WO2008129465A2 - Stable pharmaceutical compositions of bupropion - Google Patents
Stable pharmaceutical compositions of bupropion Download PDFInfo
- Publication number
- WO2008129465A2 WO2008129465A2 PCT/IB2008/051453 IB2008051453W WO2008129465A2 WO 2008129465 A2 WO2008129465 A2 WO 2008129465A2 IB 2008051453 W IB2008051453 W IB 2008051453W WO 2008129465 A2 WO2008129465 A2 WO 2008129465A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- bupropion
- salt
- disodium salt
- acid
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 59
- 229960001058 bupropion Drugs 0.000 title claims abstract description 56
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical group CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 37
- 239000003381 stabilizer Substances 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 239000000203 mixture Substances 0.000 claims abstract description 24
- 239000002245 particle Substances 0.000 claims abstract description 9
- IKBZAUYPBWFMDI-UHFFFAOYSA-N 5-bromo-4-methoxy-7-methyl-2,3-dihydro-1h-indene Chemical compound C1=C(Br)C(OC)=C2CCCC2=C1C IKBZAUYPBWFMDI-UHFFFAOYSA-N 0.000 claims description 23
- 229960004367 bupropion hydrochloride Drugs 0.000 claims description 23
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 18
- 239000008187 granular material Substances 0.000 claims description 14
- 235000016337 monopotassium tartrate Nutrition 0.000 claims description 14
- KYKNRZGSIGMXFH-ZVGUSBNCSA-M potassium bitartrate Chemical compound [K+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O KYKNRZGSIGMXFH-ZVGUSBNCSA-M 0.000 claims description 14
- 229940086065 potassium hydrogentartrate Drugs 0.000 claims description 13
- 230000000087 stabilizing effect Effects 0.000 claims description 13
- 229920000642 polymer Polymers 0.000 claims description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- 239000002552 dosage form Substances 0.000 claims description 10
- 238000003860 storage Methods 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 8
- -1 delayed release Substances 0.000 claims description 8
- 239000011248 coating agent Substances 0.000 claims description 7
- 239000000945 filler Substances 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 238000000576 coating method Methods 0.000 claims description 6
- 230000003111 delayed effect Effects 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 229960001040 ammonium chloride Drugs 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 5
- 239000008188 pellet Substances 0.000 claims description 5
- 239000012730 sustained-release form Substances 0.000 claims description 5
- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 239000001744 Sodium fumarate Substances 0.000 claims description 4
- 235000010410 calcium alginate Nutrition 0.000 claims description 4
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- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 claims description 4
- KCFCAUKZKOSSBI-UHFFFAOYSA-J copper;disodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Cu+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O KCFCAUKZKOSSBI-UHFFFAOYSA-J 0.000 claims description 4
- JFROQFOCFOKDKU-UHFFFAOYSA-L dipotassium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate;hydron;dihydrate Chemical compound O.O.[K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O JFROQFOCFOKDKU-UHFFFAOYSA-L 0.000 claims description 4
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- ZQHKAIDDHTYINE-UHFFFAOYSA-J disodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate;manganese(2+) Chemical compound [Na+].[Na+].[Mn+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ZQHKAIDDHTYINE-UHFFFAOYSA-J 0.000 claims description 4
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 4
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- 238000002156 mixing Methods 0.000 claims description 3
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- 230000006641 stabilisation Effects 0.000 claims 14
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- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims 3
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- 235000010408 potassium alginate Nutrition 0.000 description 1
- 239000000737 potassium alginate Substances 0.000 description 1
- MZYRDLHIWXQJCQ-YZOKENDUSA-L potassium alginate Chemical compound [K+].[K+].O1[C@@H](C([O-])=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@@H](O)[C@H]1O MZYRDLHIWXQJCQ-YZOKENDUSA-L 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
Definitions
- the present invention relates to stable pharmaceutical compositions comprising bupropion or salts thereof and a basic stabilizing agent, wherein the stabilizing agent is capable of maintaining a pH of less than 6 around bupropion particles.
- the invention also relates to processes for the preparation of such compositions.
- Bupropion hydrochloride is an antidepressant of the amino ketone class. Chemically, it is ( ⁇ )-l-(3-chlorophenyl)-2-[(l,ldimethylethyl)amino]-l-propanonehydrochloride. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride is a water-soluble, highly hygroscopic, crystalline and susceptible to decomposition. Because of the drug's instability, the shelf life of bupropion formulations has proved to be problematic.
