WO2023002004A1 - Composition pharmaceutique multiparticulaire - Google Patents

Composition pharmaceutique multiparticulaire Download PDF

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Publication number
WO2023002004A1
WO2023002004A1 PCT/EP2022/070585 EP2022070585W WO2023002004A1 WO 2023002004 A1 WO2023002004 A1 WO 2023002004A1 EP 2022070585 W EP2022070585 W EP 2022070585W WO 2023002004 A1 WO2023002004 A1 WO 2023002004A1
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WO
WIPO (PCT)
Prior art keywords
cellulose
mpa
levetiracetam
multiparticulate
mixture
Prior art date
Application number
PCT/EP2022/070585
Other languages
English (en)
Inventor
Devendra Ridhurkar
Carmen ÚBEDA PÉREZ
Ignacio DÍEZ MARTÍN
Original Assignee
Laboratorios Lesvi, S.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratorios Lesvi, S.L. filed Critical Laboratorios Lesvi, S.L.
Priority to MX2024001034A priority Critical patent/MX2024001034A/es
Priority to AU2022315552A priority patent/AU2022315552A1/en
Priority to EP22755145.4A priority patent/EP4373473A1/fr
Priority to CA3226799A priority patent/CA3226799A1/fr
Priority to JP2024504161A priority patent/JP2024524757A/ja
Priority to CN202280056901.5A priority patent/CN118201603A/zh
Publication of WO2023002004A1 publication Critical patent/WO2023002004A1/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
    • A61K9/2022—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • 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
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention provides an oral solid pharmaceutical composition in the form of a multiparticulate composition comprising an immediate release core comprising levetiracetam or a pharmaceutically acceptable salt thereof, coated with a modified release layer, a process for the preparation of the composition of the invention, and its use in therapy.
  • Levetiracetam having the lUPAC chemical name of (S)-2-(2-oxopyrrolidin-1- yl)butanamide , Formula (1), is a medication developed by UCB, for the treatment of epilepsy either as a monotherapy or in combination, sold under the brand name Keppra®.
  • levetiracetam acts through the binding to the synaptic vesicle protein SV2A in the brain.
  • Levetiracetam is rapidly and nearly completely absorbed upon oral administration, with peak plasma concentrations reached after approximately 1 hour, with minimal binding to plasma proteins.
  • Epilepsy is a chronic condition characterized by epileptic seizures, its clinic manifestation, which results from an abnormal, excessive electrical discharge of neurons in the brain.
  • Epileptic seizures can be classified into three categories, focal seizures, generalized seizures and unclassified epileptic seizures, which can present convulsive or non-convulsive manifestations, and consciousness can be impaired (totally or partially).
  • epilepsy requires in many patients medication for life.
  • a single-dose regimen is advantageous to increase patient compliance as well as keeping a steady level of medication in the body, thereby avoiding undesired fluctuations in medication levels.
  • levetiracetam The standard initial posology for levetiracetam is 500 mg twice daily, which upon tolerance and clinical response can be increased up to 1500 mg twice daily. In Europe it is available in the form of tablets (in different strengths), as a solution for infusion, and oral solution. An extended-release formulation of levetiracetam, is not available in Europe, despite being available in the USA as Keppra® XR.
  • Keppra XR is available in 500 mg and 750 mg strengths, in the form of film-coated tablets, wherein the tablet core is a matrix tablet comprising a hydrophilic rate controlling polymer, such as high viscosity hypromellose.
  • these tablets do not allow an easy fractioning of the dose as they should not be broken or crushed, and their size may present an issue for patient’s compliance, for instance in the paediatric population.
  • the bitter taste of levetiracetam may be experienced due to the faint odor and bitter taste of levetiracetam active drug itself.
  • Document W02006/088864 A1 discloses a controlled-release composition comprising levetiracetam capable of producing a plasma profile similar to the plasma profile produced by administering two or more levetiracetam dosage forms sequentially. However, no experimental results, or examples are provided in this document.
  • a levetiracetam controlled release formulation in the form of coated tablets is disclosed.
  • examples of tablets according to the disclosure are provided, wherein can be seen that high dose tablets, for instance 1000 mg, result in large tablets, which can be a hindrance to patient compliance, especially in the paediatric population.
  • compositions having, simultaneously, rapid and long- acting properties by comprising a sustained-release part coated with a hydrophobic polymer comprising a first active ingredient, and an immediate release part comprising a second active ingredient.
  • a controlled-release formulation wherein the core comprises an active ingredient, such as levetiracetam and a wax excipient, many of which require specific handling and/or process conditions due to their physical properties, i.e. melting point.
  • WO 2011/107855 A2 refers to a taste masked sustained release oral liquid suspension dosage form comprising a) inert pellets, surrounded by seal coating, b) drug layer surrounding the seal coated inert pellets comprising pharmaceutically active ingredient with one or more pharmaceutically acceptable excipient, and c) coating layer surrounding the drug layer comprising rate controlling polymer, wherein the sustained release pellets are suspended with viscosity modifying agent or suspending agent or thickening agent or suspension stabilizers in addition to other pharmaceutically acceptable excipients in a suspending media at a suitable pH which is maintained with or without buffer.
  • compositions comprising levetiracetam which can improve patient’s compliance with the therapeutic regime, due to their facile administration and easy posology adequation, together with an easy administration schedule (such as a once-a-day administration), while maintaining therapeutic levels of levetiracetam in the patients.
  • the present inventors have developed a multiparticulate composition
  • a multiparticulate composition comprising immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof, wherein said cores are coated with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose wherein hydroxypropylmethyl cellulose has a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, which is suitable for a once-daily therapeutic regime.
