WO2006088864A1 - Compositions à libération contrôlée comprenant du lévétiracétam - Google Patents

Compositions à libération contrôlée comprenant du lévétiracétam Download PDF

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Publication number
WO2006088864A1
WO2006088864A1 PCT/US2006/005167 US2006005167W WO2006088864A1 WO 2006088864 A1 WO2006088864 A1 WO 2006088864A1 US 2006005167 W US2006005167 W US 2006005167W WO 2006088864 A1 WO2006088864 A1 WO 2006088864A1
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levetiracetam
composition according
subsequent
formulation
population
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PCT/US2006/005167
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English (en)
Inventor
Scott Jenkins
Gary Liversidge
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Elan Pharma International Limited
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Priority to US11/568,841 priority Critical patent/US20070298098A1/en
Publication of WO2006088864A1 publication Critical patent/WO2006088864A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to controlled release compositions comprising levetiracetam that are used preferably for the treatment of epilepsy.
  • Levetiracetam is an antiepileptic drug marketed under the registered trademark Keppra® by UCB Pharma, Inc., of Smyrna, Georgia. Levetiracetam is available as 250 mg (blue), 500 mg (yellow) and 750 mg (orange) tablets and as a clear, colorless, grape-flavored liquid (100 mg/mL) for oral administration.
  • Keppra® an antiepileptic drug marketed under the registered trademark Keppra® by UCB Pharma, Inc.
  • Levetiracetam is available as 250 mg (blue), 500 mg (yellow) and 750 mg (orange) tablets and as a clear, colorless, grape-flavored liquid (100 mg/mL) for oral administration.
  • levetiracetam a single enantiomer
  • (-XS)- ⁇ -ethyl-2-oxo-l -pyrrolidine acetamide its molecular formula is CsHi 4 N 2 O 2 and its molecular weight is 170.21.
  • Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs).
  • Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent.)
  • Keppra® tablets contain the labeled amount of levetiracetam.
  • Inactive ingredients in the tablets are colloidal silicon dioxide, corn starch, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol 4000, povidone, talc, titanium dioxide and coloring agents.
  • the individual tablets contain the following coloring agents: 250 mg tablets: FD&C Blue No. 2,
  • Levetiracetam is rapidly and almost completely absorbed after oral administration. Levetiracetam tablets and oral solution are bioequivalent. The pharmokinetics are linear and time-invariant, with low intra- and inter- subject variability. The extent of bioavailability of levetiracetam is not affected by food. Levetiracetam is not protein-bound ( ⁇ 10% bound) and its volume of distribution is close to the volume of intracellular and extracellular water. Sixty-six percent (66%) of the dose is renally excreted unchanged. The major metabolic pathway of levetiracetam (24% of dose) is an enzymatic hydrolysis of the acetamide group. It is not liver cytochrome P450 dependent. The metabolites have no known pharmacological activity and are renally excreted. Plasma half-life of levetiracetam across studies is approximately 6- 8 hours. It is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment.
  • Pertinent patents are United States Patent No. 4,837,223 to Gobert et al., which is for "(S)-Alpha-Ethyl-2-Oxo-l-Pyrrolidineacetamide compositions" and United States Patent No. 4,943,639, also to Gobert et al., which is for "(S)-Alphyl-Ethyl-2-Oxo-l-Pyrrolidineacetamide.” These patents are incorporated by reference herein.
  • Another object of the invention is to provide a controlled release composition which substantially mimics the pharmacological and therapeutic effects produced by the administration of two or more immediate release dosage forms given sequentially.
  • Another object of the present invention is to provide a controlled release composition which substantially reduces or eliminates the development of patient tolerance to the levetiracetam of the composition.
  • Another object of the invention is to provide a controlled release composition in which a first portion of the levetiracetam is released immediately upon administration and a second portion of the levetiracetam is released rapidly after an initial delay period in a bimodal manner.
  • Another object of the present invention is to formulate the dosage in the form of erodable formulations, diffusion controlled formulations or osmotic controlled formulations.
