WO2007117314A2 - Procédés et formulations permettant de préparer une forme dosifiée à libération contrôlée à administrer par voie orale - Google Patents

Procédés et formulations permettant de préparer une forme dosifiée à libération contrôlée à administrer par voie orale Download PDF

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Publication number
WO2007117314A2
WO2007117314A2 PCT/US2006/061625 US2006061625W WO2007117314A2 WO 2007117314 A2 WO2007117314 A2 WO 2007117314A2 US 2006061625 W US2006061625 W US 2006061625W WO 2007117314 A2 WO2007117314 A2 WO 2007117314A2
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Prior art keywords
pharmaceutical composition
insoluble
polymers
pharmaceutical
polymer
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PCT/US2006/061625
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English (en)
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WO2007117314A3 (fr
Inventor
San-Laung Chow
David Wong
Damian Garcia
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Biokey Inc
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Biokey Inc
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Priority claimed from US11/295,995 external-priority patent/US20060099262A1/en
Priority claimed from US11/295,851 external-priority patent/US20060099261A1/en
Application filed by Biokey Inc filed Critical Biokey Inc
Priority to CN200680046024.4A priority Critical patent/CN101453990B/zh
Publication of WO2007117314A2 publication Critical patent/WO2007117314A2/fr
Anticipated expiration legal-status Critical
Publication of WO2007117314A3 publication Critical patent/WO2007117314A3/fr
Ceased legal-status Critical Current

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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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates

Definitions

  • the invention generally relates to pharmaceutical compositions, such as drug formulations present in a solid form for oral administration. More particularly, the invention relates to long-lasting sustained dosage compositions, and carriers and active ingredients in the compositions thereof, such as controlled release and extended release drug compositions for oral controlled release dosage formulations containing a drug and a carrier material.
  • Bupropion is commonly used as an antidepressant drug. It is generally formulated from its salt derivatives, such as its hydrochloride salts. A commercial example is Wellbutrin ® . However, it has been shown that immediate release formulations of bupropion hydrochloride can induce some severe side effects, such as seizures, high blood pressure, and severe allergic reactions. There is a need to prepare a new sustained release dosage form to reduce side effect problems.
  • sustained or controlled release pharmaceutical formulations such as various extended release formulations in tablet or capsule form.
  • one method of forming delayed or sustained release formulations includes coating the tablet with a release-retarding coating, or coating individual granules with such a coating, and compressing these coated granules into a tablet.
  • Exemplary techniques involving sustained release solid preparations for bupropion hydrochloride in a matrix are described in U.S. Pat. Nos. 5,358,970 and 5,427,798.
  • bupropion hydrochloride is unstable and a stabilizer, such as cysteine hydrochloride, glycine hydrochloride, malic acid, citric acid, cystine dihydrochloride, etc., as described in the above two patents is required to stabilize the drug and thus making the technique not very well suited for manufacturing.
  • a stabilizer such as cysteine hydrochloride, glycine hydrochloride, malic acid, citric acid, cystine dihydrochloride, etc.
  • Another example involves controlled release tablet formulations for bupropion hydrochloride by using a core containing bupropion hydrochloride and a coating of a mixture having a film-forming polymer, a pore-forming agent, and other excipients, as described in U.S. Pat. No. 4,687,660 and EP-A- 0171457.
  • the pore-forming agent such as sodium carbonate, renders the coating of the core non-uniform and the release rate of the tablet not stable.
  • Other examples of controlled release tablets as described in U.S. Pat. Nos.
  • 6,033,686; 6,096,341 and 6,143,327 require a water-insoluble/water- permeable film-forming polymer in a first coating solution to coat a drug- containing core and prepare a film coated tablet.
  • the water- insoluble film-forming polymer in the first coating solution is very thermodynamically unstable and tends to aggregate rapidly, resulting in clotting problems during spray-coating the drug-containing core; and plasticizers, such as polyethylene glycols (PEG), are often required to soften the film coated tablet.
  • PEG polyethylene glycols
  • a second coating or an immediate release coating is also required to coat the film coated tablet to form a delayed release tablet.
  • the invention generally provides a pharmaceutical composition having one or more pore-forming materials without the aid of any plasticizers.
  • the pharmaceutical composition includes one or more surfactants in a coating mixture to create channels or pores in a coating layer for the release of a drug from a drug-containing core.
  • the pharmaceutical composition includes one or more aqueous polymeric colloidal dispersions adapted to coat a drug-containing core.
  • one or more aqueous polymeric colloidal dispersions can also be adapted to granulate a drug and included into the core.
  • the pharmaceutical composition includes a therapeutically active agent, such as bupropion and its salts and derivatives thereof, prepared into a core.
  • the pharmaceutical composition may further include a coating outside the core.
  • the coating may include a surfactant and an aqueous dispersion of one or more insoluble pharmaceutical acceptable polymers, which may be one or more pH-independent and pH-dependent polymers.
  • a pharmaceutical composition which includes a bupropion salt containing core and a coating.
  • the coating may include one or more surfactants and aqueous dispersions of one or more insoluble pharmaceutical acceptable polymers.
  • the one or more insoluble pharmaceutical acceptable polymers may include one or more pH- independent polymers, such as swellable permeable neutral ester copolymer dispersions.
