WO2005077332A2 - Formes posologiques stables de gabapentine pour usage oral et a liberation prolongee, et procede de preparation associe - Google Patents

Formes posologiques stables de gabapentine pour usage oral et a liberation prolongee, et procede de preparation associe Download PDF

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Publication number
WO2005077332A2
WO2005077332A2 PCT/IB2005/000093 IB2005000093W WO2005077332A2 WO 2005077332 A2 WO2005077332 A2 WO 2005077332A2 IB 2005000093 W IB2005000093 W IB 2005000093W WO 2005077332 A2 WO2005077332 A2 WO 2005077332A2
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WIPO (PCT)
Prior art keywords
rate
sustained
gabapentin
controlling polymers
tablet
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PCT/IB2005/000093
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English (en)
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WO2005077332A3 (fr
Inventor
Manish Chawla
Rajeev Singh Raghuvanshi
Ashok Rampal
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Ranbaxy Laboratories Limited
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Publication of WO2005077332A2 publication Critical patent/WO2005077332A2/fr
Publication of WO2005077332A3 publication Critical patent/WO2005077332A3/fr

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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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • 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
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • Field of the Invention Provided herein are stable sustained-release oral dosage forms of gabapentin, processes for preparation thereof, and uses thereof in treating epilepsy or post herpetic neuralgia.
  • Gabapentin (l-(aminomethyl)cyclohexaneacetic acid) is a ⁇ -amino acid analogue effective in the treatment of epilepsy. Gabapentin is indicated as an adjunctive therapy in the treatment of partial seizures with and without secondary generalization in adults with epilepsy. Gabapentin is also being used to treat neuropathic pain. Gabapentin has been reported to convert to a toxic lactam compound (Impurity A) during preparation and storage. This lactam formation is also seen in formulations containing gabapentin. The cause of lactam formation in formulation during storage is apparently also the catalytic effects of excipients used. The lactam has toxicity, which exceeds that of gabapentin itself.
  • Impurity A a toxic lactam compound
  • Such stable sustained-release dosage forms of gabapentin would not only provide a safe mode of gabapentin therapy, but also other benefits, such as maintaining steady plasma levels of gabapentin and the possibility of reducing the total daily dose and frequency of dosing to once or twice a day.
  • stable sustained-release tablets of gabapentin comprising an intragranular component, which comprises gabapentin and optionally one or more rate controlling polymers; and an extragranular component, which comprises one or more rate- controlling polymers, wherein lactam content does not exceed 0.4 % by weight of gabapentin when the tablet is kept for about 3 months at about 40 °C and about 75 % relative humidity.
  • the one or more intragranular rate-controlling polymers and one or more extragranular rate controlling polymers can be the same or different.
  • Embodiments of the stable sustained-release tablets may include one or more of the following features.
  • the intragranular component can comprise one or more rate controlling polymers.
  • the one or more rate-controlling polymers in the intragranular component (i.e., the one or more intragranular rate-controlling polymers) and the extragranular component the one or more rate-controlling polymers in the extragranular component (i.e., the one or more extragranular rate-controlling polymers) together can comprise from about 5 % to about 80 % by weight of the tablet.
  • the one or more rate-controlling polymers in the intragranular component can comprise from about 0 % to about 50 % by weight of the granules and the one or more rate-controlling polymers in the extragranular component can comprise from about 5 % to about 80 % by weight of the tablet.
  • the intragranular or extragranular rate-controlling polymers can also be one or more of polyvinylpyrrolidone or derivatives thereof; a cellulosic polymer; a vinyl acetate copolymer; an alginate; xanthan gum; guar gum; starch; a starch-based polymer; polyethylene oxide; a methacrylic acid copolymer; a maleic anhydride/methyl vinyl ether copolymer or derivatives thereof; ethyl cellulose; cellulose acetate; a methacrylate; an acrylic acid polymer or copolymer; a high molecular weight polyvinyl alcohol; a wax; or mixtures thereof.
  • the cellulosic polymer can be one or more of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose or mixtures thereof, hi some embodiments, the sustained-release tablets contain hydroxypropylmethylcellulose having a viscosity of about 100 cps to about 100,000 cps, a viscosity of about 15,000 cps or even a viscosity of about 4000 cps.
  • the sustained-release tablets contain hydroxypropylcellulose having a viscosity of about 7 cps to about 30,000 cps, a viscosity of about 1000 cps to about 15000 cps, or even a viscosity of about 4000 cps.