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) at least 50% of the immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s.
  • a second aspect of the present invention provides a process for preparing the solid pharmaceutical composition according to the first aspect.
  • the third aspect of the present invention refers to the multiparticulate composition according to the first aspect for use in the treatment of epilepsy.
  • Fig. 1 is a graph showing mean plasma concentrations of a composition according to example 1 compared to reference treatment with Keppra®.
  • - Fig. 2 is a graph showing mean plasma concentrations of a composition according to example 4 compared to reference treatment with Keppra®.
  • - Fig. 3 is a graph showing mean plasma concentrations of a composition according to example 5 compared to reference treatment with Keppra®.
  • - Fig. 4 is a graph showing mean plasma concentrations of a composition according to example 6 compared to reference treatment with Keppra®.
  • Fig. 5 is a graph showing mean plasma concentrations of a composition according to example 1 compared to reference treatment with Keppra®.
  • - Fig.6 is a photograph of the mini-tablets obtained as in examples 1 to 6.
  • the term "about” as used herein refers to a statistically meaningful range of a value, typically within 10%. Such a range can lie within experimental error, typical of standard methods used for the measurement and/or determination of a given value or range. In one embodiment, the range is within 5% of the indicated value. In another embodiment, the range is within 1 % of the indicated value. In yet another embodiment, the range is within 0.5% of the indicated value.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of animals, in particular human beings, without excessive toxicity, irritation, allergic response, or other problematic complications commensurate with a reasonable benefit/risk ratio.
  • treating includes the amelioration, cure, and/or maintenance of a cure (i.e., the prevention or delay of relapse) of a disease or disorder.
  • T reatment after a disorder has started aims to reduce, alleviate, ameliorate or altogether eliminate the disorder, and/or its associated symptoms, to prevent it from becoming worse, to slow the rate of progression, or to prevent the disorder from re-occurring once it has been initially eliminated (i.e., to prevent a relapse).
  • extended release refers to a dosage form that is deliberately modified to protract the release rate of the drug substance compared to that observed for an immediate-release dosage form.
  • the release pattern in an extended-release dosage may begin with a burst effect that mimics an immediate release, followed by a slower release of the remaining drug substance in the dosage form.
  • immediate release refers to a pharmaceutical formulation which, in water at 25 °C using the paddle test (50 rpm), releases at least 80% of the active pharmaceutical ingredient within 30 minutes.
  • multiparticulate pharmaceutical composition refers to a pharmaceutical composition in the form of multiple solid units, such as, pellets, mini tablets, granules, and/or mixtures thereof.
  • pellet or “pellets” as used herein refers to free-flowing, substantially spherical particulates having a size from 90 micrometres to 2000 micrometres and which are, preferably manufactured by the agglomeration of fine powders or granules.
  • mini-tablet and “mini-tablets” refers to a solid pharmaceutical dosage form with a diameter of typically ⁇ 3 mm, preferably a diameter of less or equal to 3 mm, more preferably a diameter of less or equal to 2.5 mm, even more preferably a diameter between about 2.0 to at least 1.0 mm, manufactured by compression, which can be manufactured in a conventional tableting machine adapted to small size tablet pressing.
  • the mini-tablets may be compressed in any common tablet shape selected from flat round, biconvex round, oval convex and cylindrical, preferably in a biconvex round shape. The shape of said mini-tablets is depicted in Figure 6.
  • mini-tablet and “mini tablets” refers to a solid form manufactured by compression which has a surface area of less than 20 mm 2 , preferably from 16 to 18 mm 2 , more preferably from 12 to 15 mm 2 and has a volume of less than 10 mm 3 , preferably from 7 to 10 mm 3 , more preferably from 4 to 6 mm 3 .
  • granule and “granules” as used herein refers to a solid pharmaceutical dose form, of irregular shape, comprising powder particles that have been aggregated to form larger particles sufficiently robust to withstand handling.
  • coating refers to adherence, and/or adsorption, preferable uniformly, of at least one solution, dispersion or suspension coating material onto a substrate.
  • the coating material on the substrate may be of any thickness.
  • the coating material is a thin and uniform film applied onto the substrate.
  • a thin and uniform film can be of the type of a "film coating” or/and an “isolating film coating” or/and an “external film coating”.
  • curing refers to the process of physical or chemical hardening by any method, such as cooling, and/or drying.
  • the physical hardening of the coating mixture (film coating) applied to the immediate release cores of the multiparticulate pharmaceutical composition of the invention is not limited.
  • pharmaceutically acceptable salt refers to the relatively non toxic, inorganic and organic acid or base addition salts of a compound. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base/acid form with a suitable organic or inorganic acid/base and isolating the salt thus formed.
  • bioequivalence refers to a pharmaceutical product which is pharmaceutically equivalent or pharmaceutical alternative to another pharmaceutical product(s), and their bioavailabilities, in terms of rate (Cmax and tmax) and extent of absorption (area under the curve), after administration of the same molar dose under the same conditions, are similar to such a degree that their effects can be expected to be essentially the same. This is considered to be demonstrated if the 90% confidence intervals of the ratios between the AUCo- t and C max , between the products being compared is in the range of 80-125%.
  • the inventors of the present invention have surprisingly found that coating immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s allows the preparation of an oral solid pharmaceutical composition having a modified release suitable for a once-daily dose regimen.
  • compositions according to the invention allow the maintenance of a plasmatic concentration of levetiracetam in a once-daily dose regime identical to that achieved with the currently recommended twice-daily dosage for levetiracetam with Keppra®. Furthermore, the compositions of the invention show resistance to dose dumping when exposed to ethanol.
