WO2004072036A1 - Novel amlodipine cyclamate salt and a preparation method thereof - Google Patents
Novel amlodipine cyclamate salt and a preparation method thereof Download PDFInfo
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- WO2004072036A1 WO2004072036A1 PCT/KR2004/000285 KR2004000285W WO2004072036A1 WO 2004072036 A1 WO2004072036 A1 WO 2004072036A1 KR 2004000285 W KR2004000285 W KR 2004000285W WO 2004072036 A1 WO2004072036 A1 WO 2004072036A1
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- amlodipine
- cyclamate
- following formula
- present
- besylate
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B25—HAND TOOLS; PORTABLE POWER-DRIVEN TOOLS; MANIPULATORS
- B25B—TOOLS OR BENCH DEVICES NOT OTHERWISE PROVIDED FOR, FOR FASTENING, CONNECTING, DISENGAGING OR HOLDING
- B25B7/00—Pliers; Other hand-held gripping tools with jaws on pivoted limbs; Details applicable generally to pivoted-limb hand tools
- B25B7/12—Pliers; Other hand-held gripping tools with jaws on pivoted limbs; Details applicable generally to pivoted-limb hand tools involving special transmission means between the handles and the jaws, e.g. toggle levers, gears
- B25B7/126—Pliers; Other hand-held gripping tools with jaws on pivoted limbs; Details applicable generally to pivoted-limb hand tools involving special transmission means between the handles and the jaws, e.g. toggle levers, gears with fluid drive
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B25—HAND TOOLS; PORTABLE POWER-DRIVEN TOOLS; MANIPULATORS
- B25B—TOOLS OR BENCH DEVICES NOT OTHERWISE PROVIDED FOR, FOR FASTENING, CONNECTING, DISENGAGING OR HOLDING
- B25B27/00—Hand tools, specially adapted for fitting together or separating parts or objects whether or not involving some deformation, not otherwise provided for
- B25B27/02—Hand tools, specially adapted for fitting together or separating parts or objects whether or not involving some deformation, not otherwise provided for for connecting objects by press fit or detaching same
- B25B27/026—Hand tools, specially adapted for fitting together or separating parts or objects whether or not involving some deformation, not otherwise provided for for connecting objects by press fit or detaching same fluid driven
Definitions
- the present invention relates to a novel amlodipine cyclamate having the following formula:
- Amlodipine (3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)- 1 ,4- dihydro-6-methylpyridine-3,5-dicarboxylate) is a potent and long-acting calcium channel blocker, which is useful as an anti-ischemic and antihypertensive agent.
- EP 0 089 167 A discloses various pharmaceutically acceptable salt forms of amlodipine. Particularly, it describes pharmaceutically acceptable acid addition salts formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochlonde, hydrobromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, and gluconate. It further describes that of these salts maleate is the most preferable.
- the salts disclosed in the above patent application are pharmaceutically acceptable, but have a disadvantage hard to be manufactured into pharmaceutically suitable dosage forms.
- amlodipine benzenesulfonate hereinafter, referred to as "besylate”
- besylate amlodipine benzenesulfonate
- Korean Patent Application Laid-open No. 2002-76561 discloses that amlodipine camsylate (camphosulfonic acid) is better than amlodipine besylate in view of stability, etc.
- the present inventors have performed extensive studies to develop a novel pharmaceutically acceptable acid addition salt of amlodipine having lower toxicity as well as higher stability, solubility, non-hygroscopicity, and processability than the known acid addition salts of amlodipine.
- the present inventors completed the present invention by finding out that a salt of amlodipine prepared by reacting amlodipine with cyclamic acid, which has been widely used as a food additive and so has little problem of toxicity, exhibits not only lower toxicity but also higher stability, solubility, non- hygroscopicity, and processability than the known acid addition salts of amlodipine.
- One aspect of the present invention is to provide amlodipine cyclamate having the following formula:
- Amlodipine cyclamate according to the present invention has remarkably lower toxicity than the known acid addition salts of amlodipine. This can be supported by the fact that cyclamic acid (CA name: cyclohexylsulfamic acid) has been registered as an inert additive by the United States Food and Drug Administration, and is a safe material enough to be widely used as a food additive in many European countries. Such low toxicity of amlodipine cyclamate will be apparent from toxicity comparison between amlodipine cyclamate and amlodipine besylate. For this purpose, LD 50 values of cyclamic acid and cyclamate, and benzenesulfonic acid and besylate on animals are shown in the following Table 1.
