One formulation of bupropion hydrochloride is taught by Ruff et al., U. S.

Patent 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.

Description of the Invention In accordance with the present invention is provided a novel pharmaceutical composition comprising bupropion hydrochloride and a pharmaceutically acceptable stabilizer.

Bupropion hydrochloride is disclosed in the aforementioned patents as well as in 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 at least 90% of potency after one year of storage at room temperature (59-77°C) at 35-60% humidity. When used herein the term"potency"means the weight of bupropion hydrochloride remaining in a formulation after a period of time has elapsed, for example about a year under ambient conditions or about 12 weeks at about 40°C and about 75% relative humidity, expressed as a percentage of the initial weight of bupropion hydrochloride in that formulation. The weight is measured by suitable quantitative analytical techniques such as HPLC. 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 of the present invention are inorganic acids which at a concentration of about 0.31% w/w form an aqueous solution having a pH of from about 0.5 to about 4.0.

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 at least 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 solution pH of the stabilizers of this invention is determined by adding 15.7 grams of stabilizer to 5084 grams of deionized water in a Pyrex@ beaker.

The resulting mixture is stirred for approximately 15 minutes, using a stir plate and a magnetic stir bar. The resulting solution is examine using a Coming@ pH Meter Model 355. Solutions 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 inorganic acids meeting the aforementioned criteria and more specifically include but are not limited to hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid, or combinations thereof.

Hydrochloric 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, 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 i. e the ratio of inactive ingredient in the formulation, including the amount of stabilizer, to bupropion hydrochloride in the composition is between about 1: 2 and about 6.5: 1.

The amount of stabilizer may be from about 0.01% to 5% of the weight of bupropion hydrochloride, i. e the ratio of stabilizer to bupropion hydrochloride in the composition is between about 1: 10,000 to about 1: 20. Ideally the amount of stabilizer

is about 0.1% to about 2% of the weight of bupropion hydrochloride in the composition, i. e the ratio of stabilizer to bupropion hydrochloride in the composition is between about 1: 1000 to about 1: 50.

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, modified, or extended release profiles, or combinations thereof, are encompassed by the present invention.

Pharmaceutical compositions of the present invention are prepared by preparing a dilute solution of inorganic acid and adding the dilute inorganic acid solution to a dry blend of bupropion hydrochloride and other active and inactive ingredients. The mixture is granulated, dried and milled. Solid dosage formulations are prepared such as by compressing the milled granulation to form tablets or caplets. Alternatively, capsules may be prepared by placing the milled granulation in, for example, a two-part hard gelatin capsule.

Solid dosage forms such as the aforementioned may optionally be film coated using an aqueous coating solution or suspension which has been acidified to a pH of about 0.5 to about 4.0. In preferred embodiments of the invention, the aqueous coating solution or suspension is acidified using a dilute inorganic acid such as hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid to provide an acidic environment on the tablet surface, thereby providing improved stability and further minimizing degradation of bupropion hydrochloride. Dilute, as used herein refers to about 0.095 N to about 0.105 N and preferably 0.1 N.

Suitable coating solutions are commercially available and known to those skilled in the art. Coating agents are also described in Handbook of Pharmaceutical Excipients, (Wade and Weller, ed., 2nd ed.) The following examples are illustrative, but are not limiting of the present invention. Throughout the examples, NF and USP are designations for standards published in the National Formulary and U. S. Pharmacopoeia, respectively.

Example 1 The formulation contained the following ingredients in the following amounts: Ingredient Weight per Tablet (mg) 75 mg potency Bupropion Hydrochloride 75.0 Cellulose, Microcrystalline, NF 332.0 Talc, USP 23.0 Hydroxypropyl Cellulose, NF 10.0 0.1 N Hydrochloric Acid (0.113 mL) TOTAL 440. 0 The ingredients were measured for a 45,000 tablet batch size.

The following ingredients were sifted through a #20 mesh screen: Cellulose, Microcrystalline, NF Bupropion Hydrochloride Hydroxypropyl Cellulose, NF The screened ingredients were transferred to a Collette Gral and mixed for ten (10) minutes, with choppers on for two (2) minutes. The mixed material was granulated with 0.1 N Hydrochloric Acid for a granulation time of twelve (12) minutes.

The granulated material was dried in the tray oven at 40 degrees C to a moisture Loss on Drying (LOD) of % w/w. The moisture was measured using a Computrac@ moisture analyzer. The granulated, dried material was milled through a model D-6 Fitzmill equipped with a &num 1 plate, knives forward, at medium speed.

Talc, USP was sifted through a #30 mesh screen into the milled material. The screened and milled material was blended in a Gemco Double Cone Blender for ten (10) minutes. The blended material was compressed on a Kikusui Libra tablet compression machine at a compression weight of about 0.440 grams per tablet.

