solution. In order to efficiently promote crystallization, it is preferable to adjust the concentration of amlodipine in the range of 3 to 60 wt%. At this time, amlodipine may be added as an isomer of R-amlodipine or S-amlodipine, or may be added as a mixture of these isomers. Considering the pharmaceutical activity, it is more preferable to use S-amlodipine.

In the second step, an acid is added to the amlodipine-containing reaction solution, and malonic acid is preferably used in an amount of 0.1 to 5.0 equivalents based on amlodipine.

In the first and second steps described above, a conventional organic solvent is used as the reaction solvent, and particularly preferably, an organic solvent selected from methanol, ethanol, isopropanol and acetonitrile is used.

The third step is the formation of the crystalline acid addition salt, the reaction is carried out in the temperature range of -10 to 50 ℃.

On the other hand, the amlodipine malonate salt represented by the formula (1) according to the present invention is a low toxic and low toxicity compared to amlodipine besylate (Amlodipine besylate) as a typical example of a pharmaceutically acceptable salt of amlodipine generally known It satisfies all of the physical and chemical conditions to be provided as possible salts (see Experimental Examples 1 to 3). Accordingly, the present invention includes a pharmaceutical composition for treating cardiovascular diseases containing an isomer compound or an isomer mixture of the amlodipine malonate salt represented by Formula 1 as an active ingredient.

The pharmaceutical composition according to the present invention can be administered orally or parenterally during clinical administration and can be used in the form of general pharmaceutical preparations. That is, it can be formulated into various formulations for oral and parenteral administration, which are prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like. Such solid preparations are prepared by mixing the active compound with at least one excipient such as starch, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspending agents, solvents, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Dosage to the human body of the pharmaceutical composition according to the present invention may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, 1 day at a predetermined time interval depending on the doctor or pharmacist It may be administered in divided doses or several times. The effective dose of the amlodipine malonate salt represented by Formula 1 is 1.0 to 10.0 mg / kg, preferably 5.0 to 8.0 mg / kg.

The present invention as described above will be described in more detail based on the following Examples and Experimental Examples, but the present invention is not limited thereto.

Example 1 Preparation of Amlodipine Malonate Salt

5.0 g (0.012 mol) of amlodipine were dissolved in 40 mL of ethanol and the reaction was cooled to 5 ° C. 1.4 g (0.013 mol) of malonic acid was dissolved in 15 ml of ethanol, and then slowly added to the amlodipine reaction solution. The mixture was stirred at room temperature for 1 hour, and then the resulting solid was filtered, washed with 10 ml of ethanol and dried to give 6.07 g (yield: 96.8%) of the title compound as white crystals.

mp 164-167 ° C .; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 8.42 (brs, 1H), 7.35-7.10 (m, 4H, ArH), 5.31 (s, 1H), 4.73-4.55 (dd, 2H), 4.02 to 3.94 (m, 2H), 3.65 (brt, 2H), 3.51 (s, 3H), 3.07 (brt, 2H), 2.72 (s, 2H), 2.31 (s, 3H), 1.11 (t, 3H)

Example 2: Formulation of Amlodipine Malonate Salt-Containing Tablets

Anhydrous calcium hydrogen phosphate (315 g) and microcrystalline cellulose (525 g, 90 μm) were combined and transferred to a drum. The amlodipine malonate salt (70 g) and microcrystalline cellulose (187.5 g, 50 μm) were then combined and passed through the screen into the drum containing the powder mixture. The screen used in the previous step was washed with microcrystalline cellulose (525 g, 90 μm). Anhydrous calcium hydrogen phosphate (315 g) was added to the mixture and the entire mixture was blended for 10 minutes. Sodium starch glycolate (40 g) was then added to the mixture and blended for 6 minutes. Finally, magnesium stearate (20 g) was added and the resulting mixture was blended for 3 minutes. The powder mixture was then compressed into tablets by conventional methods.

Example 3 Formulation of Amlodipine Malonate Salt-Containing Capsules

Microcrystalline cellulose (525 g, 90 μm) and dry corn starch were premixed and then the amlodipine malonate salt (70 g) was mixed with a portion of the premix and sieved. The remaining premix was added and mixed for 10 minutes, then sieved and further mixed for 5 minutes. And the capsule of appropriate size was made to manufacture the capsule.

Example 4 Formulation of Amlodipine Malonate Salt-Containing Injections

Sodium chloride was dissolved in sterile water for injection and propylene glycol was mixed with this solution. Amlodipine malonate salt was added, and when dissolved, additional sterile water for injection was added to prepare a solution of the desired concentration. This solution was filtered through a sterile filter and filled into sterile ampoules used as injection containers.

