Classifications

• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
  • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings

Definitions

• the present invention relates to extended release dosage forms of bupropion hydrochloride and processes for their preparation.
• Bupropion hydrochloride is a well-known antidepressant and non-nicotine aid to smoking cessation. It has been observed that bupropion hydrochloride when taken in an immediate release dosage form has the risk of inducing seizures in patients. This side effect is attributed to the sudden high peak plasma concentration produced by these immediate release dosage forms. The incidences of seizures can be subsided by designing a dosage form of bupropion hydrochloride with extended release properties so that sudden high peak plasma concentration is avoided.
• 4,687,660 discloses a controlled release dosage form powered by an osmotic pumping mechanism.
• the dosage form comprises a core containing bupropion hydrochloride and osmotic enhancing agent in an amount equal to or greater than bupropion hydrochloride.
• the core is coated with a semi-permeable polymeric film consisting of water insoluble, water permeable polymer, channeling agents which dissolve in the gastrointestinal fluids and provide passage for the release of drug from the core.
• the drug release from the core is driven by osmotic pressure.
• This type of dosage form has the disadvantage that there is always a risk of dose dumping in case too much pressure is built up in the core and the dosage form may burst releasing the entire drug at once which may also precipitate a seizure.
• an extended release dosage form of bupropion hydrochloride includes a core, and a coating on the core.
• the core includes bupropion hydrochloride and, optionally, one or more pharmaceutically acceptable excipients, wherein the core is free of osmotic enhancing agents.
• the coating surrounds the core and includes one or more water-insoluble film forming polymers, channeling agents and, optionally, one or more pharmaceutically acceptable excipients.
• Embodiments of the dosage form may include one or more of the following features.
• a seal coating may be included between the core and the coating surrounding the core.
• the seal coating may include one or more water soluble polymers for example, hydroxypropylmethylcellulose and hydroxypropylcellulose.
• the one or more pharmaceutically acceptable excipients may include one or more binders, fillers, plasticizers, and lubricants /glidants.
• the binders may include one or more of polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, hydroxypropylcellulose, hydroxypropylmethylcellulose and combinations thereof.
• the fillers may be microcrystalline cellulose.
• the lubricants may include one or more of magnesium stearate, stearic acid, and glyceryl behenate.
• the plasticizers may include one or more of triacetin, acetylated monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyloxalate, diethylmalate, diethylmaleate, diethylfumarate, diethylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacetate, triethylcitrate, tributylcitrate, glyceroltributyrate, polyethyleneglycol, propylene glycol, 1,2-propyleneglycol, dibutylsebacate, diethylsebacate, and mixtures thereof.
• the coating on the core may include one or more polymers that may be permeable to gastrointestinal fluids but insoluble in the same.
• polymers include cellulose derivatives such as ethylcellulose; polyvinyl acetate; neutral copolymers based on ethyl acrylate and methylmethacrylate; copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups such as Eudragit NE, RS or RS30D, RL or RL30D; and the like.
• an enteric coating may be applied outside the coating surrounding the core.
• the enteric coating may include one or more enterosoluble polymers.
• the enterosoluble polymers may include polymers which are insoluble in the pH of the stomach but are soluble in the pH of the intestine.
• the enteric layer may serve to protect the drug from gastric contents.
• enteric polymers include esters of cellulose and its derivatives such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate; pH-sensitive methacrylic acid-methamethacrylate copolymers and shellac.
• the coatings may optionally contain one or more excipients such as plasticizers, lubricants, glidant anti-adherents for example, magnesium stearate, talc, colloidal silicon dioxide, silicon dioxide, inert fillers, and pigments. Silicon dioxide may additionally function as a wicking agent for fluids from the external media into the core.
• an extended release dosage form of bupropion hydrochloride includes a core, a first coating on the core and a second enteric coating surrounding the first coating.
• the core includes bupropion hydrochloride and, optionally, one or more pharmaceutically acceptable excipients, wherein the core is free of osmotic enhancing agents.
• the first coating surrounds the core and includes one or more water-insoluble film forming polymers, channeling agents and, optionally, one or more pharmaceutically acceptable excipients.