  • the first aspect of the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) at least about 50% of the immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s.
  • the immediate release core is solid.
  • the pharmaceutical compositions of the present invention do not comprise wax excipients. More specifically, they do not comprise any excipient selected from the group consisting of camauba wax, vegetable wax, fruit wax, microcrystalline wax (“petroleum wax”), bees wax (white or bleached, and yellow), hydrocarbon wax, paraffin wax, cetyl esters wax, non-ionic emulsifying wax, anionic emulsifying wax, candelilla wax, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or cetostearyl alcohol), hydrogenated vegetable oil, hydrogenated castor oil, fatty acids such as stearic acid, fatty acid esters including fatty acid glycerides (mono-, di-, and tri-glycerides), polyethylene glycol (PEG) having a molecular weight of greater than about 3000 number average molecular weight, Mn (e.g., PEG 3350, PEG 4000, PEG 4600,
  • PEG polyethylene
  • the hydroxypropylmethyl cellulose has a viscosity comprised between 80 mPa-s to 120 mPa-s, preferably about 100 mPa-s.
  • the ethyl cellulose has a viscosity comprised between 400 mPa-s and 1500 mPa-s.
  • the coating mixture is used in an amount comprised between 9 and 14 g of coating solution (expressed as dry matter) per 100 g of immediate release core.
  • the immediate release cores comprise levetiracetam or a pharmaceutically acceptable salt, solvate, hydrate, crystalline form, or non-crystalline form thereof, preferably the immediate release cores comprise crystalline levetiracetam
  • the final dosage form prepared for administration to a patient comprises the multiparticulate composition of the invention which is composed of various particles, preferably mini-tablets, comprising levetiracetam which may be present in the final dosage form in an amount of between 250 mg to about 3000 mg.
  • the levetiracetam may be present in the final dosage form in an amount of any of about 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000,
  • the levetiracetam may be present in the final dosage form in an amount of about 1000 mg. In one embodiment, the levetiracetam may be present in the final dosage form in an amount of about 1500 mg. In one embodiment, the levetiracetam may be present in the final dosage form in an amount of about 2000 mg. In one embodiment, the levetiracetam may be present in the final dosage form in an amount of about 3000 mg.
  • the plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof of the present invention, preferably in the form of mini-tablets, show good chemical and mechanical properties such as good uniformity, friability, hardness (resistant to crushing), and disintegration time suitable for successful coating application.
  • the dosage forms comprise the multiparticulate composition of the invention, preferably in the form of mini-tablets, so that said dosage forms comprise several mini-tablets and the total amount of levetiracetam in the dosage from will be of about 1000 mg, 1500 mg, 2000 mg, or 3000 mg of levetiracetam.
  • levetiracetam is in the form of dosage forms comprising several coated mini-tablets it is possible to dose high amounts of levetiracetam such as of about 1000 mg, 1500 mg, 2000 mg, or 3000 mg by oral administration to a patient without the patient noticing the bitter taste, undesirable taste of levetiracetam and, avoiding the need to add sweeteners or flavoring agents to the composition to mask the bitter or unpleasant taste of the drug.
  • At least about 55% of the immediate release cores are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, preferably about at least 60%, more preferably about at least 65%, more preferably about at least 70%, more preferably about at least, more preferably about at least 75%, more preferably about at least 80%, more preferably about at least 85%, more preferably about at least 90%, more preferably about at least 95%, more preferably about at least 99%, even more preferably all (100%) immediate release cores are coated.
  • the coating layer represents from about 5% to about 20% weight of the total weight of the composition, preferably from about 7% to about 15%, more preferably from about 8% to about 13%, more preferably from about 9% to about 12%, most preferably about 11.5% by weight of the total weight of the composition.
  • the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is comprised between about 4:1 to about 20:1, preferably from about 5:1 to about 18:1, more preferably from about 8:1 to about 15:1, even more preferably from about 11:1 to about 15:1, and even more preferably about 12.5:1.
  • ethyl cellulose is available in various forms, and under different brand names, such as AqualonTM, Aquacoat®, EthocelTM, Surelease®.
  • the ethyl cellulose for the compositions of the invention is an aqueous dispersion of ethyl cellulose, such as Surelease® E-7-19029, Surelease® E-7-19030, Surelease®E-7-19040, preferably Surelease®E-7-19040 (which is an 25% w/w aqueous dispersion of ethyl cellulose, comprising medium chain triglycerides, oleic acid, and ammonium hydroxide).
  • Surelease® ethyl celluloses allow obtaining a pH independent drug release.
  • hydroxypropylmethyl cellulose has a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s.
  • the hydroxypropylmethyl cellulose has a viscosity comprised between about 5 mPa-s to about 400 mPa-s, more preferably comprised between about 50 mPa-s to about 250 mPa-s, even more preferably comprised between about 70 mPa-s to about 200 mPa-s, most preferably comprised between about 80 mPa-s to about 120 mPa-s.
  • the viscosity values shown correspond to the measured viscosity of a 2% w/w aqueous solution of hydroxypropylmethyl cellulose at 20 °C, measured according to USP method.
  • the preferred hydroxypropylmethyl cellulose are selected from the group consisting of cellulose ethers graded as E5LV, E15LV, E50LV, and K100LV, preferably K100 LV, commercially available as MethocelTM (from Dow Chemicals), or BenecelTM (from Ashland).
  • the hydroxypropylmethyl cellulose has a viscosity comprised between about 80 mPa-s to about 120 mPa-s in a 2% w/w aqueous solution at 20 °C (measured according to USP method).
