Note: Descriptions are shown in the official language in which they were submitted.
. ~ CA 02253770 1998-11-23
PHARMACEUTICAL COMPOSITION COMPRISING
BUPROPION HYDROCHLORIDE
BACKGROUND OF THE INVENTION
Bupropion hydrochloride is a well known antidepressant. It is sold in the
United States by Glaxo Wellcome Inc. as prompt release tablets under the
tradename WELLBUTRIN~ and sustained release tablets under the
tradename, WELLBUTRIN SR~.
Bupropion hydrochloride is known to be relatively unstable, such that tablets
containing bupropion hydrochloride will degrade at an unacceptably high rate
unless the tablets are made by a method or using ingredients which result in
improved stability.
U.S. patent 5,358,970 discloses stabilization of bupropion hydrochloride by
including in the tablets a stabilizer. The specific stabilizers disclosed are
L
cysteine hydrochloride, glycine hydrochloride, ascorbic acid, malic acid,
sodium metabisulfite, isoascorbic acid, citric acid, and L-cysteine
hydrochloride. L-cysteine hydrochloride and glycerin hydrochloride are said to
be most preferred. All of the examples in U.S. patent 5,358,970 use L
cysteine hydrochloride or glycine hydrochloride as the stabilizer, and, in
each
example, the process of manufacture includes the steps of dissolving the
stabilizer in water and alcohol, using the solution to granulate the bupropion
hydrochloride and other ingredients, and then drying the wet mass.
Such a process has the disadvantage of requiring the use of water and
alcohol, and requiring the steps of preparing the solution, using the solution
to
granulate powder, and drying the wet granulated material.
CA 02253770 1998-11-23
2
The object of the present invention is to enable stabilization of compositions
comprising bupropion hydrochloride by using a stabilizer other than that
disclosed in U.S. patent 5,358,970.
DESCRIPTION OF THE INVENTION
It has been found that the inclusion of sodium bisulfate as an ingredient in
solid compositions comprising bupropion hydrochloride results in improved
stability, even if the ingredients are mixed in dry form without use of water,
alcohol or any other solvent.
Compositions within the scope of the present invention will thus be solid
compositions (such as tablets or capsules) comprising bupropion
hydrochloride and sodium bisulfate. Sodium bisulfate is available as both
anhydrous and monohydrate. Either form may be used in the present
invention.
A preferred ratio of sodium bisulfate to bupropion hydrochloride by weight is
from about 1 to about 20 parts sodium bisulfate per 100 parts bupropion
hydrochloride. A more preferred ratio is from about 2 to about 10 parts
sodium bisulfate per 100 parts bupropion hydrochloride. The most preferred
ratio is about 5 parts sodium bisulfate per 100 parts bupropion hydrochloride.
Solid compositions in the form of tablets, for example, can be made simply by
mixing bupropion hydrochloride and sodium bisulfate, along with other usual
tabletting ingredients, and then compressing the mixture into tablets on a
tablet process.
CA 02253770 1998-11-23
3
The other usual tabletting ingredients may include and will preferably include
a binder, such as, for example, microcrystalline cellulose or hydroxypropyl
methylcellulose; a lubricant such as, for example, magnesium stearate, zinc
stearate, or stearic acid, and a glidant such as, for example, colloidal
silicon
dioxide.
If the flowability of the mixed powder is not adequate for direct compression
into tablets, the mixture may be compacted, following which the compacted
material will be round a into free flowin
g p g granules. These granules will then
be compressed into tablets on a tablet press.
The following examples are representative of the invention, but not limiting.
Ingredients were mixed in proportions as follows:
Ex.1 Ex.2 Ex. 3 Ex.4 Ex.S
Bupropion hydrochloride 100. 100. 100 100 100.
Microcrystalline Cellulose 98. 96. 94. 90. 82.
2p Sodium Bisulfate, Monohydrate0 2. 4. 8. 16.
Zinc Stearate 1.6 1.6 1.6 1.6 1.6
Colloidal silicon dioxide 0.4 0.4 0.4 0.4 0.4
200. 200. 200.200 200.
In each case, the powder mixture was compacted, the compacted material
was ground up into granules, and the granules were recompressed on a tablet
press into tablets of net weight 200 mg each. Each tablet thus contained 100
mg of bupropion hydrochloride, and the amount of sodium bisulfate per tablet
was nil in example 1, 2 mg in example 2, 4 mg in example 3, and 8 mg in
example 4, and 16 mg in example 5.
CA 02253770 1998-11-23
4
The tablets of all 5 examples were stored for a period of one week at
50°C,
this condition of elevated temperature being known to cause accelerated
degradation of bupropion hydrochloride.
At the end of the one week period, the tablets were analyzed to determine the
total amount of degradation products as a percentage of the initial amount of
bupropion hydrochloride. The total amount of degradation products was
found to be over 25% for example 1 (which uses no sodium bisulfate), but
only 2.89% for example 2, 0.26% for example 3, and 0.11 % for examples 4
and 5.
It thus can be seen that the inclusion of sodium bisulfate in the tablets
decreases the rate of degradation. Furthermore, the rate of degradation
decreases with increased amount of sodium bicarbonate. In example 3,
which comprises 4 parts sodium bisulfate per 100 parts bupropion
hydrochloride, the rate of degradation is acceptably low, and it appears that
there is thus little to be gained by using substantially above this level of
sodium bisulfate. It is thus concluded that the most preferred ratio of sodium
bisulfate to bupropion hydrochloride is about 5 parts sodium bisulfate to 100
parts bupropion hydrochloride.
30