• the second enteric coating surrounds the first coating and includes one or more enterosoluble polymers and, optionally, one or more pharmaceutically acceptable excipients.
• Embodiments of the dosage form may include one or more of the following features.
• a seal coating may be included between the core and the first coating surrounding the core.
• the seal coating may include one or more water soluble polymers for example, hydroxypropylmethylcellulose and hydroxypropylcellulose.
• the one or more pharmaceutically acceptable excipients may include one or more binders, fillers, plasticizers, and lubricants /glidants.
• the binders may include one or more of polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, hydroxypropylcellulose, hydroxypropylmethylcellulose and combinations thereof.
• the fillers may be microcrystalline cellulose.
• the lubricants may include one or more of magnesium stearate, stearic acid, and glyceryl behenate.
• the plasticizers may include one or more of triacetin, acetylated monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyloxalate, diethylmalate, diethylmaleate, diethylfumarate, diethylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacetate, triethylcitrate, tributylcitrate, glyceroltributyrate, polyethyleneglycol, propylene glycol, 1 ,2-propyleneglycol, dibutylsebacate, diethylsebacate, and mixtures thereof.
• the coating on the core may include one or more polymers that may be permeable to gastrointestinal fluids but insoluble in the same.
• polymers include cellulose derivatives such as ethylcellulose; polyvinyl acetate; neutral copolymers based on ethyl acrylate and methylmethacrylate; copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups such as Eudragit NE, RS or RS30D, RL or RL30D; and the like.
• the enteric coating may include one or more enterosoluble polymers.
• the enterosoluble polymers may include polymers which are insoluble in the pH of the stomach but are soluble in the pH of the intestine.
• the enteric layer may serve to protect the drug from gastric contents.
• enteric polymers include esters of cellulose and its derivatives such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate; pH-sensitive methacrylic acid-methamethacrylate copolymers and shellac.
• the coatings may optionally contain one or more excipients such as plasticizers, lubricants, glidant anti-adherents for example, magnesium stearate, talc, colloidal silicon dioxide, silicon dioxide, inert fillers, and pigments.
• Silicon dioxide may additionally function as a wicking agent for fluids from the external media into the core.
• a process for the preparation of extended release dosage forms of bupropion hydrochloride includes preparing a core, and coating the core with a layer. The process also includes optionally coating the core with a seal coat and/or the coating surrounding the core with an enteric layer.
• the core may be prepared by granulating bupropion hydrochloride, and, optionally mixing with one or more pharmaceutically acceptable excipients and compressing.
• the core may be coated with a layer formed by a substantially water- insoluble film forming polymers, channeling agents and, optionally, pharmaceutically acceptable excipients.
• a method of treating depression or nicotine addiction includes administering an extended release dosage form that includes a core, and a coating on the core.
• the core includes bupropion hydrochloride and, optionally, one or more pharmaceutically acceptable excipients, wherein the core is free of osmotic enhancing agents.
• the coating surrounds the core and includes one or more water-insoluble film forming polymers, channeling agents and, optionally, one or more pharmaceutically acceptable excipients.
• the dosage form may include a seal coating which may be applied between the core and the coating surrounding the core.
• the seal coating may include one or more water soluble polymers like hydroxypropylmethylcellulose and hydroxypropylcellulose.
• the enteric coating may include one or more enterosoluble polymers.
• the details of various embodiments of the inventions are set forth in the accompanying description below. Other features and advantages of the inventions will be apparent from the description and the claims. Detailed Description of the Invention As described in detail herein, the inventors have discovered that extended release dosage forms of bupropion hydrochloride may be formulated without the need for osmotic enhancing agents. For example, the inventors have developed an extended release dosage form that includes a core, and a coating on the core. The core includes bupropion hydrochloride and, optionally pharmaceutically acceptable excipients. The core is characterized as being free of osmotic enhancing agents.
• the core is coated with a layer that includes water-insoluble film forming polymers and, optionally, one or more pharmaceutically acceptable excipients.
• a seal coating may be applied between the core and the coating surrounding the core.
• the inventors also have developed an extended release dosage form that includes a core, a first coating on the core and a second enteric coating surrounding the first coating.