- U.S. Patent Nos. 5,541,231; 5,763,493; 5,358,970; 5,427,798; 5,731,000; 6,333,332; 6,221,917 and 6,194,002 describe stable bupropion hydrochloride formulations that use an organic acid, a carboxylic acid, an amino acid salt (e.g., cysteine hydrochloride, glycine hydrochloride, and cysteine di- hydrochloride), or sodium metabisulfite as stabilizers.
- an organic acid e.g., cysteine hydrochloride, glycine hydrochloride, and cysteine di- hydrochloride
- an amino acid salt e.g., cysteine hydrochloride, glycine hydrochloride, and cysteine di- hydrochloride
- sodium metabisulfite e.g., sodium metabisulfite as stabilizers.
- U.S. Patent No. 5,968,553 discloses bupropion hydrochloride formulations using dilute inorganic acids as stabilizers including hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid.
- U.S. Patent No. 6,482,987 discloses a method for preparing a stable composition of bupropion hydrochloride by dry blending bupropion hydrochloride and solid stabilizer.
- U.S. Patent No. 6,238,697 discloses a method for preparing a stable composition of bupropion hydrochloride by direct compression of bupropion hydrochloride and other excipients.
- U.S. Patent No. 6,893,660 describes a method for stabilizing bupropion formulation by adding a sealing component in the excipients to form a sealed excipient component.
- U.S. Patent No. 6,306,436 discloses a pharmaceutical composition of bupropion that is free of added acid.
- U.S. Patent No. 6,652,882 discloses a controlled release pharmaceutical formulation of bupropion comprising uncross linked polymer and crosslinked insoluble polymer.
- U.S. Patent No. 6,210,716 discloses a controlled release dosage form of bupropion hydrochloride.
- U.S. Patent Nos. 6,096,341 , 6,033,686 and 6,143,327 disclose a delayed release coated tablet comprising a core of bupropion hydrochloride and conventional ex- cipients, free of stabilizer and coating.
- U.S. Patent No. 6,242,496 discloses a method for stabilizing bupropion by using a stabilizer wherein the stabilizer has solubility in water at 20 ° C of less than 1O g stabilizer/ 100 g water and has an aqueous suspension pH of about 0.9 to about 4.0 at a concentration of about 6% w/w.
- U.S. Application No. 2003044462 discloses a pharmaceutical composition in solid form that includes bupropion hydrochloride and an effective amount of carboxy vinyl polymer as the sole stabilizing agent and the sole controlled release material.
- 2006020040 discloses a solid dosage form that contains bupropion hydrochloride and glucono delta lactone or its corresponding open chain hydroxy acid derivative as a stabilizer.
- U.S Application No. 2006099260 discloses a pharmaceutical composition that includes a core comprising bupropion; and a coating comprising a pharmaceutically acceptable pH-independent polymer and a surfactant.
- U.S. Application No. 2005112198 discloses a pharmaceutical solid dosage form that includes bupropion hydrochloride and a member of the group selected from butylated hydroxyanisole, butylated hydroxytoluene and an ion exchange resin. [18] Summary of the Invention
- a stable pharmaceutical composition that includes bupropion or salts thereof and a basic stabilizing agent.
- the pharmaceutical composition may include one or more of the following features.
- the composition may further include one or more pharmaceutically acceptable excipients selected from diluent, filler, binder, lubricant, glidant, and rate controlling polymer.
- the pharmaceutical composition may retain at least about 80% of the potency of the bupropion after storage for three months at 40 0 C and 75% relative humidity.
- a method of stabilizing bupropion or salts thereof in a pharmaceutical composition includes a step of adding an effective amount of at least one basic stabilizing agent.
- a stable pharmaceutical composition that includes bupropion or salts thereof and an effective stabilizing amount of potassium hydrogen tartrate along with other pharmaceutically acceptable excipients.
- a method of stabilizing bupropion or salts thereof in a pharmaceutical composition includes a step of adding potassium hydrogen tartrate in an amount sufficient to attain a pH of less than 6 around the bupropion particles.
- [26] 1. a) mixing, granulating bupropion or a salt thereof, at least one basic stabilizer and other pharmaceutically acceptable excipients; and
- Embodiments of the process may include one or more of the following features.