  • the coating mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s further comprises I) plasticizers selected from the group comprising medium chain triglycerides, oleic acid, ethylene glycol, glycol, 1,2-butylene glycol, 2,3- butylene glycol, styrene glycol, diethylene glycol, triethyleneglycol, tetraethylene glycol 20, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, acetyl tributyl cit
  • medium chain triglyceride refers to triesters of glycerol and C6-C12 fatty acids, examples of said fatty acids being caproic acid (Ob), caprylic acid (Cs), capric acid (C10) and lauric acid (C12).
  • the three fatty acid residues of the MCT can be the same or different, preferably there are two different fatty acid residues.
  • Preferred medium chain triglycerides are caprylic/capric acid triglyceride (marketed as Stelliesters ® MCT 65/35, Estasan ® , Crodamol ® GTC/C, Miglyol ® 812 or 810, and Neobee ® M5).
  • the coating mixture does not comprise sodium lauryl sulfate.
  • the multiparticulate composition of the invention can be in the form of mini-tablets, pellets, granules, and/or mixtures thereof, preferably mini-tablets.
  • the mini-tablets, pellets, granules, and/or mixtures thereof can be used to fill capsules or sachets and stick-packs, preferably sachets, more suitable for packaging relatively large numbers of mini-tablets since have larger fill volumes compared to stick-packs.
  • the immediate release cores of the multiparticulate pharmaceutical composition are solid immediate release cores, preferably in the form of mini-tablets.
  • the multiparticulate composition of the present invention may comprise further pharmaceutically acceptable excipients. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, sweetening agent, colouring agent, flavouring agent, or plasticizers.
  • the multiparticulate composition does neither contain lactose nor gluten.
  • the percentage in weight of levetiracetam or a pharmaceutically acceptable salt thereof in the composition of the invention is from about 60% to about 90% by weight, preferably from about 70% to about 80% by weight, more preferably about 73% to 78% by weight of the total weight of the composition.
  • the percentage in weight of levetiracetam in the composition of the invention is from about 60% to about 90% by weight, preferably from about 70% to about 80% by weight, more preferably about 73% to 78% by weight of the total weight of the composition.
  • the immediate release cores comprising levetiracetam further comprise one or more excipients selected from the group consisting of diluents, binders, glidants, and lubricants.
  • the immediate release cores further comprise a diluent selected from the group consisting of cellulose derivatives, such as cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose; natural starches, such as maize starch and potato starch; pregelatinized starch and mixtures thereof, preferably, the diluent is a cellulose derivate selected from methyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose; pregelatinized starch and/or mixtures thereof; more preferably, the diluent is microcrystalline cellulose.
  • a diluent can be present in an amount from about 4% to about 15% by weight, preferably from about 7% to about 12% by weight, more preferably from about 8% to about 10% by weight of the total weight of the composition.
  • the immediate release cores further comprise a binder selected from the group consisting of povidone, copovidone, polyethylene glycol, gelatin, polyethylene oxide, alginic acid, modified corn starch, and/or mixtures thereof, preferably the binder is selected from povidone, copovidone and/or mixtures thereof; more preferably the binder is copovidone.
  • a binder can be present in an amount from about 0.5% to about 5% by weight, preferably from about 1% to about 3% by weight, even more preferably from about 1.5% to about 2% by weight of the total weight of the composition.
  • the immediate release cores further comprise a glidant selected from the group consisting of calcium silicate, magnesium silicate, corn starch, colloidal silicon dioxide, silicon hydrogel, talc, colloidal silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, mineral oil, and/or mixtures thereof, preferably talc.
  • a glidant can be present in an amount from about 0.5% to about 5% by weight, preferably from about 1 % to 3% by weight, more preferably about 2% by weight of the total weight of the composition.
  • the immediate release cores further comprise a lubricant selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate glyceryl behenate, mineral oil, stearic acid, and/or mixtures thereof; preferably selected from magnesium stearate, calcium stearate, zinc stearate and/or mixtures thereof; more preferably magnesium stearate.
  • a lubricant can be present in an amount from about 0.1% to about 2% by weight, preferably from about 0.3% to about 1.5% by weight, more preferably from about 0.5% to about 1.0% by weight, even more preferably about 0.5% by weight of the total weight of the composition.
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) at least about 50%, preferably about at least about 60%, more preferably about at least 65%, more preferably about at least 70%, more preferably about at least 75%, more preferably about at least 80%, more preferably about at least about 85%, more preferably about at least about 90%, more preferably about at least about 95%, more preferably about at least about 99%, even more preferably all (100%) of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) at least about 50%, preferably about at least about 60%, more preferably about at least 65%, more preferably about at least 70%, more preferably about at least 75%, more preferably about at least 80%, more preferably about at least about 85%, more preferably about at least about 90%, more preferably about at least about 95%, more preferably about at least about 99%, even more preferably all (100%) of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) at least about 50% preferably about at least about 60%, more preferably about at least 65%, more preferably about at least 70%, more preferably about at least 75%, more preferably about at least 80%, more preferably about at least 85%, more preferably about at least 90%, more preferably about at least 95%, more preferably about at least 99%, even more preferably all (100%) of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) at least about 90% of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropyl methyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is comprised between about 4:1 to about 20:1, preferably from about 5:1 to about 18:1, more preferably from about 8: 1 to about 15:1, more preferably from about 11:1 to about 15:1, and even more preferably about 12.5:1.
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) at least about 90% of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s in the coating mixture is about 12.5:1.
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) all the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is comprised between about 4:1 to about 20: 1 , preferably from about 5: 1 to about 18:1, more preferably from about 8: 1 to about 15:1, more preferably from about 11 : 1 to about 15:1, and even more preferably about 12.5:1.
