Classifications

• • 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
  • C07D211/86—Oxygen atoms
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates to a novel organic acid salt of amlodipine (2-[(2- arrinoemoxy)memyl]-4-(2-cMorophenyl) ⁇ acid 3-ethyl 5-methyl ester), represented by the following chemical formula 1, its preparation method, and a pharmaceutical composition containing the same as an effective ingredient.
• amlodipine With activity to block calcium channels in the body, amlodipine is used for the treatment of hypertension. This calcium channel blocker is found in many prior arts.
• European Pat. Laid-Open Publication No. 89,167 discloses acid salts of amlodipine which can be formed from acids which may form nontoxic acid addition salts with pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, etc.
• U. S. Pat. No. 6,291,490 introduces a pharmaceutical composition containing as an active ingredient S-(-)-amlodipine which possesses potent activity in treating hypertension while avoiding adverse effects associated with the adniinistration of the racemic mixture of amlodipine.
• amlodipine besylate saying that amlodipine besylate is superior over other salts of amlodipine, such as hydrochloride, acetate and mesylate in physicochemical properties including (1) solubility, (2) stability, (3) non-hygroscopicity, and (4) processability for tablet formulation.
• amlodipine besylate in current use is relatively low in solubility at pH 1-7.4, saturation pH is regarded as an important factor.
• Salts which provide solutions having a pH close to that of blood (7.4) in distilled water are preferred because they are readily biocompatible and can easily be buffered to the required pH range without altering their solubility.
• saturation pH of amlodipine besylate is as low as a pH of 6.6, there is a need for salts whose saturation pH in distilled water is close to 7.4 (pH of blood).
• amlodipine besylate is found to be sensitive to light, so that decomposition products are observed when the salt is exposed to light.
• amlodipine besylate is disadvantageous due to benzene sulfonic acid used in its production process. That is, benzene sulfonic acid is difficult to industrially treat as it is corrosive and toxic, hi addition, its high hygroscopicity requires special procedures for its transport, delivery and use. Another disadvantage is that the water content of benzene sulfonic acid is high content of water, amounting to about 10%. hi order to avoid these problems, ammonium benzene sulfonate is employed as an alternative, but with the concomitant generation of ammonia gas. This method needs additional processes for absorbing and inactivating ammonia gas (PCT Publication No. WO 1999/52873).
• amlodipine camphorsulfonate has excellent physicochemical properties including solubility, non-hygroscopicity, chemical and light stability, and processability for dosage formation, as well as the fact that camphorsulfonic acid is less toxic and corrosive than benzene sulfonic acid, so that the amlodipine camphorsulfonate is industrially and medically useful.
• camphorsulfonic acid salt of amlodipine preferably a hght-stable camphorsulfonic acid salt of amlodipine, more preferably amlodipine (lS)-(+)-10-camphorsulfonate or amlodipine (lR)-(-
• a method for preparing a camphorsulfonic acid salt of amlodipine in which amlodipine is reacted with camphorsulfonic acid and preferably with (lS)-(+)-10-camphorsulfonic acid or (lR)-(-)-10-camphorsulfonic acid in an inert solvent.
• a pharmaceutical composition effective for the treatment of ischemic cardiac disorders or hypertension comprising a therapeutically effective amount of amlodipine camphorsulfonate and a pharmaceutically acceptable diluent or carrier preferably in the dosage form of tablets, capsules, solutions or injectables.
• the present invention encompasses amlodipine camphorsulfonate, represented by the following chemical formula 2.
• amlodipine camphorsulfonate Compared to amlodipine besylate in a commercially acceptable form, amlodipine camphorsulfonate exhibits equal or better non-hygroscopicity, formulation processability and chemical stability. Especially, providing solutions having a pH close to that of blood (7.4) as well as being far more stable to Hght compared to conventional organic acid salts, the amlodipine camphorsulfonate of the present invention can be stably stored for a long period of time without losing its medicinal effect as an anti-hypertensive agent.
• the present invention also encompasses hght-stable amlodipine camphorsulfonate.
• Hght-stable as used herein means that after the salt is stored for 4 weeks at 25 °C with exposure to sunlight, its mass is maintained at 90 % or more of the original mass, preferably at 95 % or more, and more preferably at 98 % or more.
• Camphorsulfonic acid suitable for the preparation of the amlodipine camphorsulfonate of the present invention may be a racemic mixture or preferably an optically pure material, that is, (lS)-(+)-10-camphorsulfonic acid or (lR)-(-)-10- camphorsulfonic acid.