- the pharmaceutical composition may retain at least about 80% of the potency of the bupropion after storage for three months at 40 0 C and 75% relative humidity.
- the term 'stable pharmaceutical composition' herein refers to a pharmaceutical composition that retains at least about 80% of the potency of the bupropion after storage for three months at 40 0 C and 75% relative humidity.
- the 'basic stabilizing agent' is a pharmaceutically acceptable substance capable of preventing the degradation of bupropion by maintaining a pH of less than 6 around the bupropion particles.
- Bupropion is a highly hygroscopic drug and susceptible to decomposition. A relatively low pH environment has proven effective in stabilizing bupropion.
- the basic stabilizing agent may be one or more of ethylenediaminetetraacetic acid disodium salt, ethylenediaminetetraacetic acid calcium disodium salt, ethylenediamine tetraacetic acid dipotassium salt dihydrate, ethylenediaminetetraacetic acid manganese disodium salt, ethylenediaminetetraacetic acid copper disodium salt, sodium citrate, sodium acetate, sodium fumarate, calcium oxalate, calcium alginate, ammonium chloride, potassium hydrogen tartrate, and the like.
- Potassium hydrogen tartrate also known as potassium acid tartrate
- Saturated solution of potassium hydrogen tartrate has a pH of 3.557 at 25 0 C.
- potassium hydrogen tartrate Upon dissolution in water, potassium hydrogen tartrate dissociates into acid tartrate, potassium cation, and the conjugate base, citrate dianion.
- a solution of potassium hydrogen tartrate creates a buffer effect in an acidic pH range.
- the 'effective stabilizing amount' herein refers to the amount of basic stabilizing agent, which is capable of preventing the degradation of bupropion by maintaining a pH of less than 6 around bupropion particles under storage conditions thereby providing stable pharmaceutical compositions.
- These stabilizers can be used in a concentration which can effectively retain at least about 80% of the potency of the bupropion in the composition after storage for three months at 40 0 C and 75% relative humidity.
- the amount of bupropion or a salt thereof may vary from about 25 mg to 500 mg w/ w of the pharmaceutical composition.
- the pharmaceutical composition can be in an immediate release form, sustained release form or a delayed release form.
- the pharmaceutical composition of bupropion or salts thereof can be prepared by conventional methods of preparation like aqueous or non-aqueous wet granulation, direct compression, melt granulation or dry granulation.
- the powder blend of bupropion and a stabilizing agent along with intragranular pharmaceutically acceptable excipients having a pharmaceutically acceptable rate controlling polymer may be granulated by using a non- aqueous solvent having a suitable binder.
- the granules may be dried and passed through a sieve.
- the granules so obtained may be mixed with extragranular pharmaceutically acceptable excipients.
- the granules may be formulated as a tablet, a capsule, powder, sachets, granules, pellets and the like.
- the finished dosage form may be optionally coated with a functional and/ or non-functional coating.
- the non-aqueous solvent can be selected from one or more of isopropanol, acetone, methylene chloride, chloroform, n-propanol, and the like.
- the rate-controlling polymers may be a release rate controlling polymer and may be selected from one or more of any such pharmaceutically acceptable excipients that can control the rate of release of the active ingredient.
- the pharmaceutically acceptable rate controlling polymers can be selected from one or more of carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers and mixtures thereof.
- Suitable carbohydrate gums include one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties.
- Suitable polyuronic acid salts include one or more of alkali metal salts of alginic acid or pectic acid and mixtures thereof.
- Suitable alkali metal salts of alginic acid that may be used include one or more of sodium alginate, potassium alginate, ammonium alginate and other suitable alkali metal salts of alginic acid.
- Suitable cellulose ethers include one or more of ethyl cellulose, methylcellulose, hy- droxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, and other suitable cellulose ethers.
- Suitable acrylic acid polymers include any suitable polyacrylic acid polymers or carboxyvinyl polymers such as those available under the brand name Carbopol ® .
- the pharmaceutically acceptable excipients may be present as extragranular or intra- granular excipients and may include one or more of diluents, fillers, binders, lubricants, glidants, and the like.
- Suitable fillers may be one or more of lactose, dicalcium phosphate, microcrystalline cellulose, mannitol, and the like.