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) all the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is about 12.5:1.
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) at least 50%, preferably about at least 60%, more preferably about at least 65%, more preferably about at least 70%, more preferably about at least, more preferably about at least 75%, more preferably about at least 80%, more preferably about at least 85%, more preferably about at least 90%, more preferably about at least 95%, more preferably about at least 99%, even more preferably all (100%) of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) at least 50%, preferably about at least 60%, more preferably about at least 65%, more preferably about at least 70%, more preferably about at least, more preferably about at least 75%, more preferably about at least 80%, more preferably about at least 85%, more preferably about at least 90%, more preferably about at least 95%, more preferably about at least 99%, even more preferably all (100%) of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) at least 90% of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is comprised between about 4:1 to about 20:1, preferably from about 5:1 to about 18:1, more preferably from about 8: 1 to about 15:1, more preferably from about 11 : 1 to about 15:1, even more preferably about 12.5:1; wherein the coating mixture further comprises I) plasticizers selected from
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) all the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is comprised between about 4:1 to about 20: 1 , preferably from about 5: 1 to about 18:1, more preferably from about 8: 1 to about 15:1, more preferably from about 11:1 to about 15:1, even more preferably about 12.5:1; wherein the coating mixture further comprises I) plasticizers selected
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) at least 90% of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is comprised between about 8:1 to about 15:1, more preferably from about 11:1 to about 15:1; wherein the coating mixture further comprises I) plasticizers selected from medium chain triglycerides, oleic acid and/or mixtures thereof; and II) stabilizers selected from ammonium hydro
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) at least 90% of the immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is about 12.5:1; wherein the coating mixture further comprises I) plasticizers selected from medium chain triglycerides, oleic acid and/or mixtures thereof; and II) stabilizers selected from ammonium hydroxide; wherein the coating layer represents from about 5% to about 20% weight of
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) all the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is comprised between about 8:1 to about 15:1, more preferably from about 11:1 to about 15:1; wherein the coating mixture further comprises I) plasticizers selected from medium chain triglycerides, oleic acid and/or mixtures thereof; and II) stabilizers selected from ammonium hydro
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein b) all the immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is about 12.5:1; wherein the coating mixture further comprises I) plasticizers selected from medium chain triglycerides, oleic acid and/or mixtures thereof; and II) stabilizers selected from ammonium hydroxide; wherein the coating layer represents from about 5% to about 20% weight of the total weight
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof, and optionally one or more excipients selected from diluents, binders, glidants, lubricants; wherein b) at least about 90% of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is comprised between about 8:1 to about 15:1, more preferably from about 11:1 to about 15:1.
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof, and optionally one or more excipients selected from diluents, binders, glidants, lubricants; wherein b) at least about 90% of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s in the coating mixture is about 12.5.
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof, and optionally one or more excipients selected from diluents, binders, glidants, lubricants; wherein b) at least about 90% of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropyl methyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is comprised between about 8:1 to about 15:1, more preferably from about 11:1 to about 15:1; wherein the coating layer represents from about 5% to
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof, and optionally one or more excipients selected from diluents, binders, glidants, lubricants; wherein b) at least about 90% of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropyl methyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s in the coating mixture is about 12.5:1; wherein the coating layer represents from about 5% to about 20% weight of the total weight of the composition, preferably from about 7%
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof, and optionally one or more excipients selected from diluents, binders, glidants, lubricants; wherein b) all the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is comprised between about 8:1 to about 15:1, more preferably from about 11:1 to about 15:1; wherein the coating layer represents from about 5% to about 20% weight
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof, and optionally one or more excipients selected from diluents, binders, glidants, lubricants; wherein b) all the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is about 12.5:1; wherein the coating layer represents from about 5% to about 20% weight of the total weight of the composition, preferably from about 7% to about 15%, more
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof, and optionally one or more excipients selected from diluents, binders, glidants, lubricants; wherein b) all the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is comprised between about 8:1 to about 15:1 s more preferably from about 11:1 to about 15:1; wherein the coating mixture further comprises I) plasticizers
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof, and optionally one or more excipients selected from diluents, binders, glidants, lubricants; wherein b) all the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s in the coating mixture is about 12.5:1; wherein the coating mixture further comprises I) plasticizers selected from medium chain triglycerides, oleic acid and/or mixtures thereof
  • the optional one or more excipients are present, and the diluent is microcrystalline cellulose, the binder is copovidone, the glidant is talc, and the lubricant is magnesium stearate.
