JP2005538103A - Amlodipine organic acid salt - Google Patents

Abstract

Disclosed is a novel organic acid salt of amlodipine, a process for its production, and a pharmaceutical composition containing it as a therapeutically active ingredient.

Description

TECHNICAL FIELD The present invention relates to amlodipine (2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid) represented by the following chemical formula 1. The present invention relates to a novel organic acid salt of acid 3-ethyl 5-methyl ester), a process for producing the same, and a pharmaceutical composition containing this as an active ingredient.

BACKGROUND ART Amlodipine is used for the treatment of hypertension because of its action to block calcium channels in the body. This calcium channel blocker is found in many prior art.

  European Patent Publication No. 89,167 describes hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate Disclosed are amlodipine acid salts that can be formed from acids that can form non-toxic acid addition salts with pharmaceutically acceptable anions such as

  US Pat. No. 6,291,490 introduces a pharmaceutical composition containing as the active ingredient S-(−)-amlodipine, which has a potent action in the treatment of hypertension without the side effects associated with administration of a racemic mixture of amlodipine. doing.

  US Pat. No. 4,879,303 and Korean Patent Publication No. 1989-3375 disclose amlodipine besylate which is (1) soluble and (2) stable. Physicochemical properties such as (3) non-hygroscopicity, and (4) processability into tablet dosage forms, which are superior to amlodipine salts such as hydrochloride, acetate and mesylate ing.

  However, since amlodipine besylate currently used has a relatively low solubility at pH 1 to 7.4, saturation pH acts as an important factor. A salt that provides a solution having a pH close to that of blood (7.4) in distilled water is easily miscible in vivo without any change in its solubility, and can be easily buffered within the desired pH range. preferable. Since the saturation pH of amlodipine vegrate is as low as about 6.6, a salt with a saturation pH in distilled water close to 7.4 (blood pH) is required. Furthermore, it has been found that amlodipine besylate is sensitive to light, so that degradation products are observed when exposed to light.

  In addition, amlodipine besylate is disadvantageous because of benzenesulfonic acid used in its production process. That is, benzenesulfonic acid is corrosive and toxic, and is difficult to process industrially. In addition, because of its high hygroscopicity, special management is required during transportation, transportation and use. Another drawback is that the water content of benzenesulfonic acid is as high as about 10%. In order to solve these problems, ammonium benzene sulfonate is used as an alternative, but the generation of ammonia gas is accompanied. This method requires a separate step for absorbing and inactivating ammonia gas (PCT Publication No. WO1999 / 52873).

DISCLOSURE OF THE INVENTION As a result of thorough research on the therapeutic effective amlodipine organic acid salt to solve the problems of the prior art, the amlodipine camphorsulfonate is soluble and non-hygroscopic. As well as having excellent physicochemical properties such as chemical properties, chemical and light stability, and processability to pharmaceutical dosage forms, camphorsulfonic acid is less toxic and corrosive than benzenesulfonic acid, so amlodipine camphorsulfone It has been found that the acid salts are industrially and medically useful.

  Accordingly, it is an object of the present invention to provide amlodipine camphorsulfonate.

  It is another object of the present invention to provide a process for producing amlodipine camphorsulfonate.

  Still another object of the present invention is to provide a pharmaceutical composition containing amlodipine camphorsulfonate as a medically active ingredient.

  According to one aspect of the present invention, amlodipine camphorsulfonate, preferably amlodipine light-stable camphorsulfonate, more preferably amlodipine (1S)-(+)-10-camphorsulfonate or amlodipine (1R)- (-)-10-camphorsulfonate, most preferably crystalline form of amlodipine camphorsulfonate is provided.

  According to another feature of the invention, amlodipine is combined with camphorsulfonic acid, preferably (1S)-(+)-10-camphorsulfonic acid or (1R)-(−)-10-camphorsulfonic acid, in an inert solvent. There is provided a process for producing amlodipine camphorsulfonate comprising reacting.

  According to yet another aspect of the present invention, comprising a therapeutically effective amount of amlodipine camphorsulfonate and a pharmaceutically acceptable diluent or carrier, the composition is effective in treating ischemic heart disease or hypertension. Pharmaceutical compositions in dosage forms such as tablets, capsules, solutions or injections are provided.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention includes amlodipine camphor sulfonate represented by the following chemical formula 2.

  Compared to the commercially available form of amlodipine besylate, amlodipine camphor sulfonate exhibits a non-hygroscopicity equal to or greater than that of the amlodipine camphorsulfonate, the degree of processing into a dosage form and chemical stability. In particular, the amlodipine camphor sulfonate of the present invention has a pH close to that of blood (7.4) and has a much improved photostability compared to conventional organic acid salts. It can be stably stored for a long period of time without loss of medicinal properties.