- Suitable binders may be one or more of starch, sugars, gums, low molecular weight, polyvinylpyrrolidone and hydroxypropyl cellulose, and the like.
- Suitable lubricants may be one or more of talc, magnesium stearate, calcium Stearate, glyceryl behenate polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate, and the like.
- Suitable glidants may be one or more of colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, and the like.
- Suitable disintegrants may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and the like.
- the present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
- Examples The composition of batches is provided in table 1-2. The following compositions are representatives of the preferred compositions of the present invention.
- Example 1 The pharmaceutical composition of bupropion hydrochloride is provided in Table 1. [54] [Table 1] [Table ]
- Example 2 The pharmaceutical composition of bupropion hydrochloride is provided in Table 2. [58] [Table 2] [Table ]
Abstract
The present invention relates to stable pharmaceutical compositions comprising bupropion or salts thereof and a basic stabilizing agent, wherein the stabilizing agent is capable of maintaining a pH of less than 6 around bupropion particles. The invention also relates to processes for the preparation of such compositions.
Description
Description
STABLE PHARMACEUTICAL COMPOSITIONS OF
BUPROPION
[1] Field of the Invention
[2] The present invention relates to stable pharmaceutical compositions comprising bupropion or salts thereof and a basic stabilizing agent, wherein the stabilizing agent is capable of maintaining a pH of less than 6 around bupropion particles. The invention also relates to processes for the preparation of such compositions.
[3] Background of the Invention
[4] Bupropion hydrochloride is an antidepressant of the amino ketone class. Chemically, it is (±)-l-(3-chlorophenyl)-2-[(l,ldimethylethyl)amino]-l-propanonehydrochloride. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. Bupropion hydrochloride is a water-soluble, highly hygroscopic, crystalline and susceptible to decomposition. Because of the drug's instability, the shelf life of bupropion formulations has proved to be problematic.
[5] A number of different approaches have been tried to improve the storage stability of the drug in the formulation. For example, U.S. Patent Nos. 5,541,231; 5,763,493; 5,358,970; 5,427,798; 5,731,000; 6,333,332; 6,221,917 and 6,194,002 describe stable bupropion hydrochloride formulations that use an organic acid, a carboxylic acid, an amino acid salt (e.g., cysteine hydrochloride, glycine hydrochloride, and cysteine di- hydrochloride), or sodium metabisulfite as stabilizers.
[6] U.S. Patent No. 5,968,553 discloses bupropion hydrochloride formulations using dilute inorganic acids as stabilizers including hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid.
[7] U.S. Patent No. 6,482,987 discloses a method for preparing a stable composition of bupropion hydrochloride by dry blending bupropion hydrochloride and solid stabilizer.
[8] U.S. Patent No. 6,238,697 discloses a method for preparing a stable composition of bupropion hydrochloride by direct compression of bupropion hydrochloride and other excipients.
[9] U.S. Patent No. 6,893,660 describes a method for stabilizing bupropion formulation by adding a sealing component in the excipients to form a sealed excipient component.
[10] U.S. Patent No. 6,306,436 discloses a pharmaceutical composition of bupropion that is free of added acid. U.S. Patent No. 6,652,882 discloses a controlled release pharmaceutical formulation of bupropion comprising uncross linked polymer and crosslinked insoluble polymer. U.S. Patent No. 6,210,716 discloses a controlled release dosage form of bupropion hydrochloride.