• Camphorsulfonic acid salts of amlodipine according to the present invention maybe in a crystal form or an amorphous form with preference to a crystal form.
• the present invention also encompasses a method for preparing camphorsulfonic acid salts of amlodipine.
• the salts can be prepared by reacting amlodipine with camphorsulfonic acid in an inert solvent, as seen in the foUowing reaction formula 1.
• Camphorsulfonic acid used as reactant is preferably be an optically pure material, that is, (lS)-(+)-10-camphorsulfonic acid or (lR)-(-)-10-camphorsulfonic acid.
• Camphorsulfonic acid a stable and white soHd with FDA permission for use in pharmaceuticals, is commercially available as a white soHd (purity 98% or higher) and does not show hygroscopicity, corrosiveness and toxicity. With these properties, camphorsulfonic acid is easily handled and safely produced on a mass scale.
• inert solvent suitable for the preparation of the salts of the present invention examples include ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, hexane, isopropyl ether and etc., with preference to methanol.
• camphorsulfonic acid is used in the amount of 1-2 equivalents, and preferably in the amount of 1.02-1.2 equivalents, per equivalent of amlodipine.
• the reaction is performed at -5 to 30 °C and preferably at 0 to 15 °C for 0.5 to 5 hours and preferably for 1 to 3 hours.
• amlodipine camphorsulfonate can be prepared at a yield of 90 % or higher.
• the present invention encompasses a pharmaceutical composition effective in treating ischemic cardiac disorders or hypertension, which comprises a therapeutically effective amount of amlodipine camphorsulfonate and a pharmaceutically acceptable diluent or earner.
• the composition of the present invention may be formulated into oral dosage forms including, but not limited to, granules, powders, solutions, tablets, capsules, dry syrup and the
• composition of the present invention is preferably formulated in the dosage form of tablets, capsules, solutions or injectables.
• amlodipine camphorsulfonate is administered in the amount of 2- 10 mg per day on the basis of the weight of amlodipine.
• amlodipine camphorsulfonate is contained in the amount of 3-16 mg.
• amlodipine camphorsulfonate can be combined as the active- ingredient in admixture with a pharmaceutically acceptable diluent or carrier selected from among excipients, disintegrants, binders and lubricants, and mixtures thereof.
• the carrier may take a wide variety of forms depending on the form of the preparation desired for administration, hi preparing the composition in a soHd dosage form such as a tablet or a hard capsule, there may be employed microcrystalline cellulose, lactose, low-substituted hydroxycellulose and the Hke as an excipient; sodium starch glycollate, anhydrous monohydrogenphosphate and the Hke as a disintegrant; polyvinylpyrroHdone, low-substituted hydroxypropylcellulose, hydroxypropylcellulose and the Hke as a binder; and magnesium stearate, siHca, talc and the Hke as a lubricant.
• a formulation may comprise an additive to provide sheen to the tablet such as anhydrous dibasic calcium phosphate. To prevent atmospheric moisture from penetrating into the tablet, it may have a water-insoluble coating.
• the coating base must have a dense molecular structure and is preferably poorly soluble in water. Suitable for the base is a polymeric material selected from among methacryHc acid copolymer, hydroxypropylmethyl ceUulose phthalate, cellulose acetate phthalate, hydroypropylmethylceUulose acetate succinate, polyvinyl alcohol and combinations thereof.
• the coating may comprise conventional additives such as plasticizers, preservatives, coloring agents, Hght shielders, etc.
• composition of the present invention may be solutions such as sterile aqueous solution or injectables.
• sterile aqueous solution or injectables Preferably such solution contains from 10 to 40% of propylene glycol and sodium chloride, sufficient to avoid hemolysis (e.g. about 1%).
• Amlodipine camphorsulfonate prepared according to the present invention was tested for various physical properties. First, the salt was formulated into tablets, capsules and aqueous solutions to test the processabiHty for dosage formation. Also, amlodipine camphorsulfonate was compared with amlodipine besylate with regard to hydroscopicity, solubiUty, saturation pH, stabiHty and Hght stabiHty. In the following reference examples, conventional salts of amlodipine were prepared according to methods disclosed in the art.
• Amlodipine was prepared as disclosed in Korean Pat. PubHcation No. 87-809. The method described in Korean Pat. PubHcation No. 95-7228 was adopted to produce amlodipine besylate.
• REFERENCE EXAMPLE 2 Preparation of Amlodipine para-toluenesulfonate
• the ingredients were blended and the blend was compressed using a roller press from Jowoon Machinery, and then formulated into the tablets using a tableting machine from Erweka.