  • the one or more insoluble pharmaceutical acceptable polymers may also include one or more pH-dependent polymers, such as ionic polymer dispersions.
  • an extended release pharmaceutical composition in another embodiment, includes a core of a pharmaceutical mixture containing bupropion salt and a first aqueous dispersion of one or more insoluble pharmaceutical acceptable polymers, and a coating layer.
  • the coating layer for the core of the pharmaceutical mixture may include one or more surfactants and a second aqueous dispersion of one or more insoluble pharmaceutical acceptable polymers.
  • the invention provides a pharmaceutical composition including: a core and a coating.
  • the core may include a bupropion salt and a first swellable permeable insoluble polymer dispersion.
  • the coating may include one or more surfactants and a second swellable permeable insoluble polymer dispersion.
  • the pharmaceutical composition may further comprise an insoluble ionic polymer dispersion.
  • the invention further provides a method of preparing a pharmaceutical composition.
  • the method includes forming a core of a pharmaceutical mixture comprising bupropion salt, and coating the core with a coating mixture.
  • the coating mixture may include one or more surfactants and aqueous dispersions of one or more insoluble pharmaceutical acceptable polymers.
  • a method of administering a pharmaceutical composition containing bupropion salt includes administering to a mammal an effective amount of the pharmaceutical composition comprising a bupropion salt containing core and a coating mixture.
  • the coating mixture includes one or more surfactants and aqueous dispersions of one or more insoluble pharmaceutical acceptable polymers.
  • Figure 1 is a release profile of an exemplary pharmaceutical composition according to one embodiment of the invention.
  • Figure 2 is a release profile of an exemplary pharmaceutical composition according to another embodiment of the invention.
  • Figure 3 is a release profile of an exemplary pharmaceutical composition according to still another embodiment of the invention.
  • Figure 4 is a release profile of an exemplary pharmaceutical composition according to still another embodiment of the invention.
  • the pharmaceutical composition of the invention includes a therapeutically active agent, a surfactant, and a pharmaceutically acceptable pH-independent polymer without any stabilizer or any plasticizer.
  • the pharmaceutical composition is generally prepared into an oral dosage form or a solid dosage form, such as a tablet, a capsule, a sachet, etc., and any therapeutically acceptable form.
  • the invention provides a method of stabilizing a therapeutically active agent using a coating layer which contains a surfactant or oil to seal away any factors affecting the stability of the therapeutically active agent in an coating layer and create channels and pores during the release of the therapeutically active agent.
  • a liquid material such as surfactants or oils
  • Most pharmaceutical polymers can not absorb liquid materials since the liquids materials tend to be squeezed out of the solid dosage form, resulting in solid dosage forms with reduced compactibility and compressibility.
  • One embodiment of the invention provides using an aqueous dispersion of one or more insoluble pharmaceutical acceptable polymers or polymeric colloidal dispersions adapted to absorb a liquid material, such as surfactants or oils, into a solid dosage form without the use of any plasticizers.
  • Another embodiment of the invention provides using an aqueous dispersion of one or more insoluble pharmaceutical acceptable polymers to granulate a therapeutically active agent in a pharmaceutical composition.
  • Various insoluble pharmaceutical acceptable polymers are available in aqueous dispersion and include, but are not limited to, polyacrylates, various copolymers of acrylate and methacrylates, copolymers of ionic methacrylates and neutral methacrylates, cellulose derivatives (e.g., ethylcellulose), polyvinyl acetate (e.g., Kollicoat SR30D from BASF Corporation, Mount Olive, New Jersey), neutral copolymers based on ethyl acrylate and methylmethacrylate, ionic polymers based on methacrylic acid and methacrylate, methacylic acid copolymers, ionic polymers based on methacrylates with various side chains or functional groups (e.g., ammonium group, carboxylic acid groups, or dimethylaminoethyl groups), poly(meth)acrylate polymers with acidic functional groups, poly(meth)acrylate polymers with alkaline functional groups, hydroxypropyl
  • the aqueous dispersion of the one or more insoluble pharmaceutical acceptable polymers may include one or more pH-independent polymers, such as swellable permeable neutral ester copolymer dispersions.
  • the aqueous dispersion of the one or more insoluble pharmaceutical acceptable polymers may include one or more pH-dependent polymers, such as ionic polymer dispersions.
  • An insoluble pharmaceutical acceptable polymer includes copolymers of acrylate and methacrylates with quaternary ammonium groups, such as Eudragit ® RS, RS 30 D, RL, RL 30 D, and the like (Rohm America, LLC).
  • Another example includes neutral ester copolymers of acrylates, such as Eudragit ® NE 30 D, NE 40 D, and the like. Still, another example includes ionic polymers of methacrylates, such as Eudragit ® L, S, FS, and E, and the like (Rohm America, LLC).
  • the aqueous dispersion of the one or more insoluble pharmaceutical acceptable polymers may be used to absorb one or more surfactants or oils in the pharmaceutical composition.
  • the surfactant, oil, and detergent of the invention include any of the pharmaceutically acceptable or medicinally acceptable ionic, anionic, cationic, or non-ionic surfactant or detergent.