  • the present invention refers to a multiparticulate pharmaceutical composition
  • a multiparticulate pharmaceutical composition comprising: a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof, and one or more excipients selected from diluents, binders, glidants, and lubricants; wherein b) at least about 90% of the individual immediate release cores, preferably all (100%) of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose in the coating mixture is comprised between about 4:1 to about 20:1, preferably from about 5:1 to about 18:1, more preferably from about 8:1 to about 15:1, more preferably from about 11:1 to about 15:1, and even
  • the present invention relates to a process for the preparation of the multiparticulate composition of the first aspect, comprising: i) providing levetiracetam or a pharmaceutically acceptable salt thereof ii) optionally, mixing levetiracetam or a pharmaceutically acceptable salt thereof with a diluent from about 1 min to about 10 min, preferably from about 2 min to about 7 min, more preferably for about 5 min; iii) optionally, granulating the mixture resulting from step ii) with a solution comprising a binder; iv) optionally, drying the product resulting from step i) or from steps ii) and iii) when these steps are present, preferably at a temperature from about 55 °C to 70 °C, preferably from about 60 °C to about 65 °C, more preferably about 60 °C; v) optionally, mixing the product resulting from step i) or from steps ii), iii) and iv) when these steps are present, preferably at
  • the process comprises: i) providing levetiracetam or a pharmaceutically acceptable salt thereof ii) optionally, mixing levetiracetam or a pharmaceutically acceptable salt thereof with a diluent for about 5 min; iii) optionally, granulating the mixture resulting from step ii) with a solution comprising a binder; iv) optionally, drying the product resulting from step i) or from steps ii) and iii) when these steps are present, at a temperature from about 60 °C to about 65 °C; v) optionally, mixing the product resulting from step i) or from steps ii), iii) and iv) when these steps are present, with a glidant, from about 10 min to about 20 min; vi) optionally, mixing the product resulting from step i) or from steps ii), ii), iv) or v) when these steps are present, with a lubricant for about 5
  • the process comprises: i) providing levetiracetam or a pharmaceutically acceptable salt thereof; ii) mixing levetiracetam or a pharmaceutically acceptable salt thereof and a diluent for about 5 min; iii) granulating the product resulting from step i) with a solution comprising a binder; iv) drying the product resulting from step ii) at a temperature of about 60 °C; v) mixing the product resulting from step iii) with a glidant for about 15 min; vi) mixing the product resulting from step iv), with a lubricant for about 5 min; vii) compressing the product resulting from step v); viii) coating the product from step vi) with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s; ix) curing the product of step
  • the coating layer represents from about 5% to about 20% by weight of the total weight of the composition, preferably from about 7% to about 15%, more preferably from about 8% to about 13%, more preferably from about 9% to about 12%, most preferably about 11.5% by weight of the total weight of the composition.
  • the process comprises: i) providing levetiracetam or a pharmaceutically acceptable salt thereof; ii) optionally, mixing levetiracetam or a pharmaceutically acceptable salt thereof with a diluent from about 2 min to about 7 min; iii) optionally, granulating the mixture resulting from step ii) with a solution comprising a binder; iv) optionally, drying the product resulting from step i) or from steps ii) and iii) when these steps are present, at a temperature from about 60 °C to about 65 °C; v) optionally, mixing the product resulting from step i) or from steps ii), iii) and iv) when these steps are present with a glidant, from about 10 min to about 20 min; vi) optionally, mixing the product resulting from step i) or from steps ii), ii), iv) or v) when these steps are present, with a lub
  • the process comprises: i) providing levetiracetam or a pharmaceutically acceptable salt thereof ii) optionally, mixing levetiracetam or a pharmaceutically acceptable salt thereof with a diluent for about 5min; iii) optionally, granulating the mixture resulting from step ii) with a solution comprising a binder; iv) optionally, drying the product resulting from step i) or from steps ii) and iii) when these steps are present, at a temperature of about 60°C; v) optionally, mixing the product resulting from step i) or from steps ii), iii) and iv) when these steps are present with a glidant, for about 15 min; vi) optionally, mixing the product resulting from step i) or from steps ii), ii), iv) or v) when these steps are present, with a lubricant for about 5 min; vii) optionally, compressing the
  • steps viii) and ix) are not carried out.
  • steps ii), iii), iv), v), vi) and vii) are carried out (i.e. are present).
  • steps ii) to ix) are carried out (i.e. are present).
  • the diluent of step ii) is selected from cellulose derivatives, such as cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose; natural starches, such as maize starch and potato starch; pregelatinized starch and mixtures thereof, preferably, the diluent is a cellulose derivate selected from methyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose; pregelatinized starch and/or mixtures thereof; preferably microcrystalline cellulose.
  • cellulose derivatives such as cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose
  • natural starches such as maize starch and potato starch
  • pregelatinized starch and mixtures thereof preferably, the diluent is a cellulose derivate selected from methyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose; pregelatinized starch and/or mixtures thereof
  • the binder of step iii) is selected from povidone, copovidone, polyethylene glycol, gelatin, polyethylene oxide, alginic acid, modified corn starch, and/or mixtures thereof, preferably povidone, copovidone and/or mixtures thereof; preferably copovidone.
  • the glidant of step v) is selected from calcium silicate, magnesium silicate, corn starch, colloidal silicon dioxide, silicon hydrogel, talc, colloidal silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, mineral oil, and/or mixtures thereof, preferably talc.
  • the lubricant of step vi) is selected from magnesium stearate, calcium stearate, zinc stearate glyceryl behenate, mineral oil, stearic acid, and/or mixtures thereof; preferably selected from magnesium stearate, calcium stearate, zinc stearate and/or mixtures thereof; more preferably magnesium stearate.
  • the binder is copovidone
  • the diluent is microcrystalline cellulose
  • the glidant is talc
  • the lubricant is magnesium stearate
  • the hydroxypropyl methyl cellulose has a viscosity comprised between about 80 mPa-s to about 120 mPa-s in a 2% w/w aqueous solution at 20 °C (measured according to USP method).
  • the coating mixture of step vii) comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1 ,000 mPa-s, further comprises I) plasticizers selected from the group comprising medium chain triglycerides, oleic acid ethylene glycol, glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol 20, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, di butyl sebacate, acetyltributylcitrate, triethyl citrate,
  • plasticizers selected from
  • the coating mixture of step vii) comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, further comprises I) plasticizers selected from the group comprising medium chain triglycerides, oleic acid, and or mixtures thereof; and II) stabilizers selected from ammonium hydroxide.
  • the coating mixture of step viii) may be applied by a perforated pan coating process or a fluid-bed coating process, preferably by a fluid-bed coating process commonly used technique for coating of small particles.
  • the multiparticulate composition is in the form of mini-tablets.