Experimental Example 1: Oral Toxicity Test

Table 1 compares the oral toxicity of benzene sulfonic acid forming crystalline acid addition salts of amlodipine besylate and malonic acid forming crystalline acid addition salts of amlodipine malonate salts. Toxicity data for benzene sulfonic acid were taken from Registry of Toxic Effects of Chemical Substances (RTECS) Data.

Acid Route of administration Animals Dosage source Benzene Sulphonic Acid oral- Rat LD ₅₀ 890 μl / kg  AIHAAP 23, 95, 1962 oral- Bird LD ₅₀ 75 mg / kg  TXAPA9 21, 315, 1972 Malonic acid oral- mouse LD ₅₀ 4000 mg / kg  BIJOAK 34, 1196, 1940 oral- Rat LD ₅₀ 1310 mg / kg  BIOFX 22-3, 1971 LD ₅₀ : 50% lethal dose

As shown in Table 1, the benzene sulfonic acid used to prepare the crystalline acid addition salt of amlodipine is toxic as the compound itself, but it can be seen that the malonic acid used in the present invention exhibits relatively low toxicity compared to benzene sulfonic acid. .

Experimental Example 2: Solubility Test

In general, in preparing a pharmaceutically acceptable salt, it should be possible to prepare a solution that is close to the pH of blood (pH 7.4) and has a solubility in the pH range of 1 to 7.5 or greater than 1 mg / ml. Thus, in this experiment, the solubility and pH at saturation of the amlodipine malonate salt of the present invention was measured and compared with the conventional amlodipine besylate salt.

Solubility experiment was performed by dissolving each compound in distilled water according to the method introduced in the Korean Pharmacopoeia, and then analyzing the solution by liquid chromatography to measure the amount dissolved based on amlodipine base (free base), The results are shown in Table 2 below.

Amlodipine salt Solubility (mg / ml) PH at saturation Amlodipine Besylate 1.47 6.2 Amlodipine malonic acid 2.94 4.2

As shown in Table 2, the amlodipine malonate salt of the present invention can be confirmed that the pH and solubility at saturation is improved by more than two times compared to the conventional amlodipine besylate salt.

Experimental Example 3: Stability Test

 The following Table 3 shows the results of the light stability comparison experiment, the total amount of light is 200 W · h / ㎡ for ultraviolet (UV) and visible light (VIS) is 1,200,000 lux.h.

Amlodipine salt % Of active substance Early UV-rays Visible light Amlodipine Besylate 100 86.29 92.70 Amlodipine malonic acid 100 97.61 96.38

As shown in Table 3, compared to the conventional amlodipine besylate salt, the amlodipine malonate salt of the present invention was confirmed that the light stability to UV or visible light is much better.

As described above, the amlodipine malonate salt according to the present invention has relatively low toxicity malonic acid compared to conventional amlodipine besylate salts prepared using benzene sulfonic acid as a crystalline acid addition salt suitable for the preparation of pharmaceutical formulations. While using, it satisfies the same physicochemical criteria as the amlodipine besylate salt, and thus may be usefully used as a pharmaceutical composition for treating cardiovascular diseases.

Claims (10)

Amlodipine malonate salt characterized by the following formula (1): [Formula 1] The amlodipine malonate salt of claim 1, wherein the compound is an isomer or an isomer mixture. In an organic solvent, a method for preparing the amlodipine malonate salt represented by the following formula (1) characterized in that it is prepared by reacting amlodipine represented by the following formula (2) with malonic acid represented by the following formula (3) [Formula 1] The method of claim 3, wherein the concentration of amlodipine in the reaction solution is characterized in that 3 to 60% by weight. The method of claim 3, wherein the malonic acid represented by Formula 3 is used in the range of 0.1 to 5.0 equivalents relative to amlodipine. The method of claim 3, wherein the reaction is carried out at a temperature range of -10 to 50 ℃. The method of claim 3, wherein the reaction solvent is an organic solvent selected from the group consisting of methanol, ethanol, isopropanol and acetonitrile. The method of claim 3, wherein the amlodipine malonate salt represented by Formula 1 is an isomer compound or an isomer mixture. A pharmaceutical composition for treating cardiovascular diseases, wherein the isomeric compound or isomer mixture of the amlodipine malonate salt represented by Formula 1 is an active ingredient: [Formula 1] The pharmaceutical composition for treating cardiovascular diseases according to claim 9, wherein the composition is formulated as a tablet, capsule, or injection.