  • one or more of sodium lauryl sulfate, polysorbates, Tween 80 (available form Fisher Scientific International), Tween 20, Tween 60, Tween 100, and others can be used to a concentration of no more than 50% of the total weight, such as from about 0.01% to about 10% of the total weight of the pharmaceutical composition.
  • the use of one or more surfactants creates channels or pores in a coating layer such that water and other media can get into a drug- containing core during the release of the drug. It is thought that the use of polymeric colloidal dispersions or aqueous dispersions of the one or more insoluble pharmaceutical acceptable polymers together with the one or more channel-forming surfactants eliminates the need to use a plasticizer, or any plasticizers which are also used as pore-forming materials, e.g., polyethylene glycol, etc.
  • the aqueous dispersion of the one or more insoluble pharmaceutical acceptable polymers may also be used to granulate the therapeutically active agent in the pharmaceutical composition.
  • the pharmaceutical composition of the invention generally includes the therapeutically active agent utilized at therapeutic dose levels, which may vary from about 5% to about 95% by weight of the pharmaceutical composition, preferably, from about 30% to about 90% by weight of the pharmaceutical composition.
  • One example of the therapeutically active agent includes bupropion and its salts and derivatives thereof, such as bupropion hydrochloride at a concentration of about 45% to about 85% by weight.
  • about 10 mg to about 500 mg of bupropion hydrochloride can be prepared into the pharmaceutical composition of the invention without any stabilizer or any plasticizer and still maintaining its stability for long term storage, even under elevated storage conditions.
  • Other therapeutically active agents can also be used herein, including, but not limited to, various water-soluble drugs, water-insoluble drugs, valproic acid, benzonatate, simethicone, methylclothiazide, prednisolone, prednisone, ibuprofen, naproxen, aspirin, acetominophen, dihydroergotamine mesylate, famotidine, omeprasole, chloropheniramine, ranitidine, diclofenac sodium, cimetidine, guaifenesin, glypizide, estradiol, acyclovir, ketoprofen, desmopressin, oxybutynin hydrochloride, propranolol hydrochloride, niacin, cetirizin hydrochloride, cerivastin sodium, metoprolol fumarate, nifedipine, nisoldipine, nicardipine,
  • Suitable therapeutically active agents may be an active ingredient compound having a therapeutic effect and including antibiotics, anti-infection agents, antihypertensives, calcium channel blockers, ⁇ -blockers, analgesics, antineoplastic agents, anti-microbials, anti-malarials, non-steroidal antiinflammatory drugs (NSAID), diuretics, anti-arrythmia agents and the like.
  • the therapeutically active agent can be prepared into powder, granules, particles, beads, pellets, and other pharmaceutical acceptable sizes.
  • the therapeutically active agent can further be micronized and preferably have a particle size of less than 20 microns.
  • the invention provides a pharmaceutical composition comprising a therapeutically active agent prepared into a core which can be coated with a pharmaceutical acceptable coating mixture.
  • the core may further include an aqueous dispersion of one or more insoluble pharmaceutical acceptable polymers of the invention adapted to granulate a drug.
  • the pharmaceutical acceptable coating mixture may include one or more surfactants and an aqueous dispersion of one or more insoluble pharmaceutical acceptable polymers adapted to help absorbing the one or more surfactants or detergents and coat the core.
  • the aqueous dispersion of the one or more insoluble pharmaceutical acceptable polymers may each be used to a concentration from about 0.001% to about 50% by weight of the total weight of the pharmaceutical composition.
  • the one or more insoluble pharmaceutical acceptable polymers in the core may be the same or different polymers as the one or more insoluble pharmaceutical acceptable polymers in the pharmaceutical acceptable coating mixture.
  • the one or more insoluble pharmaceutical acceptable polymers may include pH-dependent polymers and/or pH-independent polymers.
  • an aqueous dispersion of a swellable permeable insoluble pharmaceutical acceptable polymer which may be a pH-dependent polymer or a pH- independent polymer, can be incorporated into the core of the pharmaceutical composition of the invention.
  • aqueous dispersions of one or more pH-independent polymers are included in the core to mix with the therapeutically active agent of the invention.
  • Exemplary aqueous dispersions of swellable permeable insoluble pH-independent polymers in the core include Eudragit ® NE 30 D, NE 40 D, and the like.
  • aqueous dispersions of one or more swellable permeable neutral ester copolymers are included in the core.
  • the same swellable permeable insoluble pharmaceutical acceptable polymer in the core can also be incorporated into the pharmaceutical acceptable coating mixture.
  • the pharmaceutical composition of the invention may further include additional aqueous dispersions of insoluble pharmaceutical acceptable polymers, which may be a pH-dependent polymer or a pH-independent polymer, incorporated into the pharmaceutical acceptable coating mixture.
  • one or more swellable permeable neutral ester copolymer dispersions and ionic polymer dispersions are included in the pharmaceutical acceptable coating mixture.
  • the presence of the ionic polymer dispersions in the pharmaceutical acceptable coating mixture may aid the dissolution of the therapeutically active agent under various in vitro and in vivo conditions which may require different pH or ionic interactions.
  • aqueous dispersions of one or more insoluble pharmaceutical acceptable enteric polymers are included in the pharmaceutical acceptable coating mixture.