  • Another object of the invention is to provide a controlled release composition capable of releasing the levetiracetam in a bimodal or multi- modal manner in which a first portion of the active is released either immediately or after a delay time to provide a pulse of drug release, and one or more additional portions of the levetiracetam is released, each after a respective lag time, to provide additional pulses of drug release during a period of up to twenty-four hours.
  • Another object of the invention is to provide solid oral dosage forms comprising a controlled release composition of the present invention, comprising levetiracetam.
  • Other objects of the invention include provision of a once daily dosage form of levetiracetam which, in operation, produces a plasma profile substantially similar to the plasma profile produced by the conventional administration of two immediate release dosage forms given sequentially and a method for treatment of epilepsy based on the administration of such a dosage form.
  • the present invention utilizes controlled release delivery of levetiracetam from a solid oral dosage formulation to allow dosage less frequently than before, and preferably once-a-day administration, increasing patient convenience and compliance.
  • the mechanism of controlled release would preferably utilize, but not be limited to, erodable formulations, diffusion controlled formulations and osmotic controlled formulations. A portion of the total dose may be released immediately to allow for rapid onset of effect.
  • the invention would be useful in improving compliance and, therefore, therapeutic outcome for all treatments requiring levetiracetam , including but not limited to, adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy. This approach would replace conventional levetiracetam tablets and solution, which are administered twice a day as adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy.
  • the present invention therefore, relates to a controlled modified release composition for the controlled release of levetiracetam.
  • the present invention relates to a controlled release composition that in operation delivers levetiracetam in a pulsatile manner, preferably during a period of up to twenty-four hours.
  • the present invention further relates to solid oral dosage forms containing a controlled release composition.
  • the above objects are realized by a controlled release composition having a first component comprising a first population of levetiracetam particles and a second component or formulation comprising a second population of levetiracetam particles.
  • the ingredient-containing particles of the second component further comprises a modified release constituent comprising a release coating or release matrix material, or both.
  • the composition in operation delivers the levetiracetam in a pulsatile manner.
  • Preferred controlled release formulations are erodable formulations, diffusion controlled formulations and osmotic controlled formulations. According to the invention, a portion of the total dose may be released immediately to allow for rapid onset of effect, with the remaining portion of the total dose released over an extended time period. The invention would be useful in improving compliance and, therefore, therapeutic outcome for all treatments requiring levetiracetam, including but not limited to, the treatment of epilepsy.
  • the first component includes an immediate release constituent.
  • the modified release coating when applied to the second population of levetiracetam particles, causes a lag time between the release of active from the first population of active levetiracetam containing particles and the release of active from the second population of active levetiracetam containing particles.
  • the modified release matrix material when applied to a second population of active levetiracetam particles, causes a lag time between the release of levetiracetam from the first population of levetiracetam particles and the release of active ingredient from the second population of active ingredient containing particles.
  • the duration of the lag time may be varied by altering the composition and/or the amount of the modified release coating and/or altering the composition and/or amount of modified release matrix material utilized in the composition or formulation.
  • Preferred types of formulations for use in varying the lag time are erodable formulations, diffusion controlled formulations and osmotic controlled formulations.
  • the duration of the lag time can be designed to mimic a desired plasma profile.
  • the subsequent formulations can be in the form of erodable formulations in which the active ingredients and modified release constituent consisting of at least one of modified release coatings and modified release matrix materials would dissolve in water, over time losing their structural integrity.
  • the active ingredients and modified release coatings and/or matrix materials would dissolve after human ingestion over a controlled period of time.
  • the subsequent formulations can be in the form of diffusion controlled formulations which would allow the gradual spread of the subsequent population of particles to scatter or spread out in a liquid medium, are referenced, for example, in United States Patent No. 6,586,006 to Roser et al., which is incorporated by reference herein.
  • Controlled release of the subsequent formulations could be controlled by osmosis.
  • United States Patent No. 6,110,498 to Rudnic et al. for an "osmotic drug delivery system” discloses a system which dispenses a therapeutic agent having limited water solubility in solubilized form.
