Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-25
2001-12-25
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S345000, C514S565000, C514S649000, C424S451000, C424S464000, C424S465000, C424S489000
Reexamination Certificate
active
06333332
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to stabilized pharmaceutical preparations containing bupropion hydrochloride.
BACKGROUND OF THE INVENTION
Bupropion hydrochloride is a common chloropropiophenone antidepressant, most recently found useful for helping patients stop smoking. See PCT Application No. WO 99/38,499. Novel methods of making bupropion hydrochloride include those taught by Mehta. See U.S. Pat. Nos. 3,819,706 and 3,885,046. Relative to conventional antidepressants, bupropion hydrochloride has no significant sympathomimetic, sympatholytic, anticholinergic or cardiovascular effects. Bupropion hydrochloride is sold in immediate release, modified release and extended release tablet forms. Regardless of its form, stability of bupropion hydrochloride is affected by a number of factors including formulation microenvironments and storage conditions.
Various bupropion hydrochloride formulations have been proposed in the art, designed to increase its stability. For example, one group reports that degradation can be inhibited or prevented by including in the formulation stabilizers such as L-cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid and L-cystine dihydrochloride. See U.S. Pat. Nos. 5,358,970 and 5,763,493. The same group also reports that degradation of bupropion hydrochloride can be inhibited by use of stabilizers including ascorbic acid or isoascorbic acid. See U.S. Pat. Nos. 5,541,231 and 5,731,000. Another group has reported that the drug can be stabilized by formulating it with inorganic acids such as hydrochloric acid, phosphoric acid, nitric acid and sulfuric acid or combinations thereof. See U.S. Pat. No. 5,968,553 and PCT Application No. WO 99/33,456. Still others have reported that substances such as fumaric acid can inhibit degradation of bupropion hydrochloride. See PCT Application No. WO 99/33,457.
This invention is directed to pharmaceutical formulations of bupropion hydrochloride (as the drug or active ingredient), in which the stability of the bupropion hydrochloride is augmented by the addition of a pharmaceutically acceptable stabilizer in an amount effective to increase stability.
SUMMARY OF THE INVENTION
One of the objectives of the present invention is to provide a pharmaceutical composition comprising bupropion hydrochloride and a pharmaceutically acceptable stabilizer in an effective stabilizing amount, in which at least about 80% to about 98% of an initial potency of the bupropion hydrochloride in the composition is maintained after storage for one week at 60° C. and 75% relative humidity. The stabilizer is selected from the group consisting of a salt of an organic base, such as creatinine hydrochloride, pyridoxine hydrochloride and thiamine hydrochloride, and a salt of an inorganic acid, such as potassium phosphate monobasic.
The present invention also provides for a method of stabilizing bupropion hydrochloride in a pharmaceutical composition so that at least about 80% to about 98% of the potency of bupropion hydrochloride is maintained after storage for one week at 60° C. and 75% relative humidity. This method comprises the step of mixing bupropion hydrochloride with a pharmaceutically acceptable stabilizer in an effective stabilizing amount. The method utilizes a dry blend of bupropion hydrochloride, a pharmaceutically acceptable stabilizer, and other pharmaceutically acceptable excipients.
Another objective of the present invention includes providing a pharmaceutical composition comprising bupropion hydrochloride and a pharmaceutically acceptable stabilizer in an effective stabilizing amount, in which at least about 80% to about 98% of an initial potency of the bupropion hydrochloride in the composition is maintained after storage for 4 or 12 weeks at 40° C. and 75% relative humidity, wherein the stabilizer is selected from the group consisting of a salt of an organic base, such as creatinine hydrochloride, pyridoxine hydrochloride and thiamine hydrochloride, and a salt of an inorganic acid, such as potassium phosphate monobasic.
A further objective of the present invention includes a method of stabilizing bupropion hydrochloride in a pharmaceutical composition so that at least about 80% to about 98% of the potency of bupropion hydrochloride is maintained after storage for 4 or 12 weeks at 40° C. and 75% relative humidity. This method comprises the step of mixing a dry blend of bupropion hydrochloride with a pharmaceutically acceptable stabilizer in an effective stabilizing amount.
DETAILED DESCRIPTION OF THE INVENTION
Bupropion hydrochloride is disclosed in the Merck Index, 12
th
Edition, 1996, entry no. 1523. It is known chemically as &bgr;-2-(tert-butylamino)-3′-chloropropiophenone hydrochloride. See U.S. Pat. Nos. 3,819,706 and 3,885,046.
Stabilizer, as the term is used herein, means a compound that inhibits or prevents degradation of bupropion hydrochloride so that it can be used in a pharmaceutical preparation while retaining much of its potency. Stabilizers useful in accordance with the present invention retain at least 80% of the potency of bupropion hydrochloride and up to 98% percent potency after four to twelve weeks of storage at 40° C. and 75% RH, or after one week of storage at 60° C. and 75% RH.
Indeed, the stabilizers of the present invention are contemplated, within the context of the present invention, to be used with any appropriate pharmaceutical preparation and active ingredient, so that the active ingredient's stability in the pharmaceutical preparation is augmented. In a preferred embodiment, the active ingredient is bupropion hydrochloride; yet any active ingredient whose stability can be augmented, specifically in a pharmaceutical preparation, by the stabilizers of the present invention is contemplated.
The percentage of maximum stability product of bupropion hydrochloride is the amount of bupropion hydrochloride product remaining in the preparation relative to the amount of bupropion hydrochloride product in the formulation. Thus, for example, if a tablet initially contains 150 mg of bupropion hydrochloride (labeled amount) at the time of preparation, at least about 135 mg of bupropion hydrochloride (90%) remains in the tablet after one week's storage at 60° C. and about 75% RH.
The amount of active ingredient in the formulation after storage may be determined using standard procedures such as high performance liquid chromatography (HPLC) or other validated methods.
Maximum impurity of the product is defined as the maximum degradation product among all other relatively smaller degradation products. The total impurity is defined as the sum of all degradation products (including the maximum and the rest of the impurities). Therefore, the percentage of total impurity may be larger than that of the maximum impurity, unless there is only one degradation product found.
According to the pharmaceutical industry standard, the product is generally monitored under an accelerated condition at 40° C. and about 75% RH for three months, which is believed to represent about two years of product shelf life at room temperature. In the present invention, a more stressful condition, 60° C. and 75% RH for one week, was used as the accelerated condition to monitor the stability of pharmaceutical composition comprising bupropion hydrochloride and a stabilizer.
The stability of the formulations was tested by storage for one week at 60° C. and about 75% RH in 20 gram desiccant plastic bottles. It was found that formulations containing the stabilizers of the present invention retain at least 85% potency of the bupropion hydrochloride after the storage period. The precision for this potency measurement is 0.56% based on an assay determination of twelve tablets by a validated analytical method. Moreover, the maximum impurities in the formulation were less than about 0.1 and not more than about 0.5%. Further, the total impurities in the formulation were less than about 0.2% and not more than about 1% after storage. Stability of formulations was also tested
Han Chien-Hsuan
Liaw Gary
Arent Fox Kintner Plotkin & Kahn
Impax Laboratories, Inc.
Reamer James H.
LandOfFree
Stabilized pharmaceutical compositions containing bupropion... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Stabilized pharmaceutical compositions containing bupropion..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Stabilized pharmaceutical compositions containing bupropion... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2573519