  • enteric polymers include methacylic acid copolymers (e.g., Eudragit ® S and Eudragit ® L, available from Rohm America, LLC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose succinate, carboxymethylethylcellulose, cellulose acetophthalate.
  • the one or more insoluble pharmaceutical acceptable enteric polymers may be pH-dependent ionic polymers which are only soluble under certain pH levels.
  • the pharmaceutical composition of the invention may further include additional aqueous dispersions of insoluble pharmaceutical acceptable polymers, which may be a pH-dependent polymer or a pH-independent polymer, incorporated into the core and/or the pharmaceutical acceptable coating mixture.
  • the invention provides extended release formulations for the therapeutically active agent.
  • the pharmaceutical composition of the invention includes a controlled release, sustained release, or timed release dosage formulation for the therapeutically active agent.
  • the extended release formulation as described herein can provide continuous and non-pulsating therapeutic levels of the therapeutically active agent to a mammal in need of such treatment over a period of time, such as a four-hour period or longer, a six-hour period or longer, e.g., a twelve-hour to twenty-four hour period.
  • Such an extended release, controlled release, sustained release, or timed release dosage formulation employs a core of a pharmaceutical mixture and a coating layer of a pharmaceutical acceptable coating mixture.
  • the core of the pharmaceutical mixture contains the therapeutically active agent (e.g., bupropion hydrochloride) and optionally, includes aqueous dispersions of one or more insoluble pharmaceutical acceptable polymers of the invention at a concentration of from about 0.01% to about 80% of the total weight of the pharmaceutical composition, such as from about 0.01% to about 50% by weight.
  • the core containing the therapeutically active agent generally includes a therapeutically active agent and aqueous dispersions of one or more insoluble pharmaceutical acceptable polymers, which may help swelling or gelling of the therapeutically active agent and carrying the therapeutically active agent to be released in a controlled or time-delayed manner.
  • Exemplary aqueous dispersions of the one or more insoluble pharmaceutical acceptable polymers in the core include swellable permeable neutral ester copolymer dispersions, such as Eudragit ® NE 30 D, NE 40 D, and the like, used to a concentration of from about 0.01% to about 50% by weight of the total weight of the pharmaceutical concentration.
  • the core of the pharmaceutical mixture may optionally include water- soluble polymers.
  • water-soluble polymers include polyvinylpyrrolidone, hydroxypropyl cellulose (HPC; Klucel), hydroxypropyl methylcellulose (HPMC; Methocel), nitrocellulose, hydroxypropyl ethylcellulose, hydroxypropyl butylcellulose, hydroxypropyl pentylcellulose, methyl cellulose, ethylcellulose (Ethocel), hydroxyethyl cellulose, various alkyl celluloses and hydroxyalkyl celluloses, various cellulose ethers, cellulose acetate, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, vinyl acetate/crotonic acid copolymers, poly- hydroxyalkyl methacrylate, hydroxymethyl methacrylate, methacrylic acid copolymers, polymethacrylic acid, polymethylmethacrylate, maleic anhydride/methyl vinyl ether copolymers
  • the core of the pharmaceutical mixture can be prepared in a form of granules, particles, beads, spherical beads, pellets, coated beads, coated pellets, coated particles, and other pharmaceutically acceptable shapes and sizes. This can be done by various granulation methods and other methods, such as wet and dry granulations. Wet granulation is prepared by mixing required components with various conventional well-known solvents to form granules. Alternatively, dry granulation techniques may be used to prepare the pharmaceutical composition. The mixture of the core of the pharmaceutical composition can then be incorporated into solid dosage forms, such as tablets and others, and an optional external coating is applied. For making compressed tablets, a conventional tabletting machine may be used to compress a granulated mixture of the components of the present invention into a tablet.
  • Embodiments of the invention provide a coating layer outside of the core containing the therapeutically active agent.
  • the coating layer of the pharmaceutical acceptable coating mixture includes one or more surfactants and aqueous dispersions of one or more insoluble pharmaceutical acceptable polymers of the invention.
  • Ionic surfactant, anionic surfactants, non-ionic surfactants, emulsifiers, dispersing agents, defoamers, and combinations thereof can be used to advantage.
  • Any of the pharmaceutically acceptable or medicinally acceptable surfactants, emulsifiers, dispersing agents, dispersants, and defoamers can be used herein at a concentration of no more than 50% of the total weight of the pharmaceutical concentration, such as from about 0.01% to about 10% of the total weight.
  • a surfactant can be used in the coating layer of the pharmaceutical composition to an amount varying from about 0.001 % to about 50 % by weight of the coating, such as from about 0.1 % to about 30 % by weight of the coating.
  • the surfactant in the pharmaceutical composition enhances the channeling process of the one or more insoluble pharmaceutical acceptable polymers to achieve a desired drug release profile.
  • One exemplary surfactant includes sodium lauryl sulfate, used to a concentration of no more than 50% of the total weight of the pharmaceutical concentration or from about 0.01% to about 30% by weight of the coating layer of the pharmaceutical acceptable coating mixture.
  • a second surfactant such as Tween 80 Tween 20, Tween 60, Tween 100, and others can also be included in the pharmaceutical acceptable coating mixture.