- cyclamic acid has 10,000-fold higher LD value than benzenesulfonic acid, and sodium cyclamate has 2-fold higher LD value than sodium besylate. From this result, it can be inferred that amlodipine cyclamate has much lower toxicity than amlodipine besylate.
- amlodipine cyclamate according to the present invention has much better stability, solubility, non-hygroscopicity, and processability than amlodipine besylate currently on market.
- Another aspect of the present invention is to provide a method for preparing amlodipine cyclamate having the following formula:
- amlodipine having the following formula:
- cyclamic acid having the following formula: (3) in an organic solvent; and recovering amlodipine cyclamate.
- the organic solvent is preferably selected from methanol, ethanol, isopropyl alcohol, ethyl acetate, hexane, or acetonitrile.
- the method of the present invention may be performed by introducing cyclamic acid into a solution of amlodipine of formula (2) or a reaction solution to prepare amlodipine of formula (2).
- the concentration of the solution of amlodipine base of formula (2) is controlled within the range of 3 to 30 weight%.
- To the amlodipine solution is added 1 to 2 equivalents of cyclamic acid. The mixture is stirred at -5 ° C to 50 ° C, and then, is optionally concentrated under reduced pressure to crystallize amlodipine cyclamate.
- a third aspect of the present invention is to provide a pharmaceutical composition for preventing or treating heart diseases or hypertension comprising amlodipine cyclamate of formula (1) together with one or more pharmaceutically acceptable carriers.
- the pharmaceutically acceptable carriers include excipients, binders, humectants, disintegrators, lubricants, surfactants and the like.
- Amlodipine cyclamate according to the present invention may be administered by the same administration routes, in the same dosage forms, and with the same range of effective doses, as the known amlodipine formulations.
- amlodipine cyclamate may be manufactured into various dosage forms for oral or parenteral administration.
- solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like.
- Such solid formulations may be made by mixing amlodipine cyclamate of formula (1) with one or more excipients, for example, starch, sucrose, lactose, gelatin, etc.
- excipients for example, starch, sucrose, lactose, gelatin, etc.
- lubricants such as magnesium stearate and talc may be added thereto.
- liquid formulations for oral administration include suspensions, solutions for internal use, emulsions, syrups and the like.
- diluents such as humectants, sweeteners, aromatics, and preservatives, as well as commonly used simple diluents such as water and liquid paraffin, may be added thereto.
- parenteral formulations include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulation, suppositories and the like.
- Propylene glycol, polyethylene glycol, a plant oil such as olive oil, or an injectable ester such as ethyl oleate may be used as a non-aqueous solvent or a suspending solvent.
- WitepsolTM, Macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin and the like may be used as bases for suppositories.
- the effective dose of amlodipine cyclamate according to the present invention is in the range of 1.0 to 10.0 mg/kg, and preferably, 5.0 to 8.0 mg/kg.
- Amlodipine base (34 g, 0.083 moles) was slurried in ethyl acetate (700 ml). Cyclamic acid (15 g, 0.084 moles) was dissolved in industrial ethanol (30 ml), and added to the slurry of the base. The resulting slurry was stirred at room temperature for 4 hours. The resulting crystals were filtered off and washed with ethyl acetate (20 ml) to obtain white solids, which were dried under reduced pressure at 50 ° C for 12 hours to give 42.3 g (yield: 87%) of amlodipine cyclamate with the following analytical data: Molecular formula: C 26 H 38 ClN 3 O 8 S
- Amlodipine base (34 g, 0.083 moles) was slurried in acetonitrile (680 ml). Cyclamic acid (15 g, 0.084 moles) was dissolved in methanol (30 ml), and added to the slurry of the base. The resulting slurry was stirred at room temperature for 4 hours. The resulting crystals were filtered off and washed with acetonitrile (20 ml) to obtain white solids, which were dried under reduced pressure at 50 ° C for 12 hours to give 41.5 g (yield: 85%) of amlodipine cyclamate with the analytical data in the above Example 1.
- Amlodipine base (34 g, 0.083 moles) was slurried in isopropyl alcohol (600 ml). Cyclamic acid (15 g, 0.084 moles) was dissolved in isopropyl alcohol (80 ml), and added to the slurry of the base. The resulting slurry was stirred at 0 ° C for 4 hours. The resulting crystals were filtered off and washed with isopropyl alcohol (20 ml) to obtain white solids, which were dried under reduced pressure at 50 ° C for 12 hours to give 39.8 g (yield: 82%) of amlodipine cyclamate with the analytical data in the above Example 1.