  • the sustained-release tablets can further comprise one or more additional pharmaceutical excipients, for example, diluents, lubricants, glidants, binders or mixtures thereof.
  • the diluents can be one or more of powdered sugar, calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, mannitol, kaolin, dry starch, sorbitol or mixtures thereof.
  • the lubricants can be one or more of talc, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate or mixtures thereof.
  • the glidants can be one or more of talc, silicon dioxide, corn starch or mixtures thereof.
  • the binders can be one or more of polyvinylpyrrolidone, polyvinylpyrrolidone/vinylacetate copolymer, xanthan gum, guar gum, cellulose gums (e.g., carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose), gelatin, starch pregelatinized starch or mixtures thereof.
  • processes for preparing a stable sustained-release tablet of gabapentin comprising the steps of granulating a mixture comprising gabapentin, one or more pharmaceutical excipients and optionally one or more rate-controlling polymers with a granulating liquid to form an intragranular component; drying, sizing and mixing the intragranular component with one or more extragranular rate-controlling polymers to form a blend, and compressing the blend into a tablet.
  • Such stable sustained-release tablets have a lactam content that does not exceed 0.4 % by weight of gabapentin when the tablet is kept for about 3 months at about 40 °C and about 75 % relative humidity.
  • the optional one or more intragranular rate-controlling polymers and the one or more extragranular rate-controlling polymers can be the same or different.
  • Embodiments of the processes may include one or more of the following features.
  • the intragranular component of the tablets disclosed herein can be prepared by wet granulation or dry granulation. Dry granulation can be carried out by compacting or slugging.
  • processes for preparing a stable sustained-release tablet of gabapentin comprising the steps of mixing gabapentin, one or more pharmaceutical excipients and optionally one or more rate-controlling polymers to form a mixture; compacting or slugging the mixture to form compacts or slugs; sizing the compacts or slugs to form granules; mixing the granules with one or more extragranular rate-controlling polymers to form a blend; and compressing the blend into tablets.
  • Such stable sustained-release tablets have a lactam content that does not exceed 0.4 % by weight of gabapentin when the tablet is kept for about 3 months at about 40 °C and about 75 % relative humidity.
  • the optional one or more intragranular rate-controlling polymers and the one or more extragranular rate-controlling polymers can be the same or different.
  • methods for treating epilepsy or post herpetic neuralgia comprising administering to a patient in need thereof a stable sustained- release tablet of gabapentin comprising: an intragranular component comprising a therapeutically effective amount of gabapentin and optionally one or more rate-controlling polymers; and an extragranular component comprising one or more rate-controlling polymers, wherein lactam content does not exceed 0.4 % by weight of gabapentin when the tablet when kept for about 3 months at about 40 °C and about 75 % relative humidity and wherein the optional one or more intragranular rate-controlling polymers.
  • the one or more extragranular rate-controlling polymers can be the same or different.
  • tablets prepared by processes comprising the steps of granulating a mixture comprising gabapentin, one or more pharmaceutical excipients and optionally one or more intragranular rate-controlling polymers with a granulating liquid to form an intragranular component; drying, sizing and mixing the intragranular component with one or more extragranular rate-controlling polymers to form a blend, and compressing the blend into a tablet.
  • tablets prepared by processes comprising the steps of mixing gabapentin, one or more pharmaceutical excipients and optionally one or more intragranular rate-controlling polymers to form a mixture; compacting or slugging the mixture to form compacts or slugs; sizing the compacts or slugs to form granules; mixing the granules with one or more extragranular rate-controlling polymers to form a blend; and compressing the blend into tablets.
  • the stability of gabapentin tablet is influenced by the amount of the rate-controlling polymer that is present intragranularly or extragranularly.
  • the stability is improved when the amount of rate-controlling polymer is decreased in the intragranular component.
  • the processes described herein provide flexibility and broaden the number of suitable pharmaceutical excipients, particularly rate-controlling polymers, for preparing stable sustained-release dosage forms of gabapentin.
  • Rate-controlling polymers which would typically show incompatibility with gabapentin, can be used to prepare stable compositions using the processes disclosed herein when a portion of the rate-controlling polymers is utilized extragranularly in the dosage form.
  • the processes are economical and can be easily carried out to prepare stable sustained-release tablets of gabapentin that provide therapeutically effective plasma levels of gabapentin for a period of up to about 24 hours.
  • Granules can be prepared by wet granulation or dry granulation process.