  • Exemplary aqueous dispersions of the one or more insoluble pharmaceutical acceptable polymers in the coating layer of the invention include swellable permeable neutral ester copolymer dispersions, such as copolymers of acrylate and methacryiates neutral esters, Eudragit ® NE 30 D, NE 40 D, and the like, used to a concentration of from about 0.01% to about 50% by weight of the total weight of the pharmaceutical concentration, such as from about 0.01 % to about 10 % by weight of the pharmaceutical composition.
  • the one or more insoluble pharmaceutical acceptable polymers in the coating layer can include ph-independent or pH-dependent polymers, used at a concentration from about 0.01% to about 99% by weight of the coating layer of the pharmaceutical acceptable coating mixture, e.g., from about 5% to about 99% by weight of the coating layer.
  • pH-independent polymers such as copolymers of acrylate and/or methacrylate can also be used to advantage; for example, Eudragit ® RL, Eudragit ® RS and the like.
  • water-insoluble polymers useful in the invention include polyacrylates, cellulose derivatives (e.g., ethylcellulose), polyvinyl acetate (e.g., Kollicoat SR30D from BASF Corporation, Mount Olive, New Jersey), neutral copolymers based on ethyl acrylate and methylmethacrylate, copolymers of acrylate and methacrylates, among others.
  • cellulose derivatives e.g., ethylcellulose
  • polyvinyl acetate e.g., Kollicoat SR30D from BASF Corporation, Mount Olive, New Jersey
  • neutral copolymers based on ethyl acrylate and methylmethacrylate copolymers of acrylate and methacrylates, among others.
  • aqueous dispersions of insoluble pharmaceutical acceptable polymers can also be included in the pharmaceutical acceptable coating mixture.
  • exemplary aqueous dispersions of the pH-dependent enteric polymers in the coating layer of the invention include Eudragit ® L 30 D-55, FS 3OD, and the like, used to a concentration of from about 0.01% to about 50% by weight of the total weight of the pharmaceutical concentration, such as from about 0.01 % to about 10 % by weight of the pharmaceutical composition.
  • the one or more insoluble pH-dependent polymers in the coating layer may be used at a concentration from about 0.01% to about 99% by weight of the coating layer of the pharmaceutical acceptable coating mixture, e.g., from about 5% to about 99% by weight of the coating layer.
  • Other pH-dependent ionic polymers such as Eudragit ® L 12,5 or S 12,5, and the like, can also be used to advantage.
  • enteric polymers examples include methacylic acid copolymers (e.g., Eudragit ® S and Eudragit ® L, available from Rohm America, LLC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose succinate, carboxymethylethylcellulose, cellulose acetophthalate.
  • methacylic acid copolymers e.g., Eudragit ® S and Eudragit ® L, available from Rohm America, LLC
  • enteric polymers rapidly disintegrate or dissolve at pH 5 or above.
  • enteric polymers may include cellulose acetate phthalate, polyvinyl acetate phthalate, acrylic resins, shellac, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, cellulose acetyl phthalate, cellulose triacetyl phthalate, sodium cellulose acetate phthalate, cellulose ester phthalate, cellulose ether phthalate, methylcellulose phthalate, cellulose ester-ether phthalate, hydroxy propyl cellulose phthalate, alkali salts of cellulose acetate phthalate, alkaline earth salts of cellulose acetate phthalate, calcium salt of cellulose acetate phthalate, ammonium salt of hydroxypropyl methylcellulose phthalate, cellulose acetate hexahydrophthalate, hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, and combinations thereof.
  • the enteric materials are discussed in Remington's Pharmaceutical Sciences, 17
  • the core of the pharmaceutical mixture and the coating layer of the pharmaceutical acceptable coating mixture may further include pharmaceutically acceptable excipients, fillers, diluents, binders, and blending agents, such as hydrous or anhydrous form of lactose, starches, glucose, sucrose, mannitol, sorbitol, silicic acid, microcrystalline celluloses, sodium carboxymethylcelluloses, sodium starch glycolate, and derivatives and mixtures thereof.
  • avicel can be added into the core to a concentration of from about 0.01 % to about 50% by weight of the pharmaceutical composition, such as from about 0.05% to about 40% by weight.
  • the core and coating layer of the invention may further include glidants, lubricants disintegrants, flavours, colourants, antiadherents, blenders, anti-sticking agents, wetting agents, dyes, pigments, nonstick agents, dispersants, coating materials, and mixtures thereof, to be combined into the pharmaceutical composition.
  • lubricants include, but are not limited to, talc, calcium stearate, magnesium stearate, glycerol monostearate, polyethylene glycols, inert silicon glass materials, colloidal silicon dioxide, and higher fatty acids and their alkali-metal and alkaline-earth-metal salts.
  • excipients such as diluents, lubricants, dyes, etc., which are disclosed in Remington's Pharmaceutical Sciences, 1995 Edition, may be used to optimize the pharmaceutical composition of the invention.
  • the amounts of the lubricants, anti-sticking agents, and other excipients generally vary from about 0.005 % to about 50 % by weight of the pharmaceutical composition, such as from about 0.005 % to about 30 %. It is found that the release rate of the therapeutically active agent can be controlled not only by incorporating suitable insoluble pharmaceutically acceptable polymers and surfactants therein, but also by the thickness of the coating layer having excipients applied.