- Amlodipine base (34 g, 0.083 moles) was slurried in industrial ethanol (300 ml). Cyclamic acid (15 g, 0.084 moles) was dissolved in isopropyl alcohol (80 ml), and added to the slurry of the base. While slowly stirring the mixture at 0 °C for 4 hours, hexane (300 ml) was added to the resulting slurry. The resulting crystals were filtered off and washed with hexane (50 ml) to obtain white solids, which were dried under reduced pressure at 50 ° C for 12 hours to give 41.9 g (yield: 86%) of amlodipine cyclamate with the analytical data in the above Example 1.
- Solubility test was performed according to the method of the Korean Pharmacopoeia. Specifically, each 2 g of powder of amlodipine cyclamate prepared in Example 1 and amlodipine besylate (Medicorp., India) was dissolved and saturated in 25 ml of distilled water in a separate container. Each solution was analyzed by liquid chromatography to measure its dissolved amount based on amlodipine free base. The results are shown in the following Table 2.
- solubility of 1 mg/ml or more at pH 1 to 7.5 is recommended, and salts providing solutions having a pH close to that of blood (7.4) are preferred.
- amlodipine cyclamate has higher solubility than amlodipine besylate.
- amlodipine besylate began to degrade in 20 days and 0.008% thereof was degraded in 40 days.
- amlodipine cyclamate according to the present invention began to degrade in 40 days, and further, only 0.003% thereof was degraded at that time.
- amlodipine cyclamate was confirmed to have much higher stability than amlodipine besylate.
- Moisture-absorbed films in the solid state where drug content is high can act as a vector for hydrolysis and chemical breakdown, and thus, it is preferred to prepare a non- hygroscopic salt for a stable formulation.
- amlodipine cyclamate of the present invention was confirmed to have higher non-hygroscopicity than amlodipine besylate by about 2 times.
- Test Example 4 Stickiness test in a tabletting machine
- amlodipine besylate (Medicorp., India).
- a drug which does not adhere to the surface of tablet punch has excellent processability.
- amlodipine cyclamate of the present invention was confirmed to have nearly the same amount of sticking material as amlodipine besylate, and thus, to have excellent anti-adhesion property.
- Amlodipine cyclamate of formula (1) according to the present invention has not only lower toxicity but also higher stability, solubility, non-hygroscopicity, and processability than the known amlodipine besylate, and thus, is very useful for industrial applications.
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The present invention provides amlodipine cyclamate, a novel pharmaceutically acceptable acid addition salt of amlodipine, which is a potent and long-acting calcium channel blocker useful as an anti-ischemic or anti-hypertensive agent. Amlodipine cyclamate, which may be prepared by reacting amlodipine with cyclamic acid, has pharmacologically excellent properties such as low toxicity, and high stability, solubility, non-hygroscopicity, and processability.
Description
NOVEL AMLODIPINE CYCLAMATE SALT AND A PREPARATION
METHOD THEREOF
TECHNICAL FIELD
The present invention relates to a novel amlodipine cyclamate having the following formula:
BACKGROUND ART
Amlodipine (3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)- 1 ,4- dihydro-6-methylpyridine-3,5-dicarboxylate) is a potent and long-acting calcium channel blocker, which is useful as an anti-ischemic and antihypertensive agent.
EP 0 089 167 A discloses various pharmaceutically acceptable salt forms of amlodipine. Particularly, it describes pharmaceutically acceptable acid addition salts formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochlonde, hydrobromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, and gluconate. It further describes that of these salts maleate is the most preferable. The salts disclosed in the above patent application are pharmaceutically acceptable, but have a disadvantage hard to be manufactured into pharmaceutically suitable dosage forms.
Korean Patent Publication No. 1995-7228 discloses that amlodipine benzenesulfonate (hereinafter, referred to as "besylate") has higher stability and solubility, and can be more conveniently manufactured into pharmaceutical dosage forms than the amlodipine salts disclosed in the above patent publication.
In addition, Korean Patent Application Laid-open No. 2002-76561 discloses that amlodipine camsylate (camphosulfonic acid) is better than amlodipine besylate in view of stability, etc.
However, there has still been a need to develop a novel pharmaceutically acceptable acid addition salt of amlodipine having lower toxicity as well as higher stability, solubility, non-hygroscopicity, and processability than the known acid addition salts of amlodipine.