• the core includes bupropion hydrochloride and, optionally pharmaceutically acceptable excipients.
• the core is characterized as being free of osmotic enhancing agents.
• a seal coating may be applied between the core and the first coating surrounding the core.
• the core containing bupropion hydrochloride can be prepared by either directly compressing, wet granulating or dry granulating a mixture of bupropion hydrochloride and other excipients like binders, fillers and lubricants/glidants.
• One process to formulate the extended release dosage form includes preparing a core and coating the core. To prepare the core, bupropion hydrochloride and, optionally one or more pharmaceutically acceptable excipients are dispersed in purified water, one or more solvents, or mixtures thereof to obtain dispersion. The dispersion is spray dried, mixed with optional pharmaceutically acceptable excipients, and compressed to form cores.
• the core then is coated with a layer that is formed from substantially water- insoluble film forming polymers and optional pharmaceutically acceptable excipients.
• the coated core then may be coated with an enteric coating.
• the core may also be coated with a seal coating between the core and the coating surrounding the core.
• the amount of bupropion hydrochloride may vary from about 5 mg to about
• the core as used herein refers to any structure that is enclosed or surrounded by a coating or equivalent.
• the core may be in the form of a tablet, pellet, or mixture thereof.
• the term 'pellets' as used herein may include one or more of granules, beads, pellets, slugs or mixtures thereof.
• the core may contain one or more pharmaceutically acceptable excipients, including one or more of binders, fillers, and lubricants/glidants. Suitable binders include one or more of polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, hydroxypropylcellulose, hydroxypropylmethylcellulose and combinations thereof.
• Suitable fillers include microcrystalline cellulose.
• Suitable lubricants include one or more of magnesium stearate, stearic acid, and glyceryl behenate.
• the preferred range of lubricants in the formulation depends on the type of formulations to be prepared as disclosed in various examples contained herein.
• the various coating layers can then be applied on the compressed core by conventional coating techniques like spray drying, pan coating, etc. well known to a person skilled in the art.
• the solvents used in preparing solution or dispersion of coating compositions can be aqueous or organic or a mixture of both.
• the suitable solvents include water, dichlorom ethane, isopropyl alcohol, methanol, acetone, and mixtures of isopropyl alcohol with dichloromethane or water.
• the solvent system used in preparing water insoluble coating containing channeling agents is prepared in organic solvent in which channeling agent is insoluble such as acetone, dichloromethane, isopropyl alcohol and mixtures thereof.
• the coating surrounding the core is made up of substantially water-insoluble film forming polymers, channeling agents and, optionally, plasticizers.
• the coating may contain one or more pharmaceutically acceptable excipients.
• the substantially water- insoluble film forming polymers may be selected from cellulose derivatives such as ethylcellulose; polyvinyl acetate; neutral copolymers based on ethyl acrylate and methylmethacrylate; copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups such as Eudragit NE, RS or RS30D, RL or RL30D; and the like.
• the drug may be released from the core due to the presence of water-soluble channeling agents in the coating, which upon dissolution may form a porous membrane through which the drug could diffuse out.
• channeling agents examples include lactose, sucrose, sorbitol, mannitol, sodium chloride, calcium chloride, potassium chloride, and the like.
• the range of the channeling agents in the formulations depends on the type of formulations prepared and will be apparent to one skilled in the art based on the various examples disclosed in the specification.
• the coating surrounding the core may be coated with a layer containing enterosoluble polymers.
• the enterosoluble polymers may include polymers which are insoluble in the pH of the stomach but are soluble in the pH of the intestine.
• the enteric layer may serve to protect the drug from gastric contents.
• enteric polymers examples include esters of cellulose and its derivatives such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate; pH-sensitive methacrylic acid-methamethacrylate copolymers and shellac.
• the extended release dosage form is capable of delivering bupropion hydrochloride at a predictable rate.
• the dosage form may maintain therapeutic plasma levels of bupropion from about 12 to 24 hours. Accordingly, the dosage form may be designed to be given once or twice daily.