  • Examples that can be blended into the core and coating layer of the pharmaceutical composition include glycerol monosteartae, talc, corn starch, magnesium stearate, cab-O-sil, and avicel, to a final concentration of from about 1.0% to about 20% by weight of the pharmaceutical composition.
  • glycerol monosteartae can be added into the core and/or the coating layer to a concentration of from about 0.01 % to about 50% by weight of the pharmaceutical composition, such as from about 0.05% to about 40% by weight of the pharmaceutical composition.
  • the pharmaceutical compositions of the invention may have an additional second coating layer containing a pharmaceutically acceptable coating mixture.
  • the pharmaceutically acceptable coating mixture in the second coating layer includes, but is not limited to, an enteric polymer, a salt, a rapid-disintegrating coating material, a colorant, a water-soluble polymer, a water-insoluble polymer, a dye, a pigment, other disintegrants, and combinations thereof.
  • rapid-disintegrating coating material is OPADRY, available from Colorcon, Inc.
  • Any commonly used pharmaceutically acceptable salts can be used in the coating layer, such as the first coating layer or the second coating layer. For example, sodium chloride, magnesium choride, among others.
  • the amount of the second coating layer surrounding the coated tablet is from about 0.001% to about 5% of the total weight of the pharmaceutical composition, such as from about 0.01% to about 2% based on the total weight of the pharmaceutical composition.
  • the invention provides prolonged release formulations of bupropion hydrochloride prepared by the pharmaceutical composition of the invention, such as controlled release or extended release formulations.
  • the invention provides a method of preparing a pharmaceutical composition, such as an extended release formulation, by preparing a core and coating the core with the coating layer. The coated core is then incorporated into a dosage form, such as by compressing the pharmaceutical composition into an oral dosage form, a solid dosage form, and a tablet dosage form.
  • a method of preparing the pharmaceutical composition may include forming a core of a pharmaceutical mixture and coating the core with a coating mixture.
  • the pharmaceutical mixture may include, for example, bupropion, such as bupropion salt, e.g., bupropion hydrochloride and the core of the pharmaceutical mixture may optionally include aqueous dispersions of one or more insoluble pharmaceutical acceptable polymers.
  • the coating mixture may include one or more surfactants and aqueous dispersions of one or more insoluble pharmaceutical acceptable polymers of the invention.
  • the core may be formed by mixing the pharmaceutical mixture through granulation, such as wet granulation or dry granulation, compressing the pharmaceutical mixture into a dosage form, including an oral dosage form, a solid dosage form, and a tablet dosage form, etc.
  • the pharmaceutical mixture may be mixed through wet granulation and compressed into a tablet core.
  • a coating mixture is formed by mixing one or more surfactants with aqueous dispersion of one or more insoluble pharmaceutical acceptable polymers of the invention, and the tablet core is coated with the coating mixture.
  • Coating a core with the coating mixture of the invention may employ any suitable pharmaceutical coating techniques, such as press coating, molding, spraying, dipping and/or air-suspension or air tumbling procedures.
  • One example of coating a core with a coating mixture includes pan coating, where the coating mixture is applied by spraying onto the tablet core accompanied by tumbling in a rotating pan.
  • an extended release pharmaceutical composition of the invention may include a core of a pharmaceutical mixture comprising from about 10 mg to about 500 mg of bupropion hydrochloride and a coating layer comprising one or more surfactants and one or more aqueous water-insoluble pharmaceutical acpeptable polymeric colloidal dispersions.
  • the core may further include a pharmaceutical acceptable polymer, for example, a water- soluble polymer, a water-insoluble polymer, a pH-independent polymer, a pH- dependent polymer, and any of the combinations thereof.
  • a pharmaceutical acceptable polymer for example, a water- soluble polymer, a water-insoluble polymer, a pH-independent polymer, a pH- dependent polymer, and any of the combinations thereof.
  • an aqueous water-insoluble pharmaceutical acceptable polymeric dispersion can be incorporated to the core such that the final solid dosage form of the bupropion hydrochloride is not too brittle.
  • aqueous water- insoluble pharmaceutical acceptable polymeric dispersions which can be incorporated into the core include various polymeric colloidal dispersions, such as pH-independent polymeric colloidal dispersions, pH-dependent polymeric colloidal dispersions, swellable permeable neutral ester copolymer colloidal dispersions, ionic polymeric colloidal dispersions, and any of the combinations thereof.
  • the coating layer of the extended release pharmaceutical composition of the invention may include one or more aqueous water-insoluble pharmaceutical acceptable polymeric colloidal dispersions, such as various water-insoluble polymeric colloidal dispersions, e.g., pH-independent water- insoluble polymeric colloidal dispersions, pH-dependent water-insoluble polymeric colloidal dispersions, water-insoluble swellable permeable neutral ester copolymer colloidal dispersions, water-insoluble ionic polymeric colloidal dispersions, and any of the combinations thereof.
