PHARMACEUTICAL COMPOSITION CONTAINING BUPROPION HYDROCHLORIDE AND A STABILIZER

Abstract: Novel, stable formulations of bupropion hydrochloride are provided which will maintain at least 80% of initial bupropion hydrochloride potency after one year. Methods of inhibiting degradation of bupropion hydrochloride and methods of preparing stable formulations of bupropion hydrochloride are also provided.

Description: PHARMACEUTICAL COMPOSITION CONTAINING BUPROPION HYDROCHLORIDE AND A STABILIZER Background of the Invention Bupropion hydrochloride is a common antidepressant sold in immediate release, modified release, and extended release tablet forms. See U.S. Patent 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. 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. 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. Patent 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 at least about 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 remaning 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 are those that have solubility in water at 20°C of less than about lOg stabilizer/ lOOg water and that at a concentration of about 6% w/w form an aqueous suspension having a pH of from about 0.9 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 ret.ain .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 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,, . 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 10% to 100% of the weight of bupropion hydrochloride, i.e the ratio of stabilizer to bupropion hydrochloride in the composition is between about 1:10 and about 1: 1. Ideally the amount of stabilizer is about 10% to about 40% of the weight of bupropion hydrochloride in the composition, i.e the ratio of stabilizer to bupropion hydrochloride in the composition is between about 1:10 and about 4: 10. Most preferably, the amount of stabilizer is from about 15% to about 30% of the weight of bupropion hydrochloride, i.e the ratio of stabilizer to bupropion hydrochloride in the composition is preferably between about 3:20 and about 3:10. Furthermore about 1 % to about 40% of the total weight of the composition 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 industri.al 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. The following examples are illustrative, but are not limiting of the present invention. Throughout the ex.amples, NF and USP are designations for standards published in the National Formul.ary and U.S. Pharmacopoeia, respectively. Exa ples 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 Fumaric Acid, NF 18.0 Hydroxypropyl Cellulose, EXF, NF 10.0 Core Weight 458.0 Coating Chromatone® P DDB8361-W 12.56 Polyethylene Glycol 400, NF 1.10 Polysorbate 80, NF 0.14 Purified water USP 0.1 mL TOTAL 471.8 The powder ingredients were weighed out for a 56,000 tablet batch size. The following ingredients were sifted through a clean # 20 mesh screen: Cellulose, Microcrystalline, NF Bupropion Hydrochloride Hydroxypropyl Cellulose, EXF, NF Fumaric Acid, NF The screened material was transferred into a Gemco Double Cone Blender and blended for ten (10) minutes. Thereafter, the remaining Cellulose Microcrystalline NF was transferred into the Gemco Double Cone Blender and blended for ten (10) minutes. The blended material was milled through a Model D-6 Fitzmill equipped with a #1 plate, knives forward at medium speed. Talc, USP was passed through a #30 mesh screen into the milled materi . The material was transferred into the Gemco Double Cone Blender and blended for ten (10) minutes. The blended material was compressed on a Kikusui Libra tablet compression machine at a weight of about 0.458 grams per tablet. The coating solution was prepared as follows: Purified water USP was added to a clean manufacturing tank equipped with a clean Mixer. The following ingredients were added to the manufacturing tank: Polyethylene Glycol 400, NF Polysorbate 80, NF The mixer was turned on. Chromatone® P DDB8361-W was slowly added to the manufacturing tank. After the ingredients were added, the mixing was continued until