• Lactose, cross povidone and polyvinylpyrroHdone K90 were preblended.
• the pre- blend was granulated according to a fluidized bed assembly method (SPIRA FLOW) and the granules were blended with the remaining ingredients and formulated into tablets using a tableting machine from Erweka.
• SPIRA FLOW fluidized bed assembly method
• Lactose, cross povidone and polyvinylpyrroHdone K90 were preblended.
• the pre- blend was granulated according to a fluidized bed assembly method (SPIRA flow) and the granules were blended with the remaining ingredients and filled in hard gelatin capsules using a typical capsule filHng device (Bosche).
• SPIRA flow fluidized bed assembly method
• Bosche typical capsule filHng device
• Amlodipine camphorsulfonate prepared in Example 1 and amlodipine besylate prepared in Reference Example 1 were tested for hygroscopicity by measuring their water contents (K.F. water%) at 25 °C with humidity varying. The results are given in Table 7, below. TABLE 7
• the non-hydrogscopicity of amlodipine camphorsulfonate is equal to or better than that of amlodipine besylate.
• the salt With a hygroscopicity of 0.5% or less at a relative humidity of 95%, the salt is suitable for the formulation of tablets, capsules, injectables, and the Hke
• SolubiHties of amlodipine camphorsulfonate prepared in Example 1 and amlodipine besylate prepared in Reference Example 1 in various solvents were measured at 25 °C. The results are given in Table 8, below.
• the solubiHties (mg/ml) of Table 6 are values based on the weight of amlodipine converted from the salts.
• amlodipine camphorsulfonate in buffers of various pH values and distilled water exhibits a solubiHty behavior similar to that of amlodipine besylate.
• the saturation pH of amlodipine besylate is as low as pH 6.6
• amlodipine camphorsulfonate shows a saturation pH of 7.2 which is close to the pH value of blood, indicating that amlodipine camphorsulfonate is of good pharmaceutical properties.
• Amlodipine camphorsulfonate prepared in Example 1 and amlodipine besylate prepared in Reference Example 1 were subjected to accelerated test at 60 °C and the results are summarized in Table 7, below.
• amlodipine camphorsulfonate prepared in Example 1 and amlodipine besylate prepared in Reference Example 1 were separately dissolved in distilled water.
• the resulting aqueous solutions were stored at 25 °C for 4 weeks in complete darkness, after which a measurement was made of the contents of the salts with resort to HPLC under the same conditions as in the soHd state.
• EXAMPLE 10 Test for Hght StabiHty of Amlodipine Camphorsulfonate Amlodipine camphorsulfonate prepared in Example 1, amlodipine besylate, and other salts of amlodipine prepared in Reference Examples 1 to 3 were employed. These samples were stored at 25 °C for 4 weeks while being exposed to sunlight. A measurement was made of the contents of the salts with resort to HPLC under the same conditions as in the chemical stabiHty test. The results are given in Table 10, below.
• amlodipine camphorsulfonate As shown in Table 10, a smaller reduction in the content was found in amlodipine camphorsulfonate than in the other salts of amlodipine. It was also found that amlodipine besylate turned yellow from white while amlodipine camphorsulfonate showed no color change. These data accordingly show that amlodipine camphorsulfonate is superior in Hght stabiHty to amlodipine besylate and thus is very advantageous in the appHcation for anti- hypertensives which are usually used for a long period of time.
• amlodipine camphorsulfonate of the present invention has excellent physicochemical properties including non-hygroscopicity, chemical and Hght stabiHty, solubiHty and processabiHty for dosage formulation.
• amlodipine camphorsulfonate is easy to deHver with in the body of a patient, hi addition, this salt can be stored for a long period of time due to its superior Hght stabiHty. Further, free of corrosiveness and toxicity, camphorsulfonic acid is industrially useful.

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• Urology & Nephrology (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Hydrogenated Pyridines (AREA)
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• 2002
  • 2002-07-30 KR KR1020020044856A patent/KR20040011751A/ko not_active Ceased
• 2003
  • 2003-07-30 EP EP03771480A patent/EP1549616A4/de not_active Withdrawn
  • 2003-07-30 MX MXPA05001241A patent/MXPA05001241A/es unknown
  • 2003-07-30 CN CNA038208768A patent/CN1678583A/zh active Pending
  • 2003-07-30 AU AU2003247208A patent/AU2003247208A1/en not_active Abandoned
  • 2003-07-30 WO PCT/KR2003/001522 patent/WO2004011432A1/en not_active Ceased
  • 2003-07-30 JP JP2004524369A patent/JP2005538103A/ja active Pending
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