CA3226799A1

CA3226799A1 - Multiparticulate pharmaceutical composition

Info

Publication number: CA3226799A1
Application number: CA3226799A
Authority: CA
Inventors: Devendra Ridhurkar; Carmen Ubeda Perez; Ignacio Diez Martin
Original assignee: Individual
Current assignee: Neuraxpharm Pharmaceuticals SL
Priority date: 2021-07-23
Filing date: 2022-07-22
Publication date: 2023-01-26
Also published as: AU2022315552A1; AR126544A1; WO2023002004A1

Abstract

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.

Description

MULTIPARTICULATE PHARMACEUTICAL COMPOSITION
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Levetiracetam, having the IUPAC 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 .

=-='-yi-LNE12 r (1) The exact mechanism of action is not properly understood, although it is believed that 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).
As a chronic condition, epilepsy requires in many patients medication for life. In this regard, a single-dose regimen is advantageous to increase patient compliance as well

2 as keeping a steady level of medication in the body, thereby avoiding undesired fluctuations in medication levels.
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. However, these tablets do not allow an easy fraction ing 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. Moreover, after oral administration of the tablets, the bitter taste of levetiracetam may be experienced due to the faint odor and bitter taste of levetiracetam active drug itself.
Document W02006/088864 Al discloses a controlled-release composition cornprising 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.
In W02009/069089 Al 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.
US2011/0217374 Al discloses 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.
In document US2010/0172979 Al, a controlled-release formulation is disclosed wherein the core comprises an active ingredient, such as levetiracetam and a wax

3 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.
International application WO 2014/025593 Al relates to a prolonged-release levetiracetam pharmaceutical compositions to allow a once-a-day dosage regime.
The disclosed compositions, rely on reservoir particulates having release modifiers, which can be further coated with a release-modifier polymer.
Notwithstanding the above, there is still a need for the development of pharmaceutical 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.
BRIEF DESCRIPTION OF THE INVENTION
The present inventors have developed 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 hydroxypropylmethyl 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.
In a first aspect of the present invention refers to a multiparticulate pharmaceutical composition comprising:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein

4 PC

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 mPas to about 1,000 mPas.
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.
BRIEF DESCRIPTION OF THE DRAWINGS
- 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.
DEFINITIONS
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.
The term "pharmaceutically acceptable" as used herein 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 corn plications commensurate with a reasonable benefit/risk ratio.
The term "treating", as used herein, unless otherwise indicated, includes the

5 amelioration, cure, and/or maintenance of a cure (i.e., the prevention or delay of relapse) of a disease or disorder. Treatment 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).
The term, "extended release" as used herein 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.
The term "immediate release" as used herein 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.
The term "multiparticulate pharmaceutical composition" as used herein refers to a pharmaceutical composition in the form of multiple solid units, such as, pellets, mini-tablets, granules, and/or mixtures thereof.
The term "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.
In an embodiment of the present invention the terms "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

6 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.
In another embodiment of the present invention the terms "mini-tablet" and "mini-tablets" refers to a solid form manufactured by compression which has a surface area of less than 20 mm2, preferably from 16 to 18 mm2, more preferably from 12 to 15 mm2 and has a volume of less than 10 mm3, preferably from 7 to 10 mm3, more preferably from 4 to 6 mm3.
The terms "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.
The term "coating" as used herein 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.
Preferably 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".
The term "curing" as used herein refers to the process of physical or chemical hardening by any method, such as cooling, and/or drying. In particular, the physical hardening of the coating mixture (film coating) applied to the immediate release cores of the multiparticulate pharmaceutical composition of the invention.
The term "pharmaceutically acceptable salt" as used herein 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.
The term "bioequivalence" as used herein refers to a pharmaceutical product which is pharmaceutically equivalent or pharmaceutical alternative to another pharmaceutical

7 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 Cmax, between the products being compared is in the range of 80-125%.
DETAILED DESCRIPTION OF THE INVENTION
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 hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPas allows the preparation of an oral solid pharmaceutical composition having a modified release suitable for a once-daily dose regimen.
Notably, the 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 KeppraG. Furthermore, the compositions of the invention show resistance to dose dumping when exposed to ethanol.
Thus, the first aspect of the present invention refers to 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 hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s.
In an embodiment of the present invention the immediate release core is solid.
In an embodiment of the present invention 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