  • Excipients, particularly rate-controlling polymers which are typically incompatible with gabapentin can be used in gabapentin compositions without compromising the stability of gabapentin. This can be achieved by either extragranular addition of one or more rate-controlling polymers, or intragranular addition of one portion of one or more rate-controlling polymers and extragranular addition of the remaining portion of the one or more rate-controlling polymers.
  • granules can be prepared by blending gabapentin, other pharmaceutical excipients and optionally one or more rate-controlling polymers to form a blend and granulating the blend with a granulating liquid to form a intragranular component; drying the intragranular component; sizing the intragranular component; mixing the intragranular component with one or more rate-controlling polymers and one or more additional extragranular excipients; and compressing to make tablets.
  • granules can be prepared by blending gabapentin, other pharmaceutical excipients and optionally a part of rate-controlling polymer to form a blend; compacting or slugging the blend; sizing; mixing with one or more rate-controlling polymers and other additional extragranular excipients; and compressing to make tablets.
  • the stability conditions as defined herein include tolerance of about ⁇ 2 °C in temperature and a tolerance of about ⁇ 5% in relative humidity.
  • Gabapentin may be present as a free base, hydrated form (e.g., a monohydrate) or any other pharmaceutically acceptable salt thereof. Gabapentin may comprise from about 100 mg to about 1200 mg by weight of the tablet.
  • the rate-controlling polymer may be either hydrophilic or hydrophobic in nature; particularly suitable are rate-controlling polymers that swell in aqueous media.
  • the amount of rate-controlling polymers in the tablet relative to gabapentin depends upon the rate of drug release required, as well as the type and molecular weight of the rate- controlling polymers and other excipients present in the formulation.
  • the rate-controlling polymer may be present intragranularly and extragranularly (i.e., in the intragranular component or the extragranular component) or may present only in the extragranular component.
  • the intragranular or extragranular rate-controlling polymers may be the same type or different types.
  • the amount of intragranular rate-controlling polymer may depend on its type and also on the extent of its incompatibility with gabapentin.
  • the total amount of the rate-controlling polymer in the dosage form i.e., the amount of intragranular rate-controlling polymer together with the amount of extragranular rate- controlling polymer
  • the intragranular rate-controlling polymer may comprise from about 0% to about 50% by weight of the granules or by weight of the tablet while the extragranular rate-controlling polymer may comprise from 5% to about 80% by weight of the tablet.
  • Suitable rate-controlling polymers include polyvinylpyrrolidone (PVP) and derivatives thereof (e.g., copolyvidone, mixtures of PVP and polyvinylacetate, for example, Kollidon SR); cellulosic polymers (e.g., hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose); vinyl acetate copolymers; polysaccharides (such as alginate, xanthan gum, guar gum etc.); starch, starch-based polymers or mixtures thereof; polyethylene oxide; methacrylic acid copolymers; maleic anhydride/methyl vinyl ether copolymers; or derivatives or mixtures thereof.
  • PVP polyvinylpyrrolidone
  • copolyvidone e.g., copolyvidone, mixtures of PVP and polyvinylacetate, for example, Kollidon SR
  • cellulosic polymers e.g., hydroxy
  • Particularly suitable rate-controlling polymers include hydroxypropyl methylcellulose, hydroxypropylcellulose or a mixture thereof.
  • Hydroxypropyl methylcellulose can have different viscosities, for example, having a viscosity from about 100 cps to about 100,000 cps, and even from about 4000 cps to about 15,000 cps.
  • Suitable types of hydroxypropyl methylcellulose are sold under the trade name METHOCEL by Dow Chemical Co., for example, METHOCEL K4MCR, METHOCEL K15MCR and METHOCEL K100MCR.
  • Hydroxypropylcellulose can also have different viscosities, including those sold by, for example, Aqualon under the brand name of KLUCEL, and also by Nippon Soda Co. Ltd, Japan. Suitable hydroxypropylcellulose include those having viscosities of from about 7 to about 30,000 cps, from about 1000 to about 15,000 cps, and even from about 4000 to about 15,000 cps.
  • rate-controlling polymers also include cellulose derivatives (e.g., ethyl cellulose or cellulose acetate), methacrylates, acrylic acid polymers or copolymers, high molecular weight polyvinyl alcohols or waxes (e.g., fatty acids or glycerides).
  • the sustained-release gabapentin tablets as described herein may further comprise one or more additional additives or pharmaceutical excipients such as diluents, lubricants, binders, glidants etc.