DISCLOSURE OF THE INVENTION
The present inventors have performed extensive studies to develop a novel pharmaceutically acceptable acid addition salt of amlodipine having lower toxicity as well as higher stability, solubility, non-hygroscopicity, and processability than the known acid addition salts of amlodipine. As a result, the present inventors completed the present invention by finding out that a salt of amlodipine prepared by reacting amlodipine with cyclamic acid, which has been widely used as a food additive and so has little problem of toxicity, exhibits not only lower toxicity but also higher stability, solubility, non- hygroscopicity, and processability than the known acid addition salts of amlodipine.
One aspect of the present invention is to provide amlodipine cyclamate having the following formula:
Amlodipine cyclamate according to the present invention has remarkably lower toxicity than the known acid addition salts of amlodipine. This can be supported by the fact that cyclamic acid (CA name: cyclohexylsulfamic acid) has been registered as an inert additive by the United States Food and Drug Administration, and is a safe material enough to be widely used as a food additive in many European countries. Such low toxicity of amlodipine cyclamate will be apparent from toxicity comparison between amlodipine cyclamate and amlodipine besylate. For this purpose, LD50 values of cyclamic acid and cyclamate, and benzenesulfonic acid and besylate on animals are shown in the following Table 1.
Table 1
6. HPE (Handbook of Pharmaceutical Excipients Third Edition edited by Arthur H. Kibbe- American Pharmaceutical Association and Pharmaceutical Press)
As shown in the above Table 1, cyclamic acid has 10,000-fold higher LD value than benzenesulfonic acid, and sodium cyclamate has 2-fold higher LD value than sodium besylate. From this result, it can be inferred that amlodipine cyclamate has much lower toxicity than amlodipine besylate.
Further, the following examples will clearly confirm that amlodipine cyclamate according to the present invention has much better stability, solubility, non-hygroscopicity, and processability than amlodipine besylate currently on market.
Another aspect of the present invention is to provide a method for preparing amlodipine cyclamate having the following formula:
with cyclamic acid having the following formula:
(3)
in an organic solvent; and recovering amlodipine cyclamate.
The organic solvent is preferably selected from methanol, ethanol, isopropyl alcohol, ethyl acetate, hexane, or acetonitrile. The method of the present invention may be performed by introducing cyclamic acid into a solution of amlodipine of formula (2) or a reaction solution to prepare amlodipine of formula (2).
One example of the present method will be explained in more detail. The concentration of the solution of amlodipine base of formula (2) is controlled within the range of 3 to 30 weight%. To the amlodipine solution is added 1 to 2 equivalents of cyclamic acid. The mixture is stirred at -5 °C to 50 °C, and then, is optionally concentrated under reduced pressure to crystallize amlodipine cyclamate.
A third aspect of the present invention is to provide a pharmaceutical composition for preventing or treating heart diseases or hypertension comprising amlodipine cyclamate of formula (1) together with one or more pharmaceutically acceptable carriers. Examples of the pharmaceutically acceptable carriers include excipients, binders, humectants, disintegrators, lubricants, surfactants and the like.
Amlodipine cyclamate according to the present invention may be administered by the same administration routes, in the same dosage forms, and with the same range of effective doses, as the known amlodipine formulations.
Specifically, amlodipine cyclamate may be manufactured into various dosage forms for oral or parenteral administration. Examples of solid formulations for oral
administration include tablets, pills, powders, granules, capsules and the like. Such solid formulations may be made by mixing amlodipine cyclamate of formula (1) with one or more excipients, for example, starch, sucrose, lactose, gelatin, etc. In addition to such excipients, lubricants such as magnesium stearate and talc may be added thereto. Examples of liquid formulations for oral administration include suspensions, solutions for internal use, emulsions, syrups and the like. Various diluents such as humectants, sweeteners, aromatics, and preservatives, as well as commonly used simple diluents such as water and liquid paraffin, may be added thereto. Examples of parenteral formulations include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulation, suppositories and the like. Propylene glycol, polyethylene glycol, a plant oil such as olive oil, or an injectable ester such as ethyl oleate, may be used as a non-aqueous solvent or a suspending solvent. Witepsol™, Macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin and the like may be used as bases for suppositories.
The effective dose of amlodipine cyclamate according to the present invention is in the range of 1.0 to 10.0 mg/kg, and preferably, 5.0 to 8.0 mg/kg.
