Sustained release tablets containing bupropion hydrochloride

BACKGROUND OF THE INVENTION

0001Bupropion 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®.

0002Bupropion 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 5358970 discloses stabilization of bupropion hydrochloride by including in the tablets a stabilizer selected from a specified group of acids.

0003U.S. patent 5427798 discloses that bupropion hydrochloride is advantageously administered as sustained release tablets and certain formulations for making such tablets are disclosed and claimed. The formulations disclosed and claimed all comprise hydroxypropyl methylcellulose as the agent for controlling the drug release rate. Wellbutrin SR® tablets sold in the United States appear to be made within the scope of the claims of U.S. patent 5427798.

0004U.S. patent 5427798 discloses that the dissolution rate of bupropion hydrochloride from the sustained release tablets disclosed therein is preferably as follows: <ul id="ul0001" list-style="none" compact="compact"><li>i) Between about 20% and about 60% in 1 hour,</li><li>ii) Between about 50% and about 95% in 4 hours, and</li><li>iii) Not less than about 75% in 8 hours.</li></ul>

0005The test conditions and apparatus used to determine the dissolution rate are specified to be: <ul id="ul0002" list-style="none" compact="compact"><li>Apparatus: USP Rotating Paddle (Apparatus II)</li><li>Stirring Rate: 50 rpm</li><li>Medium: 900 mL of distilled water</li><li>Temperature: 37°C</li></ul>

0006All of the tablets in the examples in U.S. patent 5427798 comprise glycine hydrochloride as acidic stabilizer, in addition to the bupropion hydrochloride and hydroxypropyl methylcellulose; and in each example the process of manufacture includes the steps of dissolving the acidic stabilizer in water and using the resultant solution to wet-granulate a mixture of hydroxypropyl methylcellulose and microcrystalline cellulose.

0007Such a process has the disadvantage of requiring the use of water and requiring the steps of preparing the solution, using the solution to wet-granulate a mixture of powders, and drying the wet mass.

0008The object of the present invention is to enable production of stable sustained release tablets comprising bupropion hydrochloride, which do not require use of hydroxypropyl methylcellulose and can be made without requiring a wet-granulation process.

DESCRIPTION OF THE INVENTION

0009It has been found that inclusion of hydroxyethylcellulose in tablets comprising bupropion hydrochloride, along with an acidic stabilizer, enables the production of stable sustained release tablets having appropriate dissolution rate, and that such tablets can be made without requiring a wet-granulation process.

0010Hydroxyethylcellulose (hereinafter referred to "HEC") is sold in the United States and elsewhere under the tradename Natrosol®. HEC is a hydroxyethyl ether of cellulose. The cellulose molecule is comprised of a chain of anhydroglucose units, each of which contains three hydroxyls capable of reaction. Hydroxyethyl groups can be introduced into the cellulose molecule by reacting with ethylene oxide at the hydroxyls in the cellulose chain. Further hydroxyethyl groups can be introduced by reacting with ethylene oxide at the hydroxyls at the end of hydroxyethyl groups that have previously been added.

0011The average number of moles of ethylene oxide that become attached to each anhydroglucose unit in cellulose in these two ways is called "moles of substituent combined" or "MS".

0012A preferred HEC is that having MS of 2.5. This is available under the tradename Natrosol 250®. Viscosity of a solution of HEC in water increases with increased molecule weight of the HEC. Natrosol 250® is available in various viscosity types as follows: <tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="4" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="39.37mm" /><colspec colnum="2" colname="col2" colwidth="39.37mm" /><colspec colnum="3" colname="col3" colwidth="39.37mm" /><colspec colnum="4" colname="col4" colwidth="39.37mm" /><thead valign="top"><row rowsep="1"><entry namest="col1" nameend="col1" /><entry namest="col2" nameend="col4" align="center">Viscosity in cps at 25°C at various concentrations in water</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="center">Viscosity Type</entry><entry namest="col2" nameend="col2" align="center">1%</entry><entry namest="col3" nameend="col3" align="center">2%</entry><entry namest="col4" nameend="col4" align="center">5%</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">250HH</entry><entry namest="col2" nameend="col2" align="center">3400-5000</entry><entry namest="col3" nameend="col3" /><entry namest="col4" nameend="col4" /></row><row><entry namest="col1" nameend="col1" align="left">250H4</entry><entry namest="col2" nameend="col2" align="center">2600-3300</entry><entry namest="col3" nameend="col3" /><entry namest="col4" nameend="col4" /></row><row><entry namest="col1" nameend="col1" align="left">250H</entry><entry namest="col2" nameend="col2" align="center">1500-2500</entry><entry namest="col3" nameend="col3" /><entry namest="col4" nameend="col4" /></row><row><entry namest="col1" nameend="col1" align="left">250MH</entry><entry namest="col2" nameend="col2" align="center">800-1500</entry><entry namest="col3" nameend="col3" /><entry namest="col4" nameend="col4" /></row><row><entry namest="col1" nameend="col1" align="left">250M</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">4500-6500</entry><entry namest="col4" nameend="col4" /></row><row><entry namest="col1" nameend="col1" align="left">250K</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">1500-2500</entry><entry namest="col4" nameend="col4" /></row><row><entry namest="col1" nameend="col1" align="left">250G</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">150-400</entry><entry namest="col4" nameend="col4" /></row><row><entry namest="col1" nameend="col1" align="left">250E</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">25-105</entry><entry namest="col4" nameend="col4" /></row><row><entry namest="col1" nameend="col1" align="left">250J</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" /><entry namest="col4" nameend="col4" align="center">150-400</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">250L</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" /><entry namest="col4" nameend="col4" align="center">75-150</entry></row></tbody></tgroup></table></tables>

0013Preferred viscosity types are those with viscosity of above about 800 cps in 1 % aqueous solution. Most preferred is the type with viscosity of about 1500 to 2500 cps in 1% aqueous solution, which is available as Natrosol 250H®.

