Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1997-12-30
2001-04-24
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C424S464000
Reexamination Certificate
active
06221917
ABSTRACT:
BACKGROUND OF THE INVENTION
Bupropion hydrochloride is a common antidepressant sold in immediate release, modified release, and extended release tablet forms. See U.S. Pat. Nos. 3,819,706 and 3,885,046. As with many pharmaceuticals, the stability of bupropion hydrochloride is affected by a number of factors including formulation microenvironments and storage conditions.
One formulation of bupropion hydrochloride is taught by Ruff et al., U.S. Pat. No. 5,358,970 to prevent or inhibit degradation of bupropion hydrochloride using one of the stabilizers L-cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid and L-cystine dihydrochloride. These solid dosage forms were prepared using alcohol granulation technology. However, granulation technology is labor intensive and costly. In addition special procedures are necessary to address safety and environment issues involving the use of alcohol.
Accordingly, stable bupropion hydrochloride formulations prepared by safe, cost effective methods are greatly desired. The present invention provides such stable bupropion hydrochloride formulations.
DESCRIPTION OF THE INVENTION
In accordance with the present invention is provided a pharmaceutical composition comprising bupropion hydrochloride and a pharmaceutically acceptable stabilizer.
Bupropion Hydrochloride is described in U.S. Pat. Nos. 3,819,706 and 3,885,046 and the Merck Index, Twelfth Edition, entry no. 1523.
Stabilizer, as the term is used herein, means a compound which inhibits or prevents the degradation of bupropion hydrochloride so that it can be used in a pharmaceutical formulation while retaining much of its potency. Stabilizers useful in accordance with the present invention retain at least about 80% of the potency of bupropion hydrochloride and preferably over 90% of potency after one year of storage at room temperature (59-77° C.) at 35-60% humidity. Thus, a tablet containing 100 mg of bupropion hydrochloride should retain at least 80 mg and preferably more than 90 mg of bupropion hydrochloride at the end of 1 year in the presence of stabilizers of the present invention.
Suitable stabilizers have an aqueous suspension pH of from about 0.9 to about 4.0 at a concentration of about 6% w/w. Further, said stabilizers have solubility in water at 20° C. of less than about 10 g stabilizer/100 g water.
The stability of the formulation was tested in accordance with industry standards by storage for four to twelve weeks at about 40° C. and about 75% relative humidity. Formulations containing stabilizers of the present invention stored under these conditions retain at least 80% of the bupropion hydrochloride in the composition at the time of storage. In many instance formulations of the present invention retain more than 85% and ideally retain at least 90% of bupropion hydrochloride in the composition at the time of storage. Standard procedures such as HPLC may be used to determine the amount of active ingredient remaining after storage.
The aqueous suspension pH of the stabilizers of this invention is determined by adding 3.75 grams of stabilizer to 60 grams of deionized water in a Pyrex® beaker. The resulting mixture is stirred for approximately 5 minutes, using a stir plate and a magnetic stir bar. The resulting suspension or dispersion is examined using a Corning® pH Meter Model 355. Suspensions are stirred with a magnetic stir bar during analysis. Measurements are performed in duplicate and the average thereof is used.
Stabilizers of the present invention include dicarboxylic acids meeting the aforementioned criteria and more specifically include, but are not limited to, oxalic, succinic, adipic, fumaric and phthalic acids, or combinations thereof. Fumaric acid is a preferred stabilizer.
Pharmaceutical compositions of the present invention may optionally include any conventional ingredients for improving the physical properties, visual appearance or odor of the pharmaceutical. Examples include, but are not limited to, lubricants such as talc; binders such as starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone; diluents such as microcrystalline cellulose and lactose; disintegrants such as sodium starch glycolate, crospovidone and croscarmellose sodium; and colorants.
The total amount of inactive ingredient in the formulation, including the amount of stabilizer, is preferably more than 50% of the weight of bupropion hydrochloride in the composition and less than 650% of the weight of bupropion hydrochloride. The amount of stabilizer may be from about 10% to 100% of the weight of bupropion hydrochloride and is ideally about 10% to about 40% of the weight of bupropion hydrochloride in the composition. Most preferably, the amount of stabilizer is from about 15% to about 30% of the weight of bupropion hydrochloride. Furthermore about 1% to about 40% of the total weight of the tablet or capsule may be stabilizer. More preferably, stabilizer accounts for about 3% to about 6% of the total weight of the composition. The suitable amount of stabilizer is based on the label strength of bupropion hydrochloride in the pharmaceutical formulation in solid dosage form and can be determined by one skilled in the art.
Pharmaceutical compositions of the present invention generally contain 25 mg to 500 mg of bupropion hydrochloride. More preferred compositions of the invention contain 50 mg, 75 mg, 100 mg or 150 mg of active ingredient and may be in the form of tablets, caplets or capsules. Immediate release, modified release, and extended release profiles, or combinations thereof, are encompassed by the present invention.
Pharmaceutical compositions of the present invention are prepared by dry blending followed by direct compression. For instance, the ingredients are screened and blended in an industrial blender such as a Gemco® Double Cone Blender. The blended materials are milled such as with a Model D-6 Fitzmill®. Blending may be performed to achieve semi-geometric dilution. Thereafter, the ingredients are directly compressed into tablets using, for instance, a Kikusui Libra® tablet compression machine.
REFERENCES:
patent: Re. 33994 (1992-07-01), Baker et al.
patent: 3819706 (1974-06-01), Mehta
patent: 3885046 (1975-05-01), Mehta
patent: 5358970 (1994-10-01), Ruff et al.
patent: 5427798 (1995-06-01), Ludwig et al.
patent: 5731000 (1998-03-01), Ruff et al.
DeVito Joseph Michael
Kulkarni Prakash Shriram
Maitra Amitava
Shah Bharat Bhogilal
American Home Products Corporation
Barrett Rebecca R.
Jones Dwayne C.
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