• Bupropion hydrochloride was granulated with an aqueous solution of polyvinyl alcohol in a fluidized bed granulator. The granules were dried and sized. The sized granules were lubricated with magnesium stearate, glyceryl behenate and colloidal silicon dioxide and compressed into tablet cores using appropriate tooling. The compressed cores were loaded in a pan coater and a solution of hydroxypropylmethylcellulose and triethyl citrate dissolved in purified water was applied to the compressed cores as a seal coating.
• coated cores were dried and coated with a water insoluble coating containing ethyl cellulose, triethyl citrate lactose monohydrate and polyvinylpyrrolidone dissolved in isopropyl alcohol: water (95:5) mixture. Finally, these coated cores were coated with an enteric coating dispersion containing Eudragit L30 D 55, triethyl citrate, silicon dioxide and polyethylene glycol dispersed in purified water.
• Bupropion hydrochloride was granulated with a solution of hydroxypropylcellulose dissolved in isopropyl alcohol: dichloromethane mixture (60:40) in a fluidized bed granulator.
• the granules were dried, sized and lubricated with stearic acid and glyceryl behenate and compressed into tablet cores using appropriate tooling.
• the compressed cores were loaded in a pan coater and a solution of hydroxypropylcellulose and triethyl citrate in isopropyl alcohol: dichloromethane mixture (60:40) was applied to the compressed cores as a seal coating.
• the coated cores were dried and coated with a water insoluble coating containing ethyl cellulose, lactose monohydrate and hydroxypropylmethylcellulose dissolved in isopropyl alcohol: dichloromethane mixture (60:40).
• Bupropion hydrochloride was granulated with a solution of hydroxypropylcellulose dissolved in isopropyl alcohol: dichloromethane mixture (60:40) in a fluidized bed granulator.
• the granules were dried, sized and lubricated with stearic acid and glyceryl behenate and compressed into tablet cores using appropriate tooling.
• the compressed cores were loaded in a pan coater and a solution of hydroxypropylcellulose in isopropyl alcohol: dichloromethane mixture (60:40) was applied to the compressed cores as a seal coating.
• the coated cores were dried and coated with a water insoluble coating containing ethyl cellulose, lactose monohydrate and hydroxypropylmethylcellulose dissolved in isopropyl alcohol: dichloromethane mixture (60:40).
• Bupropion hydrochloride was granulated with a solution of hydroxypropylcellulose dissolved in isopropyl alcohol: dichloromethane mixture (60:40) in a fluidized bed granulator.
• the granules were dried, sized and lubricated with stearic acid and glyceryl behenate and compressed into tablet cores using appropriate tooling.
• the compressed cores were loaded in a pan coater and a solution of hydroxypropylcellulose in isopropyl alcohol: dichloromethane mixture (60:40) was applied to the compressed cores as a seal coating.
• coated cores were dried and coated with a water insoluble coating containing ethyl cellulose, triethyl citrate, lactose monohydrate and polyvinylpyrrolidone dissolved in isopropyl alcohol: dichloromethane mixture (60:40).
• Bupropion hydrochloride was granulated with hydroxypropylcellulose dissolved in isopropyl alcohol: dichloromethane mixture (60:40) in a fluidized bed granulator.
• the granules were dried, sized and lubricated with glyceryl behenate and compressed into tablet cores using appropriate tooling.
• the compressed cores were loaded in a pan coater and a solution of hydroxypropylmethylcellulose in isopropyl alcohol: dichloromethane mixture (60:40) was applied to the compressed cores as a seal coating.
• coated cores were dried and coated with a water insoluble coating containing ethyl cellulose, triethyl citrate, lactose monohydrate and polyvinylpyrrolidone dissolved in isopropyl alcohol: water mixture (95:5). Finally, these coated cores were coated with an enteric coating dispersion containing Eudragit L30 D 55, triethyl citrate, silicon dioxide and polyethylene glycol dispersed in purified water.
• Example 6 Dissolution profiles of tablets of examples 1-5 as measured in a USP type I dissolution apparatus, at 75 rpm, at a temperature of 37 ⁇ 0.5°C in 900ml of 0.01N hydrochloric acid

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• 2004
  • 2004-11-18 EP EP04798903A patent/EP1686974A1/de not_active Withdrawn
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