Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-19
2001-10-02
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06297244
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a stabilized pharmaceutical composition of (R)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3′-pyrrolidine-1,2′,3,5′-tetrone (hereinafter, referred to as “AS-3201”) having a potent aldose reductase inhibitory activity.
2. Description of Related Art
AS-3201 is the compound of the following formula. Said compound is described in Example 22 of Japanese Patent No. 2516147 (U.S. Pat. No. 5,258,382), Reference Example 12 of JP-A-6-192222 (Chem. Abstr., 122, 9860 (1995)), and Experiment of JP-A-8-176105 (Chem. Abstr., 125, 221569 (1996)), and its potent aldose reductase inhibitory activities are disclosed therein.
Example 28 of Japanese Patent No. 2516147 (U.S. Pat. No. 5,258,382) describes a method for preparing specific tablets of AS-3201. That is, it is described therein that AS-3201 (1 g), corn starch (25 g), lactose (58 g), crystalline cellulose (11 g), hydroxypropylcellulose (3 g), light anhydrous silicic acid (1 g) and magnesium stearate (1 g) are blended, granulated and made into 1,000 tablets each weighing 100 mg by a conventional method.
During the studies on methods for preparing AS-3201-containing pharmaceutical compositions having a good stability on store, the present inventors have found that AS-3201 drug substance per se is stable against heat and humidity, but when AS-3201 is mixed with pharmaceutical excipients or carriers, AS-3201 shows a tendency of increasing its degradation product at a higher temperature under higher humidity.
Under such circumstances, the present inventors have further intensively studied, and have found that the stability of AS-3201-containing pharmaceutical compositions is remarkably improved by adding thereto as a stabilizer at least one acidic substance having an acidity more potent than that of AS-3201, and finally have accomplished the present invention.
SUMMARY OF THE INVENTION
The present invention provides an AS-3201-containing pharmaceutical composition which comprises as a stabilizer at least one acidic substance having an acidity more potent than that of AS-3201.
In the present specification, the term “pK
a1
” means an acid dissociation exponent of an acidic substance at 25° C. in an infinitely diluted solution thereof. When an acidic substance is a polybasic acid, it means an acid dissociation exponent at the first step of dissociation. The term “water-solubility” means a maximum amount of a solute being dissolved in 100 ml of water. The term “about” is used with the intention of including values following said term.
The stabilizer for the pharmaceutical composition of the present invention includes any pharmaceutically acceptable acidic substances having an acidity more potent than that of AS-3201, i.e., pK
a
=5.6-5.8. Examples of those substances are adipic acid, ascorbic acid, aspartic acid, glutamic acid, citric acid, succinic acid, tartaric acid, lactic acid, fumaric acid, maleic acid, malic acid, and phosphoric acid. In addition, acidic substances having a pK
a1
of less than about 4.5 and a water-solubility at 15° C. to 25° C. of larger than about 10 g/100 ml are preferable. Preferable acidic substances are, for example, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malic acid and phosphoric acid. Especially preferable acidic substances are one having a pK
a1
of less than about 3.3 and a water-solubility at 15° C. to 25° C. of larger than about 50 g/100 ml, and include, for example, citric acid, tartaric acid, maleic acid and phosphoric acid, and among these acids, tartaric acid is most preferable.
The content of the acidic substances may vary depending on the acidity or water-solubility of such substances and the kinds of pharmaceutical excipients or carriers to be combined, but it is usually in the range of about 0.2% by weight to about 10% by weight to the total weight of the pharmaceutical composition, more preferably in the range of about 0.5% by weight to about 2.5% by weight. The acidic substance is added alone or in a mixture of two or more substances.
The pharmaceutical composition of the present invention may be solid dosage forms, and includes, for example, tablets, capsules, granules, powders, etc. These pharmaceutical compositions can be prepared by mixing AS-3201 with pharmaceutical excipients or carriers such as diluents, disintegrators, binders and lubricants and an acidic substance as a stabilizer by a conventional method. The acidic substances may be added per se or in the form of a solution thereof in water or other suitable solvent which is used in the preparation procedure of the pharmaceutical composition, depending on the method of preparing the composition. The pharmaceutical composition of the present invention may optionally be coated, or may additionally contain surfactants, coloring agents, flavoring agents, etc.
The pharmaceutical excipients or carriers may be any ones except for ones showing a bad compatibility with AS-3201. The diluents include, for example, lactose, starch, crystalline cellulose, D-mannitol, sucrose, glucose, erythritol, xylitol, D-sorbitol, anhydrous dibasic calcium phosphate, and calcium sulfate. The disintegrators are, for example, starch, crystalline cellulose, low substituted hydroxypropylcellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, partly pregelatinized starch, and hydroxypropyl starch. The binders are, for example, acacia, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, pullulan, gelatin, ethylcellulose, methylcellulose, carmellose sodium, and dextrin. The lubricants are, for example, magnesium stearate, calcium stearate, stearic acid, sucrose esters of fatty acids, light anhydrous silicic acid, talc, hydrogenated oil, and macrogol.
The surfactants to be used in the present pharmaceutical composition are, for example, sorbitan fatty acid esters and polysorbates. The coloring agents are, for example, tar color, caramel, and red iron oxide. The flavoring agents are, for example, sweeteners and perfumes.
The content of AS-3201 in the pharmaceutical composition of the present invention is usually in the range of about 0.5% by weight to about 25% by weight to the total weight of the pharmaceutical composition. The acidic substance as a stabilizer is especially effective for improving stability of a pharmaceutical composition wherein the content of AS-3201 is comparatively low. In order to store the AS-3201-containing pharmaceutical composition of the present invention more stably, the present composition may be packed in a bottle using materials of low moisture-permeability or in damp-proof packages such as heat-sealed packages, if necessary.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is illustrated in more detail by Examples and Comparative Examples, but the present invention should not be construed to be limited thereto. Incidentally, AS-3201 was used after being micronized.
In Examples and Comparative Examples, the amount of degradation products of the AS-3201-containing pharmaceutical compositions was assayed by High Performance Liquid Chromatography (HPLC). A test sample was dissolved or dispersed in acetonitrile, and the solution in an amount corresponding to 2 &mgr;g of AS-3201 was charged to an HPLC column. The conditions for assay are as follows.
Column: Develosil ODS-5 (manufactured by Nomura Chemical Co., Ltd., Japan) (&PHgr; 5 mm×150 mm)
Column temperature: 40° C.
Mobile phase: a mixture of 0.1 M phosphate buffer (pH 3.3)/acetonitrile/tetrahydrofuran (3:1:1)
Flow rate: 1.0 ml/min.
Wavelength: ultraviolet absorption at 220 nm
Based on the assay results, the degradation percentage of AS-3201 was calculated by the following equation.
Degradation Percentage
=
Area (Total)
-
Area (
AS
-3201)
Area (Total)
Area (Total): Area of total peaks (retention time: 2-30 min.)
Area (AS-3201): Area of the peak of AS-3201 (retention time: about 10 min.)
REFERENCES:
patent: 5258382 (1993-11-01), Neg
Fujioka Hiroshi
Ogasawara Kazuyoshi
Ohashi Mamoru
Shirai Yoshimi
Dainippon Pharmaceutical Co., Ltd.
Jones Dwayne C.
Wenderoth , Lind & Ponack, L.L.P.
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