8 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 6000, and PEG 8000), or a combination comprising at least one of the foregoing wax excipients.
In an embodiment of the present invention the hydroxypropylmethyl cellulose has a viscosity comprised between 80 mPa-s to 120 mPa-s, preferably about 100 mPa.s.
In an embodiment of the present invention the ethyl cellulose has a viscosity comprised between 400 mPa=s and 1500 mPa=s.
In an embodiment of the present invention 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.
In an embodiment of the present invention 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.
For example, 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, 1025, 1050,1075, 1100,1125, 1150, 1175,1200, 1225,1250, 1275, 1300,1325, 1350, 1375, 1400, 1425, 1450, 1475, 1500, 1525, 1550, 1575, 1600, 1625, 1650, 1675, 1700, 1725, 1750,1775, 1800,1825, 1850, 1875, 1900, 1925,1950, 1975, 2000, 2025, 2050, 2075, or 3000 mg. In one embodiment, 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

9 of about 2000 mg. In one embodiment, the levetiracetam may be present in the final dosage form in an amount of about 3000 mg.
Advantageously, 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.
Additionally, 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. When the 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.
In an embodiment of the first aspect, 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.
Typically, 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. In an embodiment of the first aspect, 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 1 1: 1 to about 15: 1 , and even more preferably about 12.5:1.
The skilled person recognizes that ethyl cellulose is available in various forms, and under different brand names, such as AqualonTM, AquacoatO, EthocelTm, Surelease .
5 Preferably, 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, Surelease0E-7-19040, preferably Surelease0E-7-19040 (which is an 25% w/w aqueous dispersion of ethyl cellulose, comprising medium chain triglycerides, oleic acid, and ammonium hydroxide). These preferred Surelease ethyl celluloses allow

10 obtaining a pH independent drug release.
In the context of the present invention, hydroxypropylmethyl cellulose has a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s. Preferably, 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, E5OLV, and K100LV, preferably K100 LV, commercially available as MethocelTM (from Dow Chemicals), or BenecelTM (from Ashland).
In an embodiment of the first aspect 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).
In an embodiment of the first aspect, the coating mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa.s to about 1,000 mPas 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,

11 ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and/or mixtures thereof, preferably selected from medium chain triglycerides, oleic acid, and/or mixtures thereof; and II) stabilizers selected from the group comprising ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, caesium hydroxide, and/or mixtures thereof, preferably ammonium hydroxide.
The term "medium chain triglyceride" or "MCI" refers to triesters of glycerol and C6-C12 fatty acids, examples of said fatty acids being caproic acid (C6), 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 Stelliesterse MCT 65/35, Estasan , Crodamol GTC/C, Miglyol 812 or 810, and Neobee M5).
In an embodiment of the first aspect, 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.
In an embodiment of the first aspect, 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_ Preferably, the multiparticulate composition does neither contain lactose nor gluten.ln a further embodiment of the first aspect, the percentage in weight of levetiracetam or a pharmaceutically acceptable salt thereof in the composition of the invention is from

12 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.
In an embodiment of the first aspect, 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.
In an embodiment of the first aspect, the immediate release cores comprising levetiracetam, further comprise one or more excipients selected from the group consisting of diluents, binders, glidants, and lubricants.
In an embodiment of the first aspect, 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. Typically, 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.
In an embodiment of the first aspect, 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. Typically, 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.
In an embodiment of the first aspect, the immediate release cores further comprise a glidant selected from the group consisting of calcium silicate, magnesium silicate, corn

13 starch, colloidal silicon dioxide, silicon hydrogel, talc, colloidal silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, mineral oil, and/or mixtures thereof, preferably talc. Typically, 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.
In an embodiment of the first aspect, 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. Typically, 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.
In an embodiment of the first aspect, the present invention refers to 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 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.

14 In an embodiment of the first aspect, the present invention refers to 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 mPas to about 1,000 nnPa-s in the coating mixture is comprised from about 8:1 to about

15:1, preferably from about 11:1 to about 15:1.
In an embodiment of the first aspect, the present invention refers to 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 hydroxypropylnnethyl 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.
In an embodiment of the first aspect, the present invention refers to 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 5 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 10 15:1, and even more preferably about 12.5:1.
In an embodiment of the first aspect, the present invention refers to a multiparticulate pharmaceutical composition comprising:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharmaceutically acceptable salt thereof; wherein 15 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.
In an embodiment of the first aspect, the present invention refers to 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.

16 In an embodiment of the first aspect, the present invention refers to 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.
In an embodiment of the first aspect, the present invention refers to 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 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 hydroxide.
In an embodiment of the first aspect, the present invention refers to 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

17 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 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.
In an embodiment of the first aspect, the present invention refers to 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 medium chain triglycerides, oleic acid, and/or mixtures thereof; and II) stabilizers selected from ammonium hydroxide.
In an embodiment of the first aspect, the present invention refers to 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

18 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 medium chain triglycerides, oleic acid and/or mixtures thereof; and II) stabilizers selected from ammonium hydroxide.
In an embodiment of