  • Suitable diluents include, for example, one or more of powdered sugar, calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, kaolin, dry starch, sorbitol, and the like, or mixtures thereof.
  • Suitable lubricants include one or more of talc, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate or mixtures thereof.
  • Suitable glidants include one of more of talc, silicon dioxide, cornstarch, or mixtures thereof.
  • Suitable binders include one or more of polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer; xanthan gum, guar gum; cellulose ethers (e.g., carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose or mixtures thereof); gelatin, starch or derivatives thereof; or mixtures thereof.
  • Suitable granulating liquids include, for example, one or more of water, ethanol, isopropyl alcohol, acetone, dichloromethane, and the like, or mixtures thereof.
  • Suitable binders can be dissolved in suitable granulating liquids and used as a solution/dispersion.
  • Processes for the preparation of stable gabapentin sustained-release tablets include the steps of: 1. granulating a mixture comprising gabapentin and optionally one or more rate- controlling polymers with a solution/dispersion of one or more binders to form granules (i.e., an intragranular component); 2.
  • Processes for the preparation of stable gabapentin sustained-release tablets include the steps of: 1. granulating a mixture comprising gabapentin and hydroxypropylcellulose with a solution/dispersion of hydroxypropylcellulose to form granules (z, e. , an intragranular component); 2.
  • Tablets can also be coated with one or more non-rate-controlling polymers, for example, OP ADR Y® sold by Colorcon, to impart aesthetic appeal. Such coatings can comprise about 2% by weight of the tablet.
  • Stable sustained-release tablets of gabapentin as described herein may be used, for example, in the treatment of patients suffering from epilepsy of post herpetic neuralgia.
  • Also encompassed herein are methods for treating epilepsy or post herpetic neuralgia in a patient comprising administering to the patient in need thereof one or more stable sustained-release tablet of gabapentin as disclosed herein. While the present 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 included within the scope of the present invention.
  • the stable gabapentin tablets described herein is further illustrated by the following examples but these should not be construed as limiting the scope of the invention. Examples
  • Examples 1 and 2 Gabapentin was mixed with a portion of hydroxypropylcellulose and granulated with a second portion of hydroxypropylcellulose dissolved in purified water.
  • the granules were dried, sized, mixed with extragranular hydroxypropylmethylcellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet (Example 1); or hydroxypropylmethylcellulose, hydroxypropylcellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet (Example 2).
  • Examples 3 and 4 Gabapentin was mixed with a portion of hydroxypropylcellulose and granulated with second portion of hydroxypropylcellulose dissolved in isopropyl alcohol/dichloromethane mixture.
  • the granules were dried and sized, mixed with the extragranular portion of hydroxypropylcellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
  • Example 5 Gabapentin was mixed with a portion of hydroxypropylcellulose and granulated with remaining portion of hydroxypropylcellulose dissolved in purified water. The granules were dried and sized, mixed with mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
  • Example 6 Gabapentin was mixed with a portion of hydroxypropylmethylcellulose and granulated with remaining portion of hydroxypropylmethylcellulose dissolved in purified water. The granules were dried and sized, mixed with mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
  • Example 7 Gabapentin was mixed with a portion of hydroxypropylmethylcellulose and granulated with remaining portion of hydroxypropylmethylcellulose dissolved in purified water. The granules were dried and sized, mixed with extragranular hydroxypropylmethylcellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
  • Example 8 Gabapentin was mixed with a portion of hydroxypropylcellulose and granulated with the remaining portion of hydroxypropylcellulose dissolved in isopropyl alcohol. The granules were dried, mixed with hydroxypropylmethylcellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
  • Example 9 Gabapentin was mixed with a portion of hydroxypropylcellulose and granulated with second portion of hydroxypropylcellulose dissolved in isopropyl alcohol. The granules were dried and sized, mixed with hydroxypropylmethylcellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
  • Example 10 Gabapentin was mixed with a portion of hydroxypropylcellulose and granulated with second portion of hydroxypropylcellulose dissolved in isopropyl alcohol. The granules were dried and sized, mixed with hydroxypropylmethylcellulose and the extragranular portion of hydroxypropylcellulose, mannitol, copolyvidone, poloxamer, magnesium stearate and talc and compressed to form a tablet.
  • Stability testing The fundamental aims of accelerated stability testing are to ensure that the product will be safe and efficacious when administered to the patient after being subjected to the anticipated stresses of storage, transport and administration.
  • the product should remain free from toxic substances and the content of active ingredients should comply with the label claim until the expiry date.
  • the real time stability testing of a dosage form under normal conditions of storage may stretch for years.
  • the storage of a dosage form under accelerated conditions of temperature and relative humidity provides an approximate idea about the stability of the dosage form in the actual usage.
  • Examples 1, 2 and 8 which contain extragranular hydroxypropyl methylcellulose, were more stable in comparison to the tablets of Examples 6 and 7, which contain intragranular hydroxypropyl methylcellulose.
  • Tablets of Examples 1, 2 and 8 exhibited an initial lactam content of about 0.025 % (w/w), a lactam content of between about 0.25 % to about 0.36 % (w/w) after storage for 14 days at 60°C and 75% RH, an observed lactam content of between about 0.20 % to about 0.25 % (w/w) after storage 3 months at 40 °C and 75 % RH, and a predicted lactam content of between about 0.22 % to about 0.30 % (w/w).
  • the tablets of Examples 6 and 7 exhibited an initial lactam content of between about 0.030 to about 0.040 % (w/w), a lactam content of between about 1.00 % to about 1.47 % (w/w) after storage for 14 days at 60°C and 75% RH, an observed lactam content of between about 0.75 % to about 0.95 % (w/w) after storage 3 months at 40 °C and 75 % RH, and a predicted lactam content of between about 0.73 % to about 1.05 % (w/w). Further, the tablets of Example 3 and 4, which contain intragranular and extragranular hydroxypropylcellulose, were more stable than tablets of Example 5, which contain only intragranular hydroxypropylcellulose.
  • Tablets of Examples 3 and 4 exhibited an initial lactam content of about 0.040 % (w/w), a lactam content of between about 0.17 % to about 0.21 % (w/w) after storage for 14 days at 60°C and 75% RH, an observed lactam content of between about 0.12 % to about 0.16 % (w/w) after storage 3 months at 40 °C and 75 % RH, and a predicted lactam content of between about 0.16 % to about 0.19 % (w/w).
  • Example 5 exhibited an initial lactam content of about 0.040 % (w/w), a lactam content of about 0.74 % (w/w) after storage for 14 days at 60°C and 75% RH, an observed lactam content of about 0.51 % (w/w) after storage 3 months at 40 °C and 75 % RH, and a predicted lactam content of about 0.55 % (w/w).
  • Tablets of Examples 7 exhibited an initial lactam content of about 0.030 % (w/w), a lactam content of about 1.00 % (w/w) after storage for 14 days at 60°C and 75% RH, an observed lactam content of about 0.75 % (w/w) after storage 3 months at 40 °C and 75 % RH, and a predicted lactam content of about 0.73 % (w/w).
  • Example 6 The tablets of Example 6 exhibited an initial lactam content of between about 0.040 % (w/w), a lactam content of about 1.47 % (w/w) after storage for 14 days at 60 °C and 75% RH, an observed lactam content of about 0.94 % (w/w) after storage 3 months at 40 °C and 75 % RH, and a predicted lactam content of about 1.05 % (w/w). While the present invention has been described in te ⁇ ns of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Abstract

L'invention concerne des formes posologiques stables de gabapentine pour usage oral et à libération prolongée, leurs procédés de préparation, et leurs utilisations dans le traitement de l'épilepsie ou de la névralgie post-herpétique.
PCT/IB2005/000093 2004-01-19 2005-01-17 Formes posologiques stables de gabapentine pour usage oral et a liberation prolongee, et procede de preparation associe WO2005077332A2 (fr)

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US8703191B2 (en) * 2006-07-25 2014-04-22 Intelgenx Corp. Controlled-release pharmaceutical tablets
US9717682B2 (en) 2009-12-08 2017-08-01 Intelgenx Corporation Solid oral film dosage forms and methods for making same
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CN106333927A (zh) * 2015-07-08 2017-01-18 昆山龙灯瑞迪制药有限公司 修饰释放的尼麦角林组合物
CN110917164B (zh) * 2019-12-17 2022-03-29 南京康川济医药科技有限公司 一种苯磺酸米洛巴林缓释片及其制备方法

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WO2006077492A1 (fr) * 2005-01-24 2006-07-27 Ranbaxy Laboratories Limited Formes dosifiées orales à libération prolongée de gabapentine
US8703191B2 (en) * 2006-07-25 2014-04-22 Intelgenx Corp. Controlled-release pharmaceutical tablets
US9717682B2 (en) 2009-12-08 2017-08-01 Intelgenx Corporation Solid oral film dosage forms and methods for making same
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