a uniform suspension was achieved. The pan load amounts and solution amounts were calculated for solution application using the Hi Coater 60 . The tablet cores were loaded into the pan coater. The tablet bed was preheated until the exhaust air temperature was between 37° and 48°C (approximately 43°C). The pan speed was adjusted to approximately 8 RPM before starting the spray cycle. The spray cycle was activated. The exhaust temperature was maintained between 37°C and 48°C throughout the cycle. After the proper amount of solution was applied, the coated tablets were dried. Tablets were coated to an approximate weight gain of 24 mg per tablet. 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 1. Table 1 Weeks Potency (%) 0 99.9 4 97.1 12 95.8 Example 2 The formulation contained the following ingredients in the following amounts: Ingredient Weight per Tablet (mg) 75 mg potency Core Bupropion Hydrochloride 75.0 Cellulose, Microcrystalline, NF 334.0 Talc, USP 23.0 Fumaric Acid, NF 18.0 Hydroxypropyl Cellulose, EXF, NF KλO Core Weight 460.0 Coating Chromatone® P DDB8440-OR 12.56 Polyethylene Glycol 400, NF 1.10 Polysorbate 80, NF 0.14 Purified water USP 0.1 mL TOTAL 473.8 The powder ingredients were weighed out for a 500,000 tablet batch size. The blended material was prepared as described in Example 1. The blended material was then compressed on a Kikusui Libra tablet compression machine. Tablets were compressed at a weight of about 0.460 grams per tablet. Compression was performed in a room with temperature between 55°- 85°F and low humidity (approximately 30% Relative Humidity). The coating solution was prepared as follows: Ninety-eight percent (98%) of purified water USP was added to a clean manufacturing tank equipped with a clean Chemineer Mixer with a four-inch blade. The Chemineer mixer was turned on and the setting was adjusted to 2 - 10 psi. The following ingredients were added to the manufacturing tank: Polyethylene Glycol 400, NF Polysorbate 80, NF After the ingredients were added, the mixer setting was adjusted to 1 - 4 psi to minimize foaming. The Polyethylene Glycol and Polysorbate 80, NF containers were rinsed using remaining 2% of Purified Water USP and the rinse water was added to the tank. Mixing was continued for approximately ten (10) minutes. The mixer setting was adjusted to 30 - 60 psi. Mixing was continued for approximately twenty (20) minutes. Chromatone® P DDB8-440-OR was added to the manufacturing tank. The mixer setting was reduced to 1 - 4 psi to reduce foaming and mixing continued for thirty (30) minutes. The pan load amounts and solution amounts were calculated for solution application using the Hi Coater 130 . The spray guns were installed in the pan coater unit as follows: Spray Gun Nozzle Size: Air Cap 025-R, Liquid Nozzle 012. Hi Coater 130: Atomizing Air: 140 to l50 SLPM Pattern Air: 190 to 200 SLPM Four guns to equal 250 - 500 mL/min. Solution was stirred with the mixer setting of 1 - 2 psi at all times. The tablet cores were loaded into the pan coater. The tablet bed was preheated until the exhaust air temperature was between 37°C and 48°C (approximately 43 °C). The pan speed was adjusted to 5 - 9 RPM before starting the spray cycle. The spray cycle was activated. The exhaust temperature was maintained between 37°C and 48°C throughout the cycle. After the proper amount of solution was applied, the coated tablets were dried for approximately two (2) minutes. Steps were repeated for all pans to coat all tablets in the batch. All tablets were coated to an approximate weight gain of 13.8 mg per tablet. Product stability data were obtained for this formulation stored for 12 weeks at 40°C, 75% relative humidity. Potency was determined using HPLC. Data are presented in Table 2. Table 2 Weeks Potency (%) 0 100.8 4 94.9 8 92.5 12 91.0 Example 3 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 442.0 Talc, USP 30.7 Fumaric Acid, NF 24.0 Hydroxypropyl Cellulose, EXF, NF 13.3 Core Weight 610.0 Coating Chromatone® P DDB8440-OR 16.8 Polyethylene Glycol 400, NF 1.5 Polysorbate 80, NF 0.2 Purified water USP 0.14 rnL TOTAL 628.5 The powder ingredients were weighed out for a 42,001 tablet batch size and prepared as described in Example 1. The blended material was compressed on a Kikusui Libra tablet compression machine at a weight of about 0.610 grams per tablet. Tablets were coated according to the procedure described in Example 1. 