  • the third aspect of the present invention refers to the multiparticulate composition according to the first aspect for use in the treatment of epilepsy.
  • the composition according to the first aspect is for use in the treatment of epilepsy in a once-a-day administration regime.
  • the multiparticulate composition of the present invention comprises dosage strengths of levetiracetam of about 1000 mg, 1500 mg, 2000 mg, or 3000 mg for once-a-day administration to treat epilepsy.
  • the sample is placed in a basket, and then stirred at 100 rpm for 2 hours in 750 mL of HCI 0.1 N, followed by 2 hours in 900 mL of pH 4.5 acetate buffer, and finally for 8 hours in 900 mL pH 6.8, or pH 6.0 phosphate buffer. Alternatively, the last stage can be carried out until complete dissolution.
  • Phosphate buffer pH 6.0 preparation ⁇ . Dissolve 6.8 g of potassium dihydrogen phosphate and 0.2 g of sodium hydroxide in 1000 ml_ of deionized water. If necessary, adjust with 1 N sodium hydroxide to a pH 6.0.
  • Phosphate buffer pH 6.8 preparation Dissolve 6.8 g of potassium dihydrogen phosphate, and 0.896 g of sodium hydroxide in 900 ml_ of deionized water. If necessary, adjust to pH 6.8 with phosphoric acid, or sodium hydroxide.
  • Alcohol dose-dumping assay The sample is placed in a basket, and then stirred at 100 rpm in 750 ml_ of HCI 0.1 N or 900 ml_ phosphate buffer pH 6.0, in the presence of the corresponding ethanol % (v/v), and samples are taken every 15 minutes.
  • HPLC High Performance Liquid Chromatography
  • HPLC system Agilent 1260 Infinity II, equipped with pump, a diode-array detector, and an auto-sampler.
  • Buffer solution pH 5.5 Dissolve 0.26 g of potassium dihydrogen phosphate in 1000 mL of water. Adjust with 0.1 M potassium hydroxide to a pH 5.5. Filter through 0.45 pm filter.
  • Test solution Take a minimum of 5 sachets, weight and calculate the average weight. Grind the mini-tablets to a fine and homogeneous powder. Prepare a solution of the powder in solvent at a concentration of about 0.15 mg/mL of levetiracetam. Stir 30 minutes. Centrifuge.
  • Ethyl cellulose, medium chain triglycerides, oleic acid, ammonium hydroxide and water are added in the form of the commercial product Surelease ® E-7-19040 which is an aqueous dispersion of ethyl cellulose 25% w/w (solids content), comprising medium chain triglycerides, oleic acid and ammonium hydroxide.
  • MethocelTM K100LV was used having a viscosity of 80 mPa-s to about 120 mPa-s in a 2% w/w aqueous solution at 20 °C (measured according to USP method). All examples were prepared in the form of mini-tablets wherein the uncoated cores, weigh 5 mg. For Ex. 6, 10% of the mini-tablet cores, were left uncoated, thereby being a combination of 90% coated mini-tablets and 10% uncoated mini-tablets. The resulting mini-tablets have a biconvex round shape.
  • the mini-tablets were prepared as follows: i) microcrystalline cellulose PH 101 and levetiracetam were sifted through sieve 0.8 mm; ii) microcrystalline cellulose PH 101 and levetiracetam were mixed in high shear granulator for 5 min; iii) copovidone was dissolved in purified water while stirring with propeller stirrer; iv) the mixture resulting from step ii) was granulated in a high shear granulator using copovidone solution resulting from step iii); v) the granules resulting from step iv) were dried in fluid bed dryer at a temperature of about 60 °C - 65 °C; vi) the dried granules resulting from step v) were sifted using screening mill through a stainless-steel sieve of 0.8 mm; vii) talc was added to the granules resulting from step vi) in container mixer for 15 minutes; viii) magnesium
  • the white or off-white round biconvex functional coated mini-tablets of 2 mm of diameter obtained as in examples 1 to 6 showed a bulk density of 0.71-0.75 g/ml and an apparent volume of 1.33 to 1.41 ml/g.
  • the apparent volume was calculated considering the bulk density of mini-tablets (i.e. the unit in ml per 1 g of mini-tablets).
  • Ex.2 containing guar gum instead of hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s shows a pH-dependent release of levetiracetam, whereas Ex.1 and 3 show a non-pH dependent liberation profile, in line with the dissolution profile observed for Keppra XR®, the reference product on the market.
  • Example 7 Stability experiments Stability data of composition according to Ex. 1 , upon conditions at time of preparation (day 0), and after 3 months and 6 months at 40°C/75% Relative Humidity (RH) and after 12 months at 25°C/60% RH, is shown below.
  • Dissolution test according to general methods above (multimedia dissolution test: 2 hours at HCI 0.1N, then 2 hours at pH 4.5 acetate buffer, followed by pH 6.8 phosphate buffer until complete dissolution).
  • composition according to Ex. 1 was further evaluated for levetiracetam content, and impurities or degradation products that could have occurred during the storage conditions.
  • HPLC analysis (according to the general method) of levetiracetam content, and related impurities, after stability test.
  • Table 6 As can be seen, from table 5, the tablets according to the present invention show a good stability even after 6 months storage under accelerated storage conditions, since the dissolution profile is nearly identical to day 0. Additionally, the composition showed an excellent ability in preventing the degradation of levetiracetam as shown in table 6.
  • compositions according to the invention were tested to determine their resistance to an unintended, rapid release in a short period of time of the entire amount or a significant fraction of levetiracetam.
  • the test was performed in the presence of varying percentages of ethanol, and carried out at different pH.