  • various water-insoluble polymeric colloidal dispersions e.g., pH-independent water- insoluble polymeric colloidal dispersions, pH-dependent water-insoluble polymeric colloidal dispersions, water-insoluble swellable permeable neutral ester copolymer colloidal dispersions, water-insoluble ionic polymeric colloidal dispersions, and any of the combinations thereof.
  • the invention provide a method of preparing an extended release pharmaceutical composition including forming a core of a pharmaceutical mixture and coating the core with a coating mixture, wherein the pharmaceutical mixture includes from about 10 mg to about 500 mg of bupropion salt and a pharmaceutical acceptable polymer, and the coating mixture includes one or more surfactants and one or more aqueous water-insoluble pharmaceutical acceptable polymeric colloidal dispersions.
  • the dosage forms of the pharmaceutical composition prepared according to the invention exhibit a desired release profile for controlled release, sustained release, or extended release formulations.
  • release is broadly defined herein as absorption or dissolution of a compound, either in vivo or in vitro.
  • the in vivo absorption is generally performed by measuring the plasma concentration of the therapeutically active agent over a period of time.
  • the in vitro release profile of the therapeutically active agent can be tested in a USP type 2 apparatus at about 50 rpm in about 900 ml of phosphate buffer (pH 6.8) and at 37°C.
  • Other buffers at different pH ranges can be used herein, e.g., acetate buffer (pH 5) can be used.
  • USP type 1 apparatus may be used at about 75 rpm under simulated intestinal buffer (SIF) or simulated gastric buffer (SGF, low pH conditions, pH at about 1.5).
  • SIF simulated intestinal buffer
  • SGF simulated gastric buffer
  • Various SGF buffers at various low pH ranges can be used.
  • embodiments of the invention provide a release profile of the therapeutically active agent under SIF conditions having up to about 60% release of the during the initial 2 hours, preferably from about 5% to about 40% release.
  • the pharmaceutical composition further provides from about 10% to about 80% release of the therapeutically active agent within 4 hours, preferably from about 20% to about 75% release within 4 hours, and from about 30% to about 95% release of the therapeutically active agent within 6 hours, preferably from about 40% to about 90% release within 6 hours.
  • the pharmaceutical composition provides no less than about 50% release of the therapeutically active agent, preferably no less than about 75% release.
  • embodiments of the invention provide a release profile of the therapeutically active agent under SGF conditions having up to about 20% release of the therapeutically active agent during the initial 2 hours, preferably from about 1% to about 10% release.
  • the pharmaceutical composition further provides from about 10% to about 65% release of the therapeutically active agent within 4 hours, preferably from about 10% to about 40% release within 4 hours; more preferably from about 10% to about 25% within 4 hours; and from about 20% to about 75% release of the therapeutically active agent within 6 hours, preferably from about 30% to about 70% release within 6 hours.
  • Within 8 hours from about 25% to about 85% of the therapeutically active agent in the pharmaceutical composition is released, preferably, from about 40% to about 80% is released.
  • the pharmaceutical composition provides no less than about 50% release of the therapeutically active agent, preferably no less than about 75% release.
  • a method of administering a pharmaceutical composition such as an extended release pharmaceutical composition containing bupropion salt.
  • the method includes administering the pharmaceutical composition of the invention having a therapeutically active agent in an effective amount to treat a mammal.
  • the pharmaceutical composition may include a core comprising the therapeutically active agent, such as bupropion hydrochloride, and a coating mixture comprising one or more surfactants and aqueous dispersions of one or more insoluble pharmaceutical acceptable polymers.
  • an extended release formulation of bupropion hydrochloride tablet prepared according to the embodiments of the invention can be used in an effective amount of about 150 mg per day for the treatment of depression or smoke cessation, such as major depressive disorders. Initial dose of about 150 mg per day may be continued for several days. In some cases, a higher dose of about 300 mg per day may be used.
  • Exemplary controlled release dosage formulations are prepared and described herein.
  • Pharmaceutical compositions having a therapeutically active agent at a concentration of from about 40% to about 80% by total weight, aqueous dispersions of a number of insoluble pharmaceutical acceptable polymers each at a concentration of from about 0.1% to about 10% of total weight, and a surfactant at a concentration of from about 0.1 % to about 4.9% of total weight are formulated and tested herein.
  • oral dosage formulations of bupropion, such as bupropion salt, bupropion hydrochloride, etc. in the form of an extended release tablet are tested in vitro for their release profile and in some cases compared in vivo to healthy human subjects with a reference formulation.
  • the reference formulation used is the Wellbutrin ® XL tablet (GlaxoSmithKline).
  • Bupropion hydrochloride 150mg and 300 mg extended release tablets are prepared. Each tablet includes about 150 mg or about 300 mg of bupropion hydrochloride, Eudragit ® NE 30 D (USP grade) at about 0.1% to about 10% by weight, Eudragit ® L 30 D (USP grade) at about 0.01% to about 10 % by weight, sodium lauryl sulfate at about 0.001% to about 4% by weight, Tween 80 (Optional) at about 0.001% to about 2 % by weight, glycerol monostearate at about 0.01 % to about 10% by weight, talc at about 0.001% to about 10% by weight, and optionally, an anti-sticking agent and a colorant.