0014The amount of HEC per tablet will preferably be from about 10 to about 60 parts per part of bupropion hydrochloride by weight. The amount of HEC per tablet will be more preferably from about 20 to about 40 parts per part of bupropion hydrochloride by weight.

0015In addition to comprising bupropion hydrochloride and HEC, the sustained release tablets will preferably also comprise another ingredient as a binder to increase the hardness of the tablets when the mixture of ingredients is compressed into tablets on a tablet press. This binder will preferably be either microcrystalline cellulose or methylcellulose.

0016Methylcellulose is available in the United States and elsewhere under the tradename Methocel A® Methocel A® is available in several different viscosity grades corresponding to different molecular weights.

0017The lowest available viscosity grade, corresponding to the lowest molecular weight, is sold as Methocel A15LV® which has a viscosity of 15 cps in 2% aqueous solution at 25°C. This lowest viscosity grade is preferred for use in the present invention.

0018The tablets of the present invention will preferably also comprise an acidic stabilizer, which will preferably be sodium bisulfate.

0019The tablets will preferably also comprise a lubricant, such as, for example, magnesium stearate to avoid sticking to the tooling in the tabletting process.

0020The tablets will optionally also comprise a glidant such as, for example, colloidal silicon dioxide.

0021The tablets will be made by mixing the ingredients and compressing the mixture into tablets on a tablet press as it has surprisingly been found that the use HEC enables the obtention of a tablet exhibiting adequate hardness and slower-release properties without the need to wet-granulate the mixture. Preferably the mixture will be made by a simple dry mix process; that is to say, simply by mixing ingredients together in dry form, without the addition of water or another solvent and the subsequent removal of such solvent by drying.

0022If the dry mixture of ingredients does not flow well enough for direct tabletting, then the mixture can be slugged or compacted and then ground up into granules. The granules can then be compressed into tablets with or without the addition of other ingredients.

0023After the tablets are made they can optionally be coated with a film coating.

0024The tablets of the present invention will preferably have the same dissolution profile as specified in U.S. patent 5427798. That is to say; <ul id="ul0003" list-style="none" compact="compact"><li>i) Between about 20% and about 60% in 1 hour,</li><li>ii) between about 50% and about 95% in 4 hours, and</li><li>iii) not less than about 75% in 8 hours.</li></ul>

0025The test conditions and apparatus used to determine dissolution rate are: <tables id="tabl0002" num="0002"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Apparatus</entry><entry namest="col2" nameend="col2" align="left">USP Rotating Paddle (Apparatus II)</entry></row><row><entry namest="col1" nameend="col1" align="left">Stirring Rate</entry><entry namest="col2" nameend="col2" align="left">50 rpm</entry></row><row><entry namest="col1" nameend="col1" align="left">Medium</entry><entry namest="col2" nameend="col2" align="left">900 mL of distilled water</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Temperature</entry><entry namest="col2" nameend="col2" align="left">37°C</entry></row></tbody></tgroup></table></tables>

0026The following example is representative of the invention, but not limiting.

0027Ingredients were mixed in the relative amounts as follows:

Example 1

0028<tables id="tabl0003" num="0003"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Bupropion Hydrochloride</entry><entry namest="col2" nameend="col2" align="char" char=".">100.0</entry></row><row><entry namest="col1" nameend="col1" align="left">Natrosol 250H</entry><entry namest="col2" nameend="col2" align="char" char=".">32.0</entry></row><row><entry namest="col1" nameend="col1" align="left">Methocel A15LV</entry><entry namest="col2" nameend="col2" align="char" char=".">80.0</entry></row><row><entry namest="col1" nameend="col1" align="left">Sodium Bisulfate</entry><entry namest="col2" nameend="col2" align="char" char=".">5.0</entry></row><row><entry namest="col1" nameend="col1" align="left">Magnesium Stearate</entry><entry namest="col2" nameend="col2" align="char" char=".">2.2</entry></row><row><entry namest="col1" nameend="col1" align="left">Colloidal Silicon Dioxide</entry><entry namest="col2" nameend="col2" align="char" char=".">0.8</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" /><entry namest="col2" nameend="col2" align="char" char="."><maths id="math0001" num=""><math display="inline"><mrow><mover accent="true"><mrow><mtext>220.0</mtext></mrow><mo>¯</mo></mover></mrow></math><img file="EP1020184A1_D0001.tif" /></maths></entry></row></tbody></tgroup></table></tables>

0029The ingredients were mixed, the 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 220 mg each.

0030Each tablet thus contained 100 mg of bupropion hydrochloride. Sample tablets were tested for dissolution rate by the aforesaid method and the results were found to comply with the aforesaid specifications.