  • the composition of Ex.1 is able to withstand increasing alcohol concentrations up to 20%, without significantly releasing levetiracetam to the media (below 50% liberation of the active ingredient).
  • Example 9 In vivo Pharmacokinetics Assay An in vivo study was performed in healthy human volunteers to assess the plasma concentrations of levetiracetam formulated according to Ex. 1, 4, 5 and 6, compared with the reference treatment with immediate release levetiracetam tablets, Keppra®.
  • the study was designed as an open label, four-period, four-way crossover, block randomized single dose bioequivalence on healthy human, male and female, volunteers, with oral administration under fasting conditions.
  • the participants were given 1000 mg of levetiracetam, orally.
  • Keppra® tablets were provided, following the recommended posology of 500 mg twice-daily, one in the morning and one in the evening, at 12 hours after the morning administration.
  • the extended-release formulations according to Ex.1, 4, 5 and 6 were administered in the morning as a single dose.
  • Mean plasma levels of levetiracetam were determined using an HPLC validated method, with MS/MS detection, from blood samples drawn from each participant.
  • compositions according to the invention are suitable for a single-dose posology regime for levetiracetam.
  • the study was designed as open label, two-period, two-way crossover, block randomized, multiple dose bioequivalence pivotal study on healthy volunteers with administration under fasting conditions for 5 consecutive days.
  • the bioequivalence assessment was based on plasma drug levels of levetiracetam determined using an HPLC validated method, with MS/MS detection, from blood samples drawn from each participant.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Public Health (AREA)
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  • Engineering & Computer Science (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique solide orale sous la forme d'une composition multiparticulaire comprenant un noyau à libération immédiate comprenant du lévétiracétam ou un sel pharmaceutiquement acceptable de celui-ci revêtu d'une couche de libération modifiée, un procédé de préparation de la composition de l'invention, ainsi que son utilisation en thérapie.
PCT/EP2022/070585 2021-07-23 2022-07-22 Composition pharmaceutique multiparticulaire WO2023002004A1 (fr)

Priority Applications (6)

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MX2024001034A MX2024001034A (es) 2021-07-23 2022-07-22 Composicion farmaceutica multiparticulada.
AU2022315552A AU2022315552A1 (en) 2021-07-23 2022-07-22 Multiparticulate pharmaceutical composition
EP22755145.4A EP4373473A1 (fr) 2021-07-23 2022-07-22 Composition pharmaceutique multiparticulaire
CA3226799A CA3226799A1 (fr) 2021-07-23 2022-07-22 Composition pharmaceutique multiparticulaire
JP2024504161A JP2024524757A (ja) 2021-07-23 2022-07-22 多粒子医薬組成物
CN202280056901.5A CN118201603A (zh) 2021-07-23 2022-07-22 多颗粒药物组合物

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EP21382672.0 2021-07-23
EP21382672 2021-07-23

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WO2023002004A1 true WO2023002004A1 (fr) 2023-01-26

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EP (1) EP4373473A1 (fr)
JP (1) JP2024524757A (fr)
CN (1) CN118201603A (fr)
AR (1) AR126544A1 (fr)
AU (1) AU2022315552A1 (fr)
CA (1) CA3226799A1 (fr)
MX (1) MX2024001034A (fr)
WO (1) WO2023002004A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006088864A1 (fr) 2005-02-16 2006-08-24 Elan Pharma International Limited Compositions à libération contrôlée comprenant du lévétiracétam
WO2009069089A1 (fr) 2007-11-29 2009-06-04 Ranbaxy Laboratories Limited Composition de lévétiracétam à libération contrôlée de
US20100172979A1 (en) 2008-12-24 2010-07-08 Zhongshui Yu Controlled-release formulations
US20110217374A1 (en) 2009-10-09 2011-09-08 Yungjin Pharm. Co., Ltd. pharmaceutical composition simultaneously having rapid-acting property and long-acting property
WO2011107855A2 (fr) 2010-03-04 2011-09-09 Torrent Pharmaceuticals Limited Forme dosifiée sous forme de suspension liquide à libération prolongée pour une administration par voie orale
WO2014025593A1 (fr) 2012-08-08 2014-02-13 PharmTak, Inc. Lévétiracétam à libération prolongée et procédé de préparation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006088864A1 (fr) 2005-02-16 2006-08-24 Elan Pharma International Limited Compositions à libération contrôlée comprenant du lévétiracétam
WO2009069089A1 (fr) 2007-11-29 2009-06-04 Ranbaxy Laboratories Limited Composition de lévétiracétam à libération contrôlée de
US20100172979A1 (en) 2008-12-24 2010-07-08 Zhongshui Yu Controlled-release formulations
US20110217374A1 (en) 2009-10-09 2011-09-08 Yungjin Pharm. Co., Ltd. pharmaceutical composition simultaneously having rapid-acting property and long-acting property
WO2011107855A2 (fr) 2010-03-04 2011-09-09 Torrent Pharmaceuticals Limited Forme dosifiée sous forme de suspension liquide à libération prolongée pour une administration par voie orale
WO2014025593A1 (fr) 2012-08-08 2014-02-13 PharmTak, Inc. Lévétiracétam à libération prolongée et procédé de préparation
US20140044780A1 (en) * 2012-08-08 2014-02-13 PharmTak, Inc. Extended-Release Levetiracetam and Method of Preparation

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MX2024001034A (es) 2024-02-23
AR126544A1 (es) 2023-10-18
AU2022315552A1 (en) 2024-02-08
CA3226799A1 (fr) 2023-01-26
JP2024524757A (ja) 2024-07-05
CN118201603A (zh) 2024-06-14
EP4373473A1 (fr) 2024-05-29

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