The compressed tablet cores (22,727) were aqueous film coated using 2833 g of the following coating formulation: Opadry White YS-1-7003 600 g Purified Water, USP 3400 g TOTAL: 4000 g

The purified water was added to a stainless steel container. To the same container Opadry White was slowly added. The resulting suspension was stirred using a stir bar until uniform and smooth. The tablet cores were coated using a Hi-CoaterOO 60 tablet coating machine.

Bed Temperature: 38°-40°C Inlet Temperature 70° C Pan Speed during warming: 1-2 RPM Pan Speed during coating: 10-11 RPM Spray Rate: 48 g/min.-53 g/min.

Product stability data were obtained for this formulation stored for 4 weeks at 40°C, 75% relative humidity. Potency was determined using HPLC. Product stability data are presented in Table 1.

Table 1 Weeks Potency (%) 0 100.2 4 88.5

Example 2 45.000 tablet cores were prepared as described in Example 1 except that the granulated material was dried in the fluid bed dryer in two parts.

The tablet cores were coated as follows: The formulation for the acidified coating contained the following ingredients in the following amounts: Ingredient Quantity per Tablet Opadry White 18.7 mg 0.1 N Hydrochloric Acid 0.15 mL The coating was prepared as follows: Opadry White and 0.1N hydrochloric acid were mixed in a stainless steel container for approximately 30 minutes. The tablet cores were coated according to method of Example 1 using the acidified coating suspension. Product stability data were obtained for this formulation stored for 12 weeks at 40°C, 75% relative humidity. Potency was determined using HPLC. Product stability data are presented in Table 2.

Bupropion Hydrochloride-Assay Table 2 Weeks Potency (%) 0 98.5 4 99.0 8 98.4 12 96.4

Example 3 The formulation contained the following ingredients in the following amounts: Ingredient**"*'""'"Weight per Tablet (mg) *"'*" 75 mg potency Bupropion Hydrochloride 75.0 Cellulose, Microcrystalline, NF 332.0 Talc, USP 23.0 Hydroxypropyl Cellulose, NF 10.0 Crospovidone 25.0 0.1 N Hydrochloric Acid TOTAL 465. 0 The ingredients were measured for a 45,000 tablet batch size.

The following ingredients were sifted through a #20 mesh screen: Cellulose, Microcrystalline, NF Bupropion Hydrochloride Hydroxypropyl Cellulose, NF Crospovidone (64% of total amount) The screened ingredients were transferred to a 75 liter Collette Gral and blended for ten (10) minutes, with choppers on for two (2) minutes. The blended material was granulated with Hydrochloric Acid for a granulation time of eight (8) minutes.

The granulated material was dried in the fluid bed dryer in two parts to a moisture LOD of 1.5-3.5 % w/w. The moisture was measured using a Computrac (R) moisture analyzer.

The granulated, dried material was milled through a model D-6 Fitzmill equipped with a #1 plate, knives forward, at medium speed.

The milled material was blended in a 2 cu. ft. Gemco Double Cone Blender for ten (10) minutes.

The remaining Crospovidone was sifted through a #20 mesh screen into the milled material. The screened and milled material was blended in the Gemco Double Cone Blender for five (5) minutes. Thereafter, talc, USP was sifted through a #30 mesh screen into the blended material. The screened and milled material was blended in the Gemco Double Cone Blender for ten (10) minutes. The blended material was compressed on a Kikusui Libra tablet compression machine at a compression weight of about 0.465 grams per tablet.

The compressed tablet cores were aqueous film coated using the following coating formulation: Ingredient Quantity per Tablet Opadry White YS-1-7003 18. 7 mg 0.1 N Hydrochloric Acid Solution 0.15 mL The coating suspension was prepared as follows: The 0.1N Hydrochloric Acid solution was added to a container. To the same container, Opadry White was slowly added. The resulting suspension was stirred using a stir bar until uniform and smooth.

The tablet cores were coated according to the procedure described in Example 1 using a Hi-CoaterX 60 tablet coating machine.

Tablet cores were coated to an approximate weight of 0.480 grams.

Product stability data were obtained for this formulation stored for 12 weeks at 40°C, 75% relative humidity. Potency was determined using HPLC. Product stability data are presented in Table 3.

Table 3 Weeks Potency (%) 0 97.6 4 99.5 8 98.8 12 97.2

Example 4 The formulation contained the following ingredients in the following amounts: Ingredient Weight per Tablet (mg) 100 mg potency Bupropion Hydrochloride 100.0 Cellulose, Microcrystalline, NF 442.7 Talc, USP 30. 7 Hydroxypropyl Cellulose, NF 13.3 Crospovidone 33.3 0. IN Hydrochloric Acid (0.083 mL) TOTAL 620. 0 The ingredients were measured for a 42,000 tablet batch size.