  The present invention also includes a photostable amlodipine camphor sulfonate. As used herein, the term “light stable” means that after storage for 4 weeks while exposed to sunlight at 25 ° C., the mass is 90% or more of the original mass, preferably 95% or more, more preferably It means maintaining 98% or more.

  Suitable camphor sulfonic acids for the preparation of the amlodipine camphor sulfonates according to the invention are racemic mixtures, or preferably optically pure substances, ie (1S)-(+)-10-camphor sulfonic acid or (1R)-(- ) -10-camphorsulfonic acid.

  The amlodipine camphor sulfonate according to the invention may be in crystalline or amorphous form, but is preferably in crystalline form.

  The present invention also includes a process for producing amlodipine camphorsulfonate. This amlodipine camphor sulfonate can be produced by reacting amlodipine with camphor sulfonic acid in an inert solvent as shown in the following reaction formula 1.

  The camphor sulfonic acid used as the reactant is preferably an optically pure material, ie (1S)-(+)-10-camphor sulfonic acid or (1R)-(−)-10-camphor sulfonic acid.

  Camphorsulfonic acid, a stable white solid that has been FDA-accepted for use in pharmaceuticals, is commercially available as a white solid (purity 98% or higher) and is not hygroscopic, corrosive, and toxic. Due to this property, camphorsulfonic acid is easy to handle and can be safely mass-produced.

  Examples of the inert solvent suitable for the production method of the present invention include ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, hexane, isopropyl ether, and preferably methanol.

  Of the inert solvents, camphorsulfonic acid is used in an amount of 1 to 2 equivalents, preferably 1.02 to 1.2 equivalents per equivalent of amlodipine. The reaction is carried out at -5 to 30 ° C, preferably 0 to 15 ° C for 0.5 to 5 hours, preferably 1 to 3 hours.

  According to the method of the present invention, amlodipine camphor sulfonate can be produced in a yield of 90% or more.

  The present invention also includes a pharmaceutical composition useful for the treatment of ischemic heart disease or hypertension comprising a therapeutically effective amount of amlodipine camphorsulfonate and a pharmaceutically acceptable diluent or carrier.

  The composition of the present invention can be formulated into oral dosage forms such as granules, powders, liquids, tablets, capsules and dry syrups, or parenteral dosage forms such as injections, but is not limited thereto. is not. Preferably, the composition of the present invention is in the form of a tablet, capsule, solution or injection.

  To be therapeutically effective, amlodipine camphorsulfonate is administered in an amount of 2-10 mg per day based on the weight of amlodipine. The unit dosage form contains amlodipine camphorsulfonate in an amount of 3-16 mg.

  In practical use, amlodipine camphor sulfonate is a pharmaceutically acceptable diluent or carrier selected from excipients, disintegrants, binders and lubricants and mixtures thereof as active ingredients in the mixture. Can be combined. The carrier can take a wide variety of forms depending on the desired dosage form. When the composition is produced into a solid dosage form such as a tablet or a hard capsule, microcrystalline cellulose, lactose, low-substituted hydroxycellulose, etc. are used as excipients, sodium starch glycolate, anhydrous calcium hydrogen phosphate, etc. as disintegrants , Polyvinyl pyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose and the like can be used as a binder, and magnesium stearate, silica, talc and the like can be used as a lubricant.

  In order to impart gloss to the tablet, the formulation can include additives such as anhydrous dicalcium phosphate. In order to prevent moisture in the air from penetrating into the tablet, it may have a water-insoluble coat. The coat base must have a dense molecular structure and preferably have low solubility in water. Suitable for this base are methacrylic acid copolymers, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol and combinations thereof. The coat may also contain conventional additives such as plasticizers, preservatives, colorants, light-shielding agents.

  The composition of the present invention may be a liquid agent such as a bactericidal aqueous solution, or a liquid agent such as an injection. Preferably, such a solution may contain 10-40% propylene glycol and an amount (eg, approximately 1%) of sodium chloride sufficient to prevent a hemolytic reaction.

  The invention can be more clearly understood from the following examples, which are given by way of illustration and not limitation of the invention.

EXAMPLES Various physical properties of amlodipine camphorsulfonate prepared according to the present invention were tested. First, in order to test the processability to a dosage form, amlodipine camphor sulfonate was formulated into tablets, capsules and aqueous solutions. Amlodipine camphor sulfonate was also compared to known amlodipine salts in terms of hygroscopicity, solubility, stability, and photostability.

  In the following reference examples, conventional amlodipine salts were prepared by known methods.