BESTMODE FORCARRYINGOUTTHE INVENTION
The present invention will be more specifically illustrated by the following examples. However, the following examples should not be construed to limit the scope of the present invention.
Example 1
Amlodipine base (34 g, 0.083 moles) was slurried in ethyl acetate (700 ml). Cyclamic acid (15 g, 0.084 moles) was dissolved in industrial ethanol (30 ml), and added
to the slurry of the base. The resulting slurry was stirred at room temperature for 4 hours. The resulting crystals were filtered off and washed with ethyl acetate (20 ml) to obtain white solids, which were dried under reduced pressure at 50 °C for 12 hours to give 42.3 g (yield: 87%) of amlodipine cyclamate with the following analytical data: Molecular formula: C26H38ClN3O8S
Melting point: 187. 6 °C
Molecular weight: 588.11
Atomic analysis (%)
Calculated: C; 53.10, H; 6.51, N; 7.14, S; 5.45 Found: C; 52.86, H; 6.49, N; 7.18, S; 5.46
1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.43 (s, 1H), 7.83 (br. 3H), 7.33-7.11 (m, 4H, ArH), 5.29 (s, 1H), 4.72-4.54 (d.d., 2H), 3.96 (q, 2H), 3.65 (m, 2H), 3.49 (s, 3H), 3.06 (m, 2H), 2.87 (m, 1H), 2.30 (s, 3H), 1.86 (m, 2H), 1.58 (m, 2H), 1.47 (m, 1H), 1.14-1.03 (m, 9H)
Example 2
Amlodipine base (34 g, 0.083 moles) was slurried in acetonitrile (680 ml). Cyclamic acid (15 g, 0.084 moles) was dissolved in methanol (30 ml), and added to the slurry of the base. The resulting slurry was stirred at room temperature for 4 hours. The resulting crystals were filtered off and washed with acetonitrile (20 ml) to obtain white solids, which were dried under reduced pressure at 50 °C for 12 hours to give 41.5 g (yield: 85%) of amlodipine cyclamate with the analytical data in the above Example 1.
Example 3
Amlodipine base (34 g, 0.083 moles) was slurried in isopropyl alcohol (600 ml). Cyclamic acid (15 g, 0.084 moles) was dissolved in isopropyl alcohol (80 ml), and added to the slurry of the base. The resulting slurry was stirred at 0 °C for 4 hours. The
resulting crystals were filtered off and washed with isopropyl alcohol (20 ml) to obtain white solids, which were dried under reduced pressure at 50 °C for 12 hours to give 39.8 g (yield: 82%) of amlodipine cyclamate with the analytical data in the above Example 1.
Example 4
Amlodipine base (34 g, 0.083 moles) was slurried in industrial ethanol (300 ml). Cyclamic acid (15 g, 0.084 moles) was dissolved in isopropyl alcohol (80 ml), and added to the slurry of the base. While slowly stirring the mixture at 0 °C for 4 hours, hexane (300 ml) was added to the resulting slurry. The resulting crystals were filtered off and washed with hexane (50 ml) to obtain white solids, which were dried under reduced pressure at 50 °C for 12 hours to give 41.9 g (yield: 86%) of amlodipine cyclamate with the analytical data in the above Example 1.
Test Example 1: Solubility Test
Solubility test was performed according to the method of the Korean Pharmacopoeia. Specifically, each 2 g of powder of amlodipine cyclamate prepared in Example 1 and amlodipine besylate (Medicorp., India) was dissolved and saturated in 25 ml of distilled water in a separate container. Each solution was analyzed by liquid chromatography to measure its dissolved amount based on amlodipine free base. The results are shown in the following Table 2.
Table 2
In general, solubility of 1 mg/ml or more at pH 1 to 7.5 is recommended, and salts providing solutions having a pH close to that of blood (7.4) are preferred. As shown in the above Table 2, amlodipine cyclamate has higher solubility than amlodipine besylate.
Test Example 2: Stability Test
Each 1 g of powder of amlodipine cyclamate prepared from Example 1 and amlodipine besylate (Medicorp., India) was placed in each Petri dish. Each dish was stored at the temperature of 40 °C and the relative humidity of 75% for 10, 20, 30 and 40 days. Then, the residual rate based on the initial amount of the active ingredient was measured by liquid chromatography to evaluate its stability. The results are shown in the following Table 3.