[11] U.S. Patent Nos. 6,096,341 , 6,033,686 and 6,143,327 disclose a delayed release coated tablet comprising a core of bupropion hydrochloride and conventional ex- cipients, free of stabilizer and coating. [12] U.S. Patent No. 6,333,332 discloses a pharmaceutical composition comprising bupropion hydrochloride and a pharmaceutically acceptable stabilizer. [13] U.S. Patent No. 6,242,496 discloses a method for stabilizing bupropion by using a stabilizer wherein the stabilizer has solubility in water at 20 ° C of less than 1O g stabilizer/ 100 g water and has an aqueous suspension pH of about 0.9 to about 4.0 at a concentration of about 6% w/w. [14] U.S. Application No. 2003044462 discloses a pharmaceutical composition in solid form that includes bupropion hydrochloride and an effective amount of carboxy vinyl polymer as the sole stabilizing agent and the sole controlled release material. [15] U.S. Application No. 2006020040 discloses a solid dosage form that contains bupropion hydrochloride and glucono delta lactone or its corresponding open chain hydroxy acid derivative as a stabilizer. [16] U.S Application No. 2006099260 discloses a pharmaceutical composition that includes a core comprising bupropion; and a coating comprising a pharmaceutically acceptable pH-independent polymer and a surfactant. [17] U.S. Application No. 2005112198 discloses a pharmaceutical solid dosage form that includes bupropion hydrochloride and a member of the group selected from butylated hydroxyanisole, butylated hydroxytoluene and an ion exchange resin. [18] Summary of the Invention
[19] In one general aspect there is provided a stable pharmaceutical composition that includes bupropion or salts thereof and a basic stabilizing agent. [20] Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the composition may further include one or more pharmaceutically acceptable excipients selected from diluent, filler, binder, lubricant, glidant, and rate controlling polymer. [21] The pharmaceutical composition may retain at least about 80% of the potency of the bupropion after storage for three months at 400C and 75% relative humidity. [22] In another aspect there is provided a method of stabilizing bupropion or salts thereof in a pharmaceutical composition. The method includes a step of adding an effective amount of at least one basic stabilizing agent. [23] In another aspect there is provided a stable pharmaceutical composition that includes bupropion or salts thereof and an effective stabilizing amount of potassium hydrogen tartrate along with other pharmaceutically acceptable excipients. [24] In another aspect there is provided a method of stabilizing bupropion or salts thereof in a pharmaceutical composition. The method includes a step of adding potassium
hydrogen tartrate in an amount sufficient to attain a pH of less than 6 around the bupropion particles.
[25] In another aspect there is provided a process for preparing a stable pharmaceutical composition of bupropion or a salt thereof. The process includes:
[26] 1. a) mixing, granulating bupropion or a salt thereof, at least one basic stabilizer and other pharmaceutically acceptable excipients; and
[27] 1. b) formulating the granules into a suitable dosage form.
[28] Embodiments of the process may include one or more of the following features. For example, the pharmaceutical composition may retain at least about 80% of the potency of the bupropion after storage for three months at 400C and 75% relative humidity.
[29] The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
[30] Detailed Description of the Invention
[31] It is well known from the prior art that a relatively low pH environment has proven effective in stabilizing bupropion. The use of acidic materials in pharmaceutical compositions requires specialized procedures and equipment. Therefore, it would be desirable to produce a stable bupropion hydrochloride composition without the use of acid stabilizers. We have now found that pharmaceutical compositions of bupropion or salts thereof can be stabilized by adding an effective stabilizing amount of a basic stabilizing agent. The stabilizing agent is capable of maintaining a pH of less than 6 around the bupropion particles, which prevents the degradation of bupropion.
[32] The term 'stable pharmaceutical composition' herein refers to a pharmaceutical composition that retains at least about 80% of the potency of the bupropion after storage for three months at 400C and 75% relative humidity.
[33] The 'basic stabilizing agent' is a pharmaceutically acceptable substance capable of preventing the degradation of bupropion by maintaining a pH of less than 6 around the bupropion particles. Bupropion is a highly hygroscopic drug and susceptible to decomposition. A relatively low pH environment has proven effective in stabilizing bupropion.
[34] The basic stabilizing agent may be one or more of ethylenediaminetetraacetic acid disodium salt, ethylenediaminetetraacetic acid calcium disodium salt, ethylenediamine tetraacetic acid dipotassium salt dihydrate, ethylenediaminetetraacetic acid manganese disodium salt, ethylenediaminetetraacetic acid copper disodium salt, sodium citrate, sodium acetate, sodium fumarate, calcium oxalate, calcium alginate, ammonium chloride, potassium hydrogen tartrate, and the like.
[35] Potassium hydrogen tartrate, also known as potassium acid tartrate, is used as a primary reference standard for a pH buffer. Saturated solution of potassium hydrogen
tartrate has a pH of 3.557 at 250C. Upon dissolution in water, potassium hydrogen tartrate dissociates into acid tartrate, potassium cation, and the conjugate base, citrate dianion. Thus, a solution of potassium hydrogen tartrate creates a buffer effect in an acidic pH range.
[36] The 'effective stabilizing amount' herein refers to the amount of basic stabilizing agent, which is capable of preventing the degradation of bupropion by maintaining a pH of less than 6 around bupropion particles under storage conditions thereby providing stable pharmaceutical compositions. These stabilizers can be used in a concentration which can effectively retain at least about 80% of the potency of the bupropion in the composition after storage for three months at 400C and 75% relative humidity.