Reference Example 1: Production of amlodipine besylate Amlodipine was produced as disclosed in Korean Patent Publication No. 87-809. Also, amlodipine besylate was produced by adopting the method described in Korean Patent Publication No. 95-7228.

Reference Example 2: Production of amlodipine para-toluenesulfonate 20 g of para-toluenesulfonic acid was dissolved in 100 ml of methanol. To this solution, 40 g of amlodipine produced in Reference Example 1 and 500 ml of methanol were added dropwise, followed by stirring at 23 ° C. for 3 hours.

  The solid thus produced was filtered, washed with 100 ml of methanol and 100 ml of n-hexane and dried in vacuum.

Reference Example 3: Production of amlodipine hydrochloride 12 ml concentrated hydrochloric acid was added to 100 ml methanol. After 54 g of amlodipine produced in Reference Example 1 and 500 ml of methanol were added dropwise, the mixture was stirred at 23 ° C. for 3 hours.

  The solid thus produced was filtered, washed with 100 ml of methanol and 100 ml of n-hexane and dried in vacuum.

Example 1: Preparation of amlodipine (1S)-(+)-10-camphorsulfonic acid salt In a 1 L 3-neck flask, (1S)-(+)-10-camphorsulfonic acid (24.36 g, 1.05) Equivalent) was dissolved in methanol (200 ml). To this flask was added dropwise a solution of amlodipine (40.8 g, 0.1 mol) and methanol (300 ml). The resulting solution was stirred at 23 ° C. for 2 hours, cooled at 7 ° C., and stirred for 1 hour to produce a precipitate. This precipitate was washed with methanol (100 ml) and n-hexane (100 ml) at 5 ° C., filtered, and then vacuum dried at 35 ° C. to give 57.6 g of amlodipine (1S)-(+) as a white crystalline solid. -Camphorsulfonate was obtained (90% yield).

  Elemental analysis and melting point determination of the produced amlodipine (1S)-(+)-10-camphorsulfonate were performed.

Example 2: Preparation of amlodipine (1R)-(-)-10-camphorsulfonic acid salt In a 1 L 3-neck flask, (1R)-(-)-10-camphorsulfonic acid (24.36 g, 1.05) Equivalent) was dissolved in methanol (200 ml). To this flask was added dropwise a solution of amlodipine (40.8 g, 0.1 mol) and methanol (300 ml). The resulting solution was stirred at 22 ° C. for 2 hours, cooled at 7 ° C., stirred for 1 hour, and then filtered to produce a precipitate. This precipitate was washed with methanol (100 ml) and n-hexane (100 ml) at 5 ° C., dried in vacuo at 35 ° C., and 57.6 g of amlodipine (1R)-(−)-camphorsulfonic acid as a white crystalline solid. A salt was obtained (90% yield).

  Elemental analysis and melting point determination of the produced amlodipine (1R)-(−)-10-camphorsulfonate were performed.

Example 3: Manufacture of tablets containing amlodipine camphor sulfonate The ingredients shown in Table 3 were formulated to produce tablets containing amlodipine camphor sulfonate.

  The components were mixed, the mixture was compressed with a roller compressor manufactured by Jowoon Machinery, and the compressed product was produced into tablets using a tableting machine manufactured by Erweka.

Example 4: Manufacture of tablets containing amlodipine camphor sulfonate The ingredients shown in Table 4 were formulated to produce tablets containing amlodipine camphor sulfonate.

  Lactose, crospovidone and polyvinylpyrrolidone K90 were premixed. The premix was granulated by fluid bed assembly (SPIRA FLOW), the granules were mixed with the remaining ingredients and made into tablets on an Erweka tablet press.

Example 5: Production of capsules containing amlodipine camphor sulfonate From the components shown in Table 5, capsules containing amlodipine camphor sulfonate were produced.

  The components were mixed, the mixture was compressed with a roller compressor manufactured by Jowoon Machinery, and the compressed product was filled into hard gelatin capsules using a capsule filler manufactured by Boshe.

Example 6: Production of capsules containing amlodipine camphor sulfonate The ingredients shown in Table 6 were formulated to produce capsules containing amlodipine camphor sulfonate.

  Lactose, crospovidone and polyvinylpyrrolidone K90 were premixed. The premix was granulated by fluid bed assembly (SPIRA FLOW), the granules were mixed with the remaining ingredients and filled into hard gelatin capsules with a Boshe capsule filling machine.

Example 7: Hygroscopicity Test of Amlodipine Camphor Sulfonate Water Content by Measuring Amlodipine Camphor Sulfonate Produced in Example 1 and Amlodipine Besylate Produced in Reference Example 1 at Various Humidities of 25 ° C (K. F.% water) was tested. The results are shown in Table 7 below.