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 ; * weekss Potency (%) 0 97.7 4 91.3 8 93.4 12 88.1 Example 4 The formulation contained the following ingredients in the following amounts: Ingredient Weight per Tablet (mg) 100 mg potency Core Bupropion Hydrochloride 100.0 Cellulose, Microcrystalline, NF 445.0 Talc, USP 30.7 Fumaric Acid, NF 24.0 Hydroxypropyl Cellulose, EXF, NF 13.3 Core Weight 613.0 Coating Chromatone® P DDB8440-OR 16.8 Polyethylene Glycol 400, NF 1.5 Polysorbate 80, NF 0.2 Purified water USP 0.14 mL TOTAL 631.5 The powder ingredients were weighed out for a 375,000 tablet batch size and prepared as described as in Example 2. Tablets were compressed at a compression weight of about 0.613 grams per tablet. Tablets were coated as described in Example 2 to an approximate weight gain of 18.5 mg per tablet. 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 4. Table 4 weeks Potency (%) 0 98.7 4 94.4 8 93.9 12 92.1 Example 5 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 Fumaric Acid, NF 18.0 Hydroxypropyl Cellulose, EXF, NF 10.0 TOTAL 458.0 The powder ingredients were weighed out for a 45,000 tablet batch size. The composition was prepared as described in Example 1. Tablets were compressed at a compression weight of about 0.458 grams per tablet. Tablets were film coated as described in Example 2 to an approximate weight gain of 4.25% (19.5 mg). Product stability data were obtained for this formulation stored for 12 weeks at 40°C, 75% relative humidity. Potency was determined using HPLC. The following product stability data shown in Table 5 were obtained for this formulation. Table 5 Weeks Potency (%) 0 98.5 4 95.0 8 93.0

Claims: CLAIMS What is claimed is: 1. A pharmaceutical composition in solid form comprising bupropion hydrochloride and a pharmaceutically acceptable stabilizer in an effective stabilizing amount wherein said stabilizer has solubility in water at 20°C of less than about lOg stabilizer/ lOOg water and at a concentration of about 6% w/w forms an aqueous suspension pH of about 0.9 to about 4.0. 2. The composition of claim 1 wherein the stabilizer is a dicarboxylic acid. 3. The composition of claim 2 wherein the dicarboxylic acid is oxalic, succinic, adipic, fumaric or phthalic acid. 4. The composition of claim 1 wherein the amount of stabilizer in the composition is from about 10% to about 100% of the amount of bupropion hydrochloride in the composition. 5. The composition of claim 4 wherein the composition comprises from about 50 mg to about 300 mg of bupropion hydrochloride. 6. A method for stabilizing bupropion hydrochloride in solid form comprising adding an effective stabilizing amount of a stabilizer wherein said stabilizer has solubility in water at 20°C of less th.an about lOg stabilizer/ lOOg water and at a concentration of about 6% w/w forms an aqueous suspension pH of about 0.9 to about 4.0 to a pharmaceutically effective amount of bupropion hydrochloride. 7. The method of claim 6 wherein the stabilizer is fumaric acid. 8. A method for preparing a stable composition of bupropion hydrochloride in solid form comprising: dry blending bupropion hydrochloride and solid stabilizer to equally distribute the components; dry milling the blended material; and preparing a solid dosage form. 9. The method of claim 8 wherein the stabilizer is fumaric acid. 10. A pharmaceutical composition in solid form prepared according to Claim 8.

Inventors: DE VITO JOSEPH MICHAEL, KULKARNI PRAKASH SHRIRAM, MAITRA AMITAVA, SHAH BHARAT BOGILAL, DE VITO, JOSEPH, MICHAEL, KULKARNI, PRAKASH, SHRIRAM, MAITRA, AMITAVA, SHAH, BHARAT, BOGILAL
Applicants: AMERICAN HOME PROD, AMERICAN HOME PRODUCTS CORPORATION
Application year: 1998
Main classification: A61K31
IPC codes: A61K9, A61K47