  • Eudragit ® NE 30 D USP grade
  • Eudragit ® L 30 D USP grade
  • sodium lauryl sulfate at about 0.001% to about 4% by weight
  • Tween 80 Optional
  • glycerol monostearate at about 0.01
  • Granulation First of all, bupropion hydrochloride is charged in a vertical granulator and pre-blended for about 10 to 20 minutes. An aqueous dispersion of Eudragit ® NE 3OD is added to the blend and isopropylalcohol can be optionally added to achieve granulation consistency. The granules are then placed at about 50 0 C until its moisture content (Ae., loss-on-drying at 105 °C, 10 minutes) is below 1.5%. Once the drying is completed, granules are milled in a comill and mixed with required amounts of glycerol monostearate and talc in a V-blender.
  • Tabletting The resulting granule mixture is compressed into tablet cores (11/32" diameter, standard concave punch) with average hardness being between 7 and 13 Kp, each tablet core having a drug content of about 150 mg or about 300 mg. These tablet cores are then coated with a coating mixture.
  • First coating The coating mixture is prepared by first dissolving sodium lauryl sulfate and Tween 80 (optional) in water and mixing the resulting surfactant-containing solution with aqueous dispersions of Eudragit ® NE 30 D and Eudragit ® L 30 D. The coating mixture or dispersion is then sprayed onto the tablet cores in a coating pan (O'Harra) at about 47 0 C.
  • a coating pan O'Harra
  • Second coating or color coating The coated tablet may be optionally coated again with colorants, such as Opadry, using a pan coater. Typically, a theoretical coating level of approximately 1% is obtained.
  • Figure 1 is a release profile 120 of an exemplary pharmaceutical composition of about 150 mg bupropion hydrochloride tested in about 900 ml SIF buffer (pH 6.8) using an USP Apparatus 2, at a speed of about 50 rpm with paddle as compared to a release profile 110 of a reference tablet, Wellbutrin ® XL tablet.
  • Figure 2 is a release profile 220 of an exemplary pharmaceutical composition of bupropion hydrochloride tested in about 900 ml SIF buffer (pH 6.8) using an USP Apparatus 2, at a speed of about 75 rpm with paddle as compared to a release profile 210 of a reference tablet, Wellbutrin ® XL tablet.
  • Figure 3 is a release profile 320 of an exemplary pharmaceutical composition of bupropion hydrochloride tested in about 900 ml SIF buffer (pH 6.8) using an USP Apparatus 2, at a speed of about 100 rpm with paddle as compared to a release profile 310 of a reference tablet, Wellbutrin ® XL tablet.
  • FIG. 4 is a release profile 420 of an exemplary pharmaceutical composition of about 150 mg bupropion hydrochloride tested in about 900 ml SGF buffer (pH 1.5) using an USP Apparatus 410 of a reference tablet, Wellbutrin ® XL tablet.
  • the results demonstrate consistent extended release profiles of bupropion hydrochloride prepared by the method and formulation of the invention, as compared to the reference tablets.

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Abstract

Des modes de réalisation de l'invention concernent généralement des compositions médicamenteuses pharmaceutiques, des procédés de préparation de compositions médicamenteuses à administrer par voie orale, notamment des compositions dosifiées à libération prolongée, et des procédés destinés à traiter un patient sous traitement d'antidépresseurs ou un patient qui arrête de fumer. Dans un aspect de l'invention, l'invention concerne une formulation pharmaceutique comprenant un noyau renfermant du bupropion et ses dérivés formant sel, ainsi qu'un enrobage. L'enrobage peut comprendre au moins un agent tensio-actif et des dispersions aqueuses d'au moins un polymère insoluble pharmaceutiquement acceptable. Le noyau peut également comprendre des dispersions aqueuses d'au moins un polymère insoluble pharmaceutiquement acceptable. Dans un autre aspect, l'invention concerne des procédés destinés à préparer et à administrer une composition pharmaceutique se présentant sous une forme dosifiée à administrer par voie orale, notamment un comprimé.
PCT/US2006/061625 2005-12-06 2006-12-05 Procédés et formulations permettant de préparer une forme dosifiée à libération contrôlée à administrer par voie orale Ceased WO2007117314A2 (fr)

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CN200680046024.4A CN101453990B (zh) 2005-12-06 2006-12-05 丁氨苯丙酮可控释放配方及其制造方法

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US11/295,995 US20060099262A1 (en) 2004-11-08 2005-12-06 Methods and formulations for making controlled release oral dosage form
US11/295,851 2005-12-06
US11/295,995 2005-12-06
US11/295,851 US20060099261A1 (en) 2004-11-08 2005-12-06 Methods and formulations for making controlled release oral dosage form

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Cited By (1)

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WO2023285977A1 (fr) * 2021-07-14 2023-01-19 Zydus Lifesciences Limited Compositions pharmaceutiques d'ozanimod

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US6210716B1 (en) * 1999-02-26 2001-04-03 Andrx Pharmaceuticals, Inc. Controlled release bupropion formulation
US8586085B2 (en) * 2004-11-08 2013-11-19 Biokey, Inc. Methods and formulations for making pharmaceutical compositions containing bupropion

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023285977A1 (fr) * 2021-07-14 2023-01-19 Zydus Lifesciences Limited Compositions pharmaceutiques d'ozanimod

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