Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-07-29
2004-06-29
Owens, Amelia A. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S284400
Reexamination Certificate
active
06756390
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel organic acid salt of amlodipine (2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic 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.
2. Description of the Prior Art
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 both systolic and diastolic hypertension while avoiding adverse effects associated with administration of the racemic mixture of amlodipine.
Both U.S. Pat. No. 4,879,303 and Korean Pat. Laid-Open Publication No. 1989-3375 disclose 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.
However, since amlodipine besylate in current use is relatively low in solubility at pH 1-7.4, there is a need for novel salts which are of sufficient solubility, so as to increase the bioavailability of amlodipine and easily formulate its injections. Additionally, amlodipine besylate has been found to be sensitive to light. Therefore lysates are generated when the salt is exposed to light.
Further, amlodipine besylate is disadvantageous due to benzene sulfonic acid being used in its production process. That is, benzene sulfonic acid is difficult to industrially treat because it is corrosive and toxic. In 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 too high, amounting to about 10%. In order to avoid these problems, ammonium benzene sulfonate is employed as an alternative, but with concomitant generation of ammonia gas. This method needs additional processes for absorbing and inactivating ammonia gas (PCT Publication No. WO1999/52873).
By contrast, tetrahydro-5-oxo-2-furancarboxylic acid (commercially available as purity 98% or higher) is non-toxic to the body and is easy to handle in preparing amlodipine tetrahydro-5-oxo-2-furancarboxylate.
DISCLOSURE OF THE INVENTION
Leading to the present invention, the intensive and thorough research into therapeutically effective organic acid salts of amlodipine, conducted by the present inventors aiming to overcome the problems encountered in prior arts, resulted in the finding that amlodipine tetrahydro-5-oxo-2-furancarboxylate has excellent physicochemical properties including solubility, non-hygroscopicity, chemical and light stability, and processability for dosage formation, as well as the fact that tetrahydro-5-oxo-2-furancarboxylic acid(TOF acid) is less toxic and corrosive than benzene sulfonic acid so that the amlodipine tetrahydro-5-oxo-2-furancarboxylate is industrially and medically useful.
Therefore, it is an object of the present invention to provide a tetrahydro-5-oxo-2-furancarboxylic acid salt of amlodipine.
It is another object of the present invention to provide a method for preparing a tetrahydro-5-oxo-2-furancarboxylic acid salt of amlodipine.
It is a further object of the present invention to provide a pharmaceutical composition containing the tetrahydro-5-oxo-2-furancarboxylic acid salt of amlodipine as a therapeutically active ingredient.
In accordance with an aspect of the present invention, there is provided a tetrahydro-5-oxo-2-furancarboxylic acid salt of amlodipine, preferably a light-stable tetrahydro-5-oxo-2-furancarboxylic acid salt of amlodipine, more preferably amlodipine (S)-tetrahydro-5-oxo-2-furancarboxylate or amlodipine (R)-tetrahydro-5-oxo-2-furancarboxylate, and most preferably a crystalline tetrahydro-5-oxo-2-furancarboxylic acid salt of amlodipine.
In accordance with another aspect of the present invention, there is provided a method for preparing a tetrahydro-5-oxo-2-furancarboxylate acid salt of amlodipine, in which amlodipine is reacted with tetrahydro-5-oxo-2-furancarboxylic acid and preferably with (S)-tetrahydro-5-oxo-2-furancarboxylic acid or (R)-tetrahydro-5-oxo-2-furancarboxylic acid in an inert solvent.
In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition effective for the treatment of ischemic cardiac disorders or hypertension, comprising a therapeutically effective amount of amlodipine tetrahydro-5-oxo-2-furancarboxylate and a pharmaceutically acceptable diluent or carrier preferably in the dosage form of tablets, capsules, solutions or injectables.
REFERENCES:
patent: 4572909 (1986-02-01), Campbell et al.
patent: 4758569 (1988-07-01), Swindell
patent: 4879303 (1989-11-01), Davison et al.
patent: 6291490 (2001-09-01), Young
patent: 0089167 (1983-09-01), None
patent: 95-7228 (1989-04-01), None
patent: 19912145 (1989-04-01), None
patent: 99/52873 (1999-10-01), None
Cheon Jun Hee
Cho Seong Hwan
Jeong Eun Ju
Jin Hae Tak
Jung Sung Hak
CJ Corp.
Greenblum & Bernstein P.L.C.
Owens Amelia A.
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