The following ingredients were through a #20 mesh screen: Cellulose, Microcrystalline, NF (50% of total) Bupropion Hydrochloride Hydroxypropyl Cellulose, NF Crospovidone (64% of total) The screened ingredients were transferred to a Collette Gral and blended for ten (10) minutes, with choppers on for two (2) minutes.

The blended material was granulated with Hydrochloric Acid for a granulation time of approximately 5-6 minutes.

The granulated material was dried in the fluid bed dryer to a moisture LOD of 1.5-3.5 % w/w.

The moisture was measured using a ComputracO moisture analyzer.

The granulated, dried material was milled through a model D-6 Fitzmill equipped with a #1 plate, knives forward, at medium speed.

The remaining cellulose microcrystalline, NF and crospovidone were screened through a #20 mesh screen. The screened and milled material was blended in a Gemco Double Cone Blender for ten (10) minutes.

The talc, USP was screened through a #30 mesh screen: The screened and milled materials were blended in a Gemco Double Cone Blender for ten (10) minutes.

The blended material was compressed on a Kikusui Libra tablet compression machine at a compression weight of about 0.620 grams per tablet.

Product stability data were obtained for tablet cores prepared according to this formulation stored for 12 weeks at 40°C, 75% relative humidity. Potency was determined using HPLC. Product stability data are presented in Table 4.

Table 4 Weeks Potency (%) 0 99.1 4 99.7 8 97.2 12 98.8 Example 5 The formulation was prepared as described in Example 4 using 100 mg of bupropion hydrochloride per tablet core. The granulated material was dried to a moisture LOD of 1.5-3.5 % w/w. The blended material was compressed on a Kikusui Libra tablet compression machine at a compression weight of about 0.620 grams per tablet.

Tablet cores were coated according to the procedure listed in Example 2 using Chromatone P instead of Opadry White.

The formulation for the acidified coating contained the following ingredients in the following amounts: Ingredient'****'-------Quantity per Tablet Polyethylene Glycol, NF 1.6 mg Polysorbate 80, NF 0.2 mg Chromatone (R) P DDB 8440-OR 17.9 mg 0.1 N Hydrochloric Acid (0.11 mL) The coating was prepared as follows: The 0.1N hydrochloric acid was transferred to a stainless steel container with a mixer.

Polysorbate 80, NF, Polyethylene glycol, NF and Chromatone (g) P DDB 8440-OR were added to the container. The resulting acidified coating suspension was stirred during this Step and for approximately 30 minutes before use. The tablet cores were coated according to method of Example 1 using the acidified coating suspension.

Product stability data were obtained for this formulation stored for 4 weeks at 40°C, 75% relative humidity. Potency was determined using HPLC. Product stability data are presented in Table 5.

Table 5 Weeks Potency (%) 0 97.5 4 99.6 Example 6 The formulation contained the following ingredients in the following amounts: Ingredient Weight per Tablet (mg) 100 mg potency Bupropion Hydrochloride 100.0 Cellulose, Microcrystalline, NF 420.2 Talc, USP 30.7 Hydroxypropyl Cellulose, NF 13.3 Crospovidone, NF 55.8 0.1 N Hydrochloric Acid (0.083 mL) TOTAL 620. 0 The ingredients were measured for a 42,000 tablet batch size.

The following ingredients were sifted through a #20 mesh screen: Cellulose, Microcrystalline, NF (50% of total) Bupropion Hydrochloride Hydroxypropyl Cellulose, NF Crospovidone, NF (55% of total) The screened ingredients were transferred to a Collette Gral and blended for ten (10) minutes, with choppers on for two (2) minutes. The blended material was granulated with Hydrochloric Acid for a granulation time of approximately 5-6 minutes.

The granulated material was dried in two parts in the fluid bed dryer to a moisture LOD of 1.5-3.5 % w/w.

The moisture was measured using a Computrac moisture analyzer.

The granulated, dried material was milled through a model D-6 Fitzmill equipped with a #0 plate, knives forward, at medium speed.

The remaining cellulose microcrystalline, NF and crospovidone were screened through a #20 mesh screen.

The screened and milled material was blended in a Gemco Double Cone Blender for ten (10) minutes. Thereafter the talc, USP was screened through a #30 mesh screen. The screened and milled material was blended in a Gemco Double Cone Blender for ten (10) minutes.

The blended material was compressed on a Kikusui Libra tablet compression machine at a compression weight of about 0.620 grams per tablet.

Tablet cores were coated according to the procedure described in Example 5.

Product stability data were obtained for this formulation stored for 8 weeks at 40°C, 75% relative humidity. Potency was determined using HPLC. Product stability data are presented in Table 6.

Table 6 Weeks Potency (%) 0 96.7 4 97.6 8 95.3