Table 3
Good stability in the solid state is important for tablets or capsules, while good stability in solution is important for aqueous injectable solutions. As shown in the above Table 3, amlodipine besylate began to degrade in 20 days and 0.008% thereof was degraded in 40 days. In comparison, amlodipine cyclamate according to the present invention began to degrade in 40 days, and further, only 0.003% thereof was degraded at that time. Thus, amlodipine cyclamate was confirmed to have much higher stability than amlodipine besylate.
Test Example 3: Non-hygroscopicity test
Each 1 g of powder of amlodipine cyclamate prepared in Example 1 and amlodipine besylate (Medicorp., India) was placed in each Petri dish. Each dish was
stored at the temperature of 40 °C and the relative humidity of 75% for 4 days. Its moisture content was measured according to the moisture quantitation method in the Pharmacopoeia (Karl Fisher method, Metrohm 682 Titroprocessor, Switzerland) in 0, 1, 2, 3 and 4 days, respectively. The results are shown in the following Table 4.
Table 4
Moisture-absorbed films in the solid state where drug content is high can act as a vector for hydrolysis and chemical breakdown, and thus, it is preferred to prepare a non- hygroscopic salt for a stable formulation. As shown in the above Table 4, amlodipine cyclamate of the present invention was confirmed to have higher non-hygroscopicity than amlodipine besylate by about 2 times.
Test Example 4: Stickiness test in a tabletting machine
Fifty tablets containing amlodipine cyclamate prepared in Example 1, potassium sulfate dihydrate, and microcrystalline cellulose (5:47.5:47.5) were made using a conventional tabletting machine. The material sticking to the tablet punch was extracted with methanol, and its amount was measured using a spectrophotometer (Caryl C, UN- Visible Spectrophotometer, Australia). The above procedure was repeated for runs of 100, 150, 220, 250 and 300 tablets. After each run, the amount of material sticking to the tablet punch was measured by extracting with methanol. The obtained values were plotted and the average value was calculated from the slope of the line produced.
The above procedure was repeated for amlodipine besylate (Medicorp., India).
The results are shown in the following Table 5.
Table 5
A drug which does not adhere to the surface of tablet punch has excellent processability. As shown in the above Table 5, amlodipine cyclamate of the present invention was confirmed to have nearly the same amount of sticking material as amlodipine besylate, and thus, to have excellent anti-adhesion property.
INDUSTRIAL APPLICABILITY
Amlodipine cyclamate of formula (1) according to the present invention has not only lower toxicity but also higher stability, solubility, non-hygroscopicity, and processability than the known amlodipine besylate, and thus, is very useful for industrial applications.
Claims
1. Amlodipine cyclamate of the following formula:
A method for preparing amlodipine cyclamate of the following formula:
, comprising the steps of reacting amlodipine of the following formula:
3. The method of Claim 2, wherein the organic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethyl acetate, hexane, and acetonitrile.
4. A pharmaceutical composition for preventing or treating heart diseases or hypertension, comprising amlodipine cyclamate of Claim 1 together with one or more pharmaceutically acceptable carriers.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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KR10-2003-0008818 | 2003-02-12 | ||
KR1020030008818A KR20040072363A (en) | 2003-02-12 | 2003-02-12 | Novel amlodipine cyclamate salt and a preparation method thereof |
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WO2004072036A1 true WO2004072036A1 (en) | 2004-08-26 |
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PCT/KR2004/000285 WO2004072036A1 (en) | 2003-02-12 | 2004-02-12 | Novel amlodipine cyclamate salt and a preparation method thereof |
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WO (1) | WO2004072036A1 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4879303A (en) * | 1986-04-04 | 1989-11-07 | Pfizer Inc. | Pharmaceutically acceptable salts |
US6057344A (en) * | 1991-11-26 | 2000-05-02 | Sepracor, Inc. | Methods for treating hypertension, and angina using optically pure (-) amlodipine |
-
2003
- 2003-02-12 KR KR1020030008818A patent/KR20040072363A/en not_active Application Discontinuation
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2004
- 2004-02-12 WO PCT/KR2004/000285 patent/WO2004072036A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4879303A (en) * | 1986-04-04 | 1989-11-07 | Pfizer Inc. | Pharmaceutically acceptable salts |
US6057344A (en) * | 1991-11-26 | 2000-05-02 | Sepracor, Inc. | Methods for treating hypertension, and angina using optically pure (-) amlodipine |
Non-Patent Citations (1)
Title |
---|
"Handbook of pharmaceutical excipients", 1994, THE PARMACEUTICAL PRESS, article WADE A. AND WELLER P.J., pages: 446 - 447 * |
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