[37] The amount of bupropion or a salt thereof may vary from about 25 mg to 500 mg w/ w of the pharmaceutical composition. The pharmaceutical composition can be in an immediate release form, sustained release form or a delayed release form.
[38] The pharmaceutical composition of bupropion or salts thereof can be prepared by conventional methods of preparation like aqueous or non-aqueous wet granulation, direct compression, melt granulation or dry granulation.
[39] The powder blend of bupropion and a stabilizing agent along with intragranular pharmaceutically acceptable excipients having a pharmaceutically acceptable rate controlling polymer may be granulated by using a non- aqueous solvent having a suitable binder. The granules may be dried and passed through a sieve. The granules so obtained may be mixed with extragranular pharmaceutically acceptable excipients. The granules may be formulated as a tablet, a capsule, powder, sachets, granules, pellets and the like. The finished dosage form may be optionally coated with a functional and/ or non-functional coating.
[40] The non-aqueous solvent can be selected from one or more of isopropanol, acetone, methylene chloride, chloroform, n-propanol, and the like.
[41] The rate-controlling polymers may be a release rate controlling polymer and may be selected from one or more of any such pharmaceutically acceptable excipients that can control the rate of release of the active ingredient.
[42] The pharmaceutically acceptable rate controlling polymers can be selected from one or more of carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers and mixtures thereof.
[43] Suitable carbohydrate gums include one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties. Suitable polyuronic acid salts include one or more of alkali metal salts of alginic acid or pectic acid and mixtures thereof. Suitable alkali metal salts of alginic acid that may be used include one or more of sodium alginate,
potassium alginate, ammonium alginate and other suitable alkali metal salts of alginic acid. [44] Suitable cellulose ethers include one or more of ethyl cellulose, methylcellulose, hy- droxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, and other suitable cellulose ethers. Suitable acrylic acid polymers include any suitable polyacrylic acid polymers or carboxyvinyl polymers such as those available under the brand name Carbopol®. [45] The pharmaceutically acceptable excipients may be present as extragranular or intra- granular excipients and may include one or more of diluents, fillers, binders, lubricants, glidants, and the like. [46] Suitable fillers may be one or more of lactose, dicalcium phosphate, microcrystalline cellulose, mannitol, and the like. [47] Suitable binders may be one or more of starch, sugars, gums, low molecular weight, polyvinylpyrrolidone and hydroxypropyl cellulose, and the like. [48] Suitable lubricants may be one or more of talc, magnesium stearate, calcium Stearate, glyceryl behenate polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate, and the like. [49] Suitable glidants may be one or more of colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, and the like. [50] Suitable disintegrants may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and the like. [51] The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. [52] Examples : The composition of batches is provided in table 1-2. The following compositions are representatives of the preferred compositions of the present invention.
The preparation method of dosage form is detailed below. [53] Example 1 - The pharmaceutical composition of bupropion hydrochloride is provided in Table 1. [54]
[Table 1] [Table ]
[55] Procedure: [56] Bupropion hydrochloride, potassium hydrogen tartrate, hydroxypropyl cellulose, microcrystalline cellulose is mixed together followed by granulation with a mixture of isopropyl alcohol and methylene chloride. The granules so obtained were dried and mixed with weighed amount of extragranular excipients i.e. microcrystalline cellulose, stearic acid and glyceryl behenate and magnesium stearate. These granules were compressed to tablets using appropriate tooling. The tablets were coated with hy- droxypropylcellulose based coating.
[57] Example 2 - The pharmaceutical composition of bupropion hydrochloride is provided in Table 2. [58]
[Table 2] [Table ]
[59] Procedure: Accurately weighed bupropion hydrochloride, ammonium chloride, and hydroxypropyl cellulose were mixed together followed by granulation with a mixture of isopropyl alcohol. The granules so obtained were dried and mixed with weighed amount of extragranular excipients i.e. microcrystalline cellulose, stearic acid, glyceryl behenate and magnesium stearate. These granules were compressed to tablets using appropriate tooling. The tablets were coated with hydroxypropylcellulose based coating.
[60] While the invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims
[1] We Claim:
A stable pharmaceutical composition comprising bupropion or salts thereof and a basic stabilizing agent.