  As shown in Table 7, the non-hygroscopicity of amlodipine camphor sulfonate is more than the non-hygroscopic property of amlodipine besylate. Since it has a hygroscopicity of 0.5% or less at a relative humidity of 95%, this amlodipine camphor sulfonate is suitable for preparations such as tablets, capsules and injections.

Example 8: Solubility Test of Amlodipine Camphorsulfonate Salts of amlodipine camphorsulfonate prepared in Example 1 and amlodipine besylate prepared in Reference Example 1 were measured in various solvents at 25 ° C. The results are shown in Table 7 below. The solubility (mg / ml) in Table 8 is a value based on the weight of amlodipine converted from salt.

  As shown in Table 8, the solubility of amlodipine camphorsulfonate in distilled water and various pH buffers is similar to that of amlodipine besylate. However, while the saturation pH of the proposed alluvial pinbesylate is low at 6.6, amlodipine camphorsulfonate has an excellent pharmacological property since amlodipine camphorsulfonate is 7.2 close to the pH value of blood. Indicates.

Example 9: Stability test of amlodipine camphor sulfonate The amlodipine camphor sulfonate produced in Example 1 and the amlodipine besylate produced in Reference Example 1 were accelerated at 60 ° C. and the results are summarized in Table 9 below.

  As shown in Table 9, when measured by an accelerated test at 60 ° C., the content of amlodipine camphorsulfonate was almost unchanged as in amlodipine besylate. The data in Table 9 shows that the chemical stability of amlodipine camphor sulfonate is superior to that of amlodipine besylate over temperature.

2. Chemical stability of amlodipine camphor sulfonate in aqueous solution In order to examine the stability in aqueous solution, amlodipine camphor sulfonate prepared in Example 1 and amlodipine besylate prepared in Reference Example 1 were distilled separately. Dissolved in water. After this aqueous solution was stored at 25 ° C. in a completely light-shielded state for 4 weeks, the salt content was measured by HPLC under the same conditions as in the solid state.

  According to the results of this light-shielding stability test, no degradation products or content changes were found in both amlodipine camphorsulfonate and amlodipine besylate.

Example 10: Photostability test of amlodipine camphor sulfonate Amlodipine camphor sulfonate manufactured in Example 1, amlodipine besylate, and other amlodipine salts prepared in Reference Examples 1 to 3 were used. These were stored at 25 ° C. for 4 weeks while exposed to sunlight. The salt content was measured by HPLC under the same conditions as in the chemical stability test, and the results are shown in Table 10 below.

  As shown in Table 10, the decrease in the content of amlodipine camphor sulfonate was smaller than the other amlodipine salts. It was also found that amlodipine besylate changed from white to yellow, and there was no color change of amlodipine camphorsulfonate. Therefore, according to these data, since amlodipine camphor sulfonate is superior in photostability compared to amlodipine besylate, it is very advantageous to be applied to a blood pressure lowering agent taken for a long time.

In terms of industrial applicability, the data shown in the above examples show that the amlodipine camphor sulfonate of the present invention is excellent in non-hygroscopicity, chemical and light stability, solubility, and processability to a dosage form. It has a good physicochemical property. In particular, since it has a saturated pH value (pH 7.2) close to the saturated pH of blood, the amlodipine camphor sulfonate of the present invention is easily transmitted to the body of a patient. Also, camphorsulfonic acid is industrially useful because it is not corrosive and toxic.

Claims (9)

  Amlodipine camphor sulfonate.   The camphorsulfonate salt of amlodipine according to claim 1, wherein the camphorsulfonate salt is stable to light.   The camphorsulfonic acid of amlodipine according to claim 1, wherein the camphorsulfonic acid is (1S)-(+)-10-camphorsulfonic acid or (1R)-(-)-10-camphorsulfonic acid. Acid salt.   The amlodipine camphor sulfonate according to claim 1, wherein the amlodipine camphor sulfonate is in a crystalline form.   A method for producing amlodipine camphor sulfonate, comprising reacting amlodipine with camphor sulfonic acid in an inert solvent.   The amlodipine camphor sulfonic acid according to claim 5, wherein the camphor sulfonic acid is (1S)-(+)-10-camphor sulfonic acid or (1R)-(−)-10-camphor sulfonic acid. Method for producing salt.   A therapeutically effective amount of camphorsulfonate of amlodipine according to any one of claims 1 to 4, and a pharmaceutically acceptable diluent or carrier, for the treatment of ischemic heart disease or hypertension Pharmaceutical composition.   The pharmaceutical composition according to claim 7, characterized in that the composition is in the form of a tablet or capsule.   The pharmaceutical composition according to claim 7, wherein the composition is in the form of a solution or an injection.