  • the delivery system comprises a core that is free of swellable polymers and comprises nonswelling solubilizing agents and wicking agents.
  • the solubilized therapeutic agent is delivered through a passageway in the semipermeable coating of the tablet.
  • United States Patent No. 5,814,979 B2 also to Rudnic et al. describes an osmotic pharmaceutical delivery system comprising (a) a semipermeable wall that maintains its integrity during pharmaceutical delivery and which has at least one passage therethrough; (b) a single, homogeneous composition within said wall, which composition consists essentially of (I) a pharmaceutically active agent, (ii) at least one non-swelling solubilizing agent which enhances the solubility of the pharmaceutically active agent; (iii) at least one non-swelling osmotic agent and (iv) a non-swelling wicking agent dispersed throughout the composition which enhances the surface area contact of the pharmaceutical agent with the incoming aqueous fluid.
  • the plasma profile associated with the administration of a drug compound may be described as a "pulsatile profile" in which pulses of high levetiracetam concentration, interspersed with low concentration troughs, are observed.
  • a pulsatile profile containing two peaks may be described as "bimodal.”
  • a composition or a dosage form which produces such a profile upon administration maybe said to exhibit "pulsed release" of the levetiracetam.
  • the controlled release composition of the present invention is particularly useful for administering levetiracetam for which patient tolerance may be problematical.
  • This controlled release composition is, therefore, advantageous for reducing or minimizing the development of patient tolerance to the active ingredient in the composition.
  • the active composition is levetiracetam and the composition in operation delivers the levetiracetam in a bimodal or pulsed manner.
  • Such a composition in operation produces a plasma profile which substantially mimics that obtained by the sequential administration of two IR doses as, for instance, in a typical levetiracetam treatment regime.
  • the present invention also provides solid oral dosage forms comprising a composition according to the invention.
  • the present invention further provides a method of treating a patient suffering from epilepsy utilizing levetiracetam, comprising administering a therapeutically effective amount of a composition or solid oral dosage form according to the invention to provide pulsed or bimodal administration of the levetiracetam.
  • Advantages of the present invention include reducing the dosing frequency required by conventional multiple IR dosage regimes while still maintaining the benefits derived from a pulsatile plasma profile. This reduced dosing frequency is advantageous in terms of patient compliance to have a formulation which may be administered at reduced frequency.
  • the reduction in dosage frequency made possible by utilizing the present invention would contribute to reducing health care costs by reducing the amount of time spent by health care workers on the administration of drugs.
  • pill refers to a state of matter which is characterized by the presence of discrete particles, pellets, beads or granules irrespective of their size, shape or morphology.
  • multiparticulate as used herein means a plurality of discrete, or aggregated, particles, pellets, beads, granules or mixture thereof irrespective of their size, shape or morphology.
  • controlled release as used herein in relation to the composition according to the invention or used in any other context means release of levetiracetam over time and is taken to encompass sustained release and delayed release.
  • time delay refers to the duration of time between administration of the composition and the release of the levetiracetam from a particular component.
  • lag time refers to the time between delivery of active ingredient from one component and the subsequent delivery of levetiracetam from another component.
  • the active ingredient in each component consists of at least levetiracetam, although a second active ingredient may be desirable for combination therapies. Indeed, two or more active ingredients may be incorporated into the same component when the active ingredients are compatible with each other.
  • a drug compound present in one component of the composition may be accompanied by, for example, an enhancer compound or a sensitizer compound in another component of the composition, in order to modify the bioavailability or therapeutic effect of the drug compound.
  • the levetiracetam present in the first and second or subsequent components of the composition may be accompanied by, for example, an enhancer compound or a sensitizer compound in order to modifiy the bioavailability or the therapeutic effect of the levetiracetam.
  • the term “enhancer” refers to a compound which is capable of enhancing the absorption and/or bioavailability of an active ingredient by promoting net transport across the gastro-intestinal tract in an animal, such as a human.
  • Enhancers include but are not limited to medium chain fatty acids; salts, esters, ethers and derivatives thereof, including glycerides and triglycerides; non-ionic surfactants such as those that can be prepared by reacting ethylene oxide with a fatty acid, a fatty alcohol, an alkylphenol or a sorbitan or glycerol fatty acid ester; cytochrome P450 inhibitors, P-glycoprotein inhibitors and the like; and mixtures of two or more of these agents.
  • the proportion of the levetiracetam contained in each component may be the same or different depending on the desired dosing regime.
  • the levetiracetam is present in the first component and in any subsequent component in any amount sufficient to elicit a therapeutic response.
  • the levetiracetam when applicable may be present either in the form of one substantially optically pure enantiomer or as a mixture, racemic or otherwise, of enantiomers.
  • the levetiracetam is preferably present in a composition in an amount of from 0.1-500 mg, preferably in the amount of from 1—100 mg.
  • Levetiracetam is preferably present in the first component in an amount of from 0.5-60 mg. More preferably, the levetiracetam is present in the first component in an amount of from 2.5-30 mg.
  • the levetiracetam is present in the subsequent components in an amount within a similar range to that described for the first component.
  • the time release characteristics for the release of the levetiracetam from each of the components may be varied by modifying the composition of each component, including modifying any of the excipients or coatings which may be present.
  • the release of levetiracetam may be controlled by changing the modified release constituent, including the amount of the modified release coating on the particles, if such a coating is present.
  • the time release profiles may be controlled by making the subsequent components or formulations in the form of erodable formulations, diffusion controlled formulations or osmotic controlled formulations. If more than one modified release constituent is present, the modified release coating for each of the subsequent components may be the same or different.
  • release of the active ingredient maybe controlled by the choice and amount of modified release matrix material utilized.
  • the modified release coating may be present, in each component, in any amount that is sufficient to yield the desired delay time for each particular component.
  • the modified release coating may be present, in each component, in any amount that is sufficient to yield the desired time lag between components.
  • the lag time or delay time for the release of the levetiracetam from each component may also be varied by modifying each of the components, including modifying any excipients and coatings which may be present.
  • the first component may be an immediate release component wherein the levetiracetam is released substantially immediately upon administration.
  • the first component may be, for example, a time-delayed immediate release component in which the levetiracetam is released substantially immediately after a time delay.
  • the second component may be, for example, a time-delayed immediate release component as just described or, alternatively, a time-delayed sustained release or extended release component in which the levetiracetam is released in a controlled fashion for up to twenty-four hours.
  • the exact nature of the plasma concentration curve will be influenced by the combination of all of these factors just described.
  • the lag time between the delivery (and thus also the onset of action) of the levetiracetam in each component may be controlled by varying the levetiracetam and coating (if present) of each of the components.
  • numerous release and plasma profiles may be obtained.
  • the controlled release composition according to the present invention has a first immediate release component and at least one subsequent or modified release component.
  • the immediate release component comprises a first population of active ingredient containing particles and the modified release components or formulations comprise second or subsequent populations of active ingredient containing particles.
  • the second and subsequent modified release components or formulations may comprise a controlled release coating.
  • the second and subsequent modified release components or formulations may comprise a modified release matrix material.
  • administration of such a modified release composition or formulation having, for example, a single modified release component results in characteristic pulsatile plasma concentration levels of the levetiracetam in which the immediate release constituent of the composition gives rise to a first peak in the plasma profile and the modified release constituent gives rise to a second peak in the plasma profile.
  • Embodiments of the invention comprising more than one modified release constituent give rise to further peaks in the plasma profile.
  • Such a plasma profile produced from the administration of a single dosage unit is advantageous when it is desirable to deliver two (or more) pulses of active ingredient without the need for administration of two (or more) dosage units.
  • epilepsy it is particularly useful to have such a bimodal plasma profile.
  • a typical levetiracetam treatment regime consists of administration of two doses of an immediate release dosage formulation given four hours apart. This type of regime has been found to be therapeutically effective and is widely used.
  • the development of patient tolerance is an adverse effect sometimes associated with levetiracetam treatments. It is believed that the trough in the plasma profile between the two peak plasma concentrations is advantageous in reducing the development of patient tolerance by providing a period of wash-out of the levetiracetam. Drug delivery systems which provide zero order or pseudo zero order delivery of the levetiracetam do not facilitate this wash-out process.
  • coating material which modifies the release of the levetiracetam in the desired manner may be used.
  • coating materials suitable for use in the practice of the invention include but are not limited to polymer coating materials, such as cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, ammonio methacrylate copolymers such as those sold under the Trade Mark Eudragit.RTM.
  • poly acrylic acid and poly acrylate and methacrylate copolymers such as those sold under the Trade Mark Eudragite S and L, polyvinyl acetaldietbylamino acetate, hydroxypropyl methylcellulose acetate succinate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch, and cellulose based cross-linked polymers — in which the degree of crosslinking is low so as to facilitate adsorption of water and expansion of the polymer matrix, hydoxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, aminoacryl-methacrylate copolymer (Eudragit.RTM.
  • polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, Polyox.RTM. polyethylene oxides (m. wt. .about.100 k- 5,000 k), AquaKeep.RTM. acrylate polymers, diesters of polyglucan, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glucolate (e.g., Explotab.RTM.; Edward Mandell C.
  • hydrophilic polymers such as polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, polyethylene oxides (e.g., Polyox.RTM., Union Carbide), methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of methacrylic acid or methacrylic acid (e.g., Eudragit.RTM., Rohm and Haas), other acrylic acid derivatives, sorbitan esters, natural gums, water
  • plasticizers include for example acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil; triethyl citrate; polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl
  • modified release matrix materiaP'as used herein includes hydrophilic polymers, hydrophobic polymers and mixtures thereof which are capable of modifying the release of the levetiracetam dispersed therein in vitro or in vivo.
  • Modified release matrix materials suitable for the practice of the present invention include but are not limited to microcrystalline cellulose, sodium carboxymethyl-cellulose, hydoxyalkylcelluloses such as hydroxypropylmethyl- cellulose and hydroxypropylcellulose, polyethylene oxide, alkylcelluloses such as methylcellulose and ethylcellulose, polyethylene glycol, polyvinylpyrrolidone, cellulose acteate, cellulose acetate butyrate, cellulose acteate phthalate, cellulose acteate trimellitate, polyvinylacetate phthalate, polyalkylmethacrylates, polyvinyl acetate and mixtures thereof.
  • a controlled release composition according to the present invention may be incorporated into any suitable dosage form which facilitates release of the active ingredient in a pulsatile manner.
  • the dosage form may be a blend of the different populations of levetiracetam for the treatment of epilepsy containing particles which make up the immediate release and the modified release components, the blend being filled into suitable capsules, such as hard or soft gelatin capsules.
  • suitable capsules such as hard or soft gelatin capsules.
  • the different individual populations of active ingredient containing particles may be compressed (optionally with additional excipients) into mini-tablets which may be subsequently filled into capsules in the appropriate proportions.
  • Another suitable dosage form is that of a multilayer tablet.
  • the first component of the controlled release composition may be compressed into one layer, with the second component or formulation being subsequently added as a second layer of the multilayer tablet.
  • the populations of levetiracetam containing particles making up the composition of the invention may further be included in rapidly dissolving dosage forms such as an effervescent dosage form or a fast-melt dosage form.
  • the composition according to the invention preferably comprises at least two populations of levetiracetam particles which have different in vitro dissolution profiles.
  • the composition of the invention and the solid oral dosage forms containing the composition release the levetiracetam in a manner that substantially all of the levetiracetam contained in the first component is released prior to release of the levetiracetam from the second component.
  • the first component comprises an IR component
  • Release of the levetiracetam from the second component may be delayed as detailed above by the use of a modified release coating and/or a modified release matrix material as part of erodable, diffusion controlled or osmotic controlled formulations.
  • release of the levetiracetam from the second component or formulation is delayed until substantially all of the levetiracetam contained in the first component has been released, and further delayed until at least a portion of the levetiracetam released from the first component has been cleared from the patient's system.
  • release of the levetiracetam from the second component of the composition in operation is substantially, if not completely, delayed for a period of at least about two hours after administration of the composition and is released preferably over the remaining twenty-four hour period after administration.

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Abstract

L'invention concerne une composition à libération contrôlée comprenant du lévétiracétam pour le traitement de l'épilepsie. La composition à libération contrôlée comprend un composant à libération immédiate et un composant ou une formulation à libération modifiée. Le composant à libération immédiate comprend une première partie de lévétiracétam et le composant ou la formulation à libération modifiée comprend de préférence une seconde partie de lévétiracétam et un constituant de libération contrôlée. La formulation à libération modifiée est de préférence sous la forme d'une formulation qui peut s'éroder, d'une formulation à diffusion contrôlée ou d'une formulation osmotique contrôlée. L'association du composant à libération immédiate et du composant ou de la formulation à libération modifiée en fonctionnement délivre l'ingrédient actif d'une manière pulsée ou bimodale.
PCT/US2006/005167 2005-02-16 2006-02-14 Compositions à libération contrôlée comprenant du lévétiracétam WO2006088864A1 (fr)

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Cited By (9)

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WO2009069089A1 (fr) * 2007-11-29 2009-06-04 Ranbaxy Laboratories Limited Composition de lévétiracétam à libération contrôlée de
WO2010025349A1 (fr) * 2008-08-29 2010-03-04 Teva Pharmaceutical Industries Ltd. Composition de lévétiracétam à libération modifiée et procédé de préparation associé
WO2010057870A1 (fr) * 2008-11-18 2010-05-27 Ucb Pharma, S.A. Formules à libération prolongée comprenant un dérivé de 2-oxo-1-pyrrolidine
WO2010057869A1 (fr) * 2008-11-18 2010-05-27 Ucb Pharma, S.A. Formules à libération prolongée comprenant un dérivé de 2-oxo-1-pyrrolidine
EP2277511A1 (fr) 2009-07-22 2011-01-26 Sanovel Ilac Sanayi ve Ticaret A.S. Composition pharmaceutique de levetiracetam à libération prolongée
EP2298290A1 (fr) 2009-09-16 2011-03-23 LEK Pharmaceuticals d.d. Composition de libération contrôlée comprenant du lévétiracetam
WO2011136751A3 (fr) * 2010-04-26 2011-12-29 Mahmut Bilgic Composition pharmaceutique hydrosoluble
WO2023002004A1 (fr) 2021-07-23 2023-01-26 Laboratorios Lesvi, S.L. Composition pharmaceutique multiparticulaire
CN118518805A (zh) * 2024-07-25 2024-08-20 成都诺和晟泰生物科技有限公司 一种左乙拉西坦口服溶液中右乙拉西坦的检测方法

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US6110498A (en) * 1996-10-25 2000-08-29 Shire Laboratories, Inc. Osmotic drug delivery system

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US4837223A (en) * 1984-05-15 1989-06-06 Ucb Societe Anonyme (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide compositions
US6110498A (en) * 1996-10-25 2000-08-29 Shire Laboratories, Inc. Osmotic drug delivery system

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009069089A1 (fr) * 2007-11-29 2009-06-04 Ranbaxy Laboratories Limited Composition de lévétiracétam à libération contrôlée de
WO2010025349A1 (fr) * 2008-08-29 2010-03-04 Teva Pharmaceutical Industries Ltd. Composition de lévétiracétam à libération modifiée et procédé de préparation associé
EA019572B1 (ru) * 2008-11-18 2014-04-30 Юсб Фарма, С.А. Фармацевтические пероральные композиции с пролонгированным высвобождением, включающие производные 2-оксо-1-пирролидина
AU2009317279B2 (en) * 2008-11-18 2013-10-24 Ucb Pharma, S.A. Prolonged release formulations comprising an 2-oxo-1-pyrrolidine derivate
US10172805B2 (en) 2008-11-18 2019-01-08 Ucb Biopharma Sprl Prolonged release formulations comprising an 2-oxo-1-pyrrolidine derivative
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