The pharmaceutical composition according to claim 1, wherein the basic stabilizing agent in an effective stabilizing amount which is capable of maintaining a pH of less than 6 around the bupropion particles.
The pharmaceutical composition according to claim 1, wherein the basic stabilizing agent comprises one or more ofethylenediaminetetraacetic acid disodium salt, ethylenediaminetetraacetic acid calcium disodium salt, ethylenediamine tet- raacetic acid dipotassium salt dihydrate, ethylenediaminetetraacetic acid manganese disodium salt, ethylenediaminetetraacetic acid copper disodium salt, sodium citrate, sodium acetate, sodium fumarate, calcium oxalate, calcium alginate, ammonium chloride and potassium hydrogen tartrate. The pharmaceutical composition according to claim 1, wherein the bupropion retains at least about 80% of the potency of bupropion in the pharmaceutical composition after storage for three months at 400C and 75% relative humidity. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an immediate release, delayed release or a sustained release dosage form.
The pharmaceutical composition according to claim 1, wherein the amount of- bupropion or a salt thereof is from about 25 mg to about 500 mg w/w of the composition.
The pharmaceutical composition according to claim 1, wherein the bupropionor a salt thereof is bupropion hydrochloride.
The pharmaceutical composition according to claim 1, further comprising one or more of pharmaceutically acceptable excipients comprising one or more of diluents, fillers, binders, lubricants, glidants, and rate controlling polymers. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in the form of a tablet, a capsule, granules, or pellets meant for oral administration.
A method of stabilizing bupropion or salts thereof in a pharmaceutical composition wherein the method comprises a step of adding an effective amount of at least one basic stabilizing agent.
The method of stabilization according to claim 10, wherein the basic stabilizing agent is capable of maintaining a pH of less than 6 around the bupropion particles.
The method of stabilization according to claim 10, wherein the basic stabilizing agent comprises one or more ofethylenediaminetetraacetic acid disodium salt, ethylenediaminetetraacetic acid calcium disodium salt, ethylenediamine tet- raacetic acid dipotassium salt dihydrate, ethylenediaminetetraacetic acid manganese disodium salt, ethylenediaminetetraacetic acid copper disodium salt, sodium citrate, sodium acetate, sodium fumarate, calcium oxalate, calcium alginate, ammonium chloride and potassium hydrogen tartrate. The method of stabilization according to claim 10, wherein the bupropion retains at least about 80% of the potency of bupropion in the pharmaceutical composition after storage for three months at 400C and 75% relative humidity in the pharmaceutical composition.
The method of stabilization according to claim 10, wherein the pharmaceutical composition is an immediate release, delayed release, or a sustained release dosage form.
The method of stabilization according to claim 10, whereinthe amount of- bupropion or a salt thereof is from about 25 mg to about 500 mg w/w of the composition.
The method of stabilization according to claim 10, wherein the bupropionor a salt thereof is bupropion hydrochloride.
The method of stabilization according to claim 10, further comprising one or more of diluents, fillers, binders, lubricants, glidants, and rate controlling polymers.
The method of stabilization according to claim 10, wherein the pharmaceutical composition is in the form of a tablet, a capsule, granules, or pellets meant for oral administration.
A stable pharmaceutical composition comprising bupropion or salts thereof and an effective stabilizing amount of potassium hydrogen tartrate along with other pharmaceutically acceptable excipients.
The stable pharmaceutical composition according to claim 19, wherein the bupropion retains at least about 80% of the potency of bupropion in the pharmaceutical composition after storage for three months at 400C and 75% relative humidity.
The stable pharmaceutical composition according to claim 19, wherein the pharmaceutical composition is an immediate release, delayed release, or a sustained release dosage form.
The stable pharmaceutical composition according to claim 19, whereinthe amount ofbupropion or a salt thereof is from about 25 mg to about 500 mg w/w of the composition.
The stable pharmaceutical composition according to claim 19, wherein the bupropionor a salt thereof is bupropion hydrochloride.
The stable pharmaceutical composition according to claim 19, wherein the pharmaceutically acceptable excipients comprise one or more of diluents, fillers, binders, lubricants, glidants, and rate controlling polymers. The stable pharmaceutical composition according to claim 19, wherein the pharmaceutical composition is in the form of a tablet, a capsule, granules, or pellets meant for oral administration.
. A method of stabilizing bupropion or salts thereof in a pharmaceutical composition wherein the method comprises a step of adding potassium hydrogen tartrate in an amount sufficient to attain a pH of less than 6 around the bupropion particles.
The method of stabilization according to claim 26, wherein the bupropion retains at least about 80% of the potency of bupropion in the pharmaceutical composition after storage for three months at 400C and 75% relative humidity. The method of stabilization according to claim 26, wherein the pharmaceutical composition is an immediate release, delayed release, or a sustained release dosage form.
The method of stabilization according to claim 26, whereinthe amount of- bupropion or a salt thereof is from about 25 mg to about 500 mg w/w of the composition.
The method of stabilization according to claim 26, wherein the bupropionor a salt thereof is bupropion hydrochloride.
The method of stabilization according to claim 26, wherein the pharmaceutically acceptable excipients comprise one or more of diluents, fillers, binders, lubricants, glidants, and rate controlling polymers.
The method of stabilization according to claim 26, wherein the pharmaceutical composition is in the form of a tablet, a capsule, granules, or pellets meant for oral administration.
A process for preparing a stable pharmaceutical composition comprising bupropion or a salt thereof, the process comprising: a) mixing, granulating bupropion or a salt thereof, one or more basic stabilizers and pharmaceutically acceptable excipients; and b) formulating the granules into a suitable dosage form.
The process according according to claim 33, wherein the basic stabilizing agent comprises one or more ofethylenediaminetetraacetic acid disodium salt, ethyle- nediaminetetraacetic acid calcium disodium salt, ethylenediamine tetraacetic acid dipotassium salt dihydrate, ethylenediaminetetraacetic acid manganese disodium
salt, ethylenediaminetetraacetic acid copper disodium salt, sodium citrate, sodium acetate, sodium fumarate, calcium oxalate, calcium alginate, ammonium chloride and potassium hydrogen tartrate.
The process according to claim 33, wherein the process further comprises optionally coating the dosage form with suitable coating agents.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN769/MUM/2007 | 2007-04-20 | ||
| IN771/MUM/2007 | 2007-04-20 | ||
| IN771MU2007 | 2007-04-20 | ||
| IN769MU2007 | 2007-04-20 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| WO2008129465A2 true WO2008129465A2 (en) | 2008-10-30 |
| WO2008129465A3 WO2008129465A3 (en) | 2009-08-20 |
| WO2008129465A9 WO2008129465A9 (en) | 2009-10-15 |
Family
ID=39876034
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2008/051453 WO2008129465A2 (en) | 2007-04-20 | 2008-04-16 | Stable pharmaceutical compositions of bupropion |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2008129465A2 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5358970A (en) * | 1993-08-12 | 1994-10-25 | Burroughs Wellcome Co. | Pharmaceutical composition containing bupropion hydrochloride and a stabilizer |
| US6238697B1 (en) * | 1998-12-21 | 2001-05-29 | Pharmalogix, Inc. | Methods and formulations for making bupropion hydrochloride tablets using direct compression |
| US6333332B1 (en) * | 2000-08-25 | 2001-12-25 | Impax Laboratories, Inc. | Stabilized pharmaceutical compositions containing bupropion hydrochloride |
| US20050112198A1 (en) * | 2003-10-27 | 2005-05-26 | Challapalli Prasad V. | Bupropion formulation for sustained delivery |
-
2008
- 2008-04-16 WO PCT/IB2008/051453 patent/WO2008129465A2/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5358970A (en) * | 1993-08-12 | 1994-10-25 | Burroughs Wellcome Co. | Pharmaceutical composition containing bupropion hydrochloride and a stabilizer |
| US6238697B1 (en) * | 1998-12-21 | 2001-05-29 | Pharmalogix, Inc. | Methods and formulations for making bupropion hydrochloride tablets using direct compression |
| US6333332B1 (en) * | 2000-08-25 | 2001-12-25 | Impax Laboratories, Inc. | Stabilized pharmaceutical compositions containing bupropion hydrochloride |
| US20050112198A1 (en) * | 2003-10-27 | 2005-05-26 | Challapalli Prasad V. | Bupropion formulation for sustained delivery |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008129465A3 (en) | 2009-08-20 |
| WO2008129465A9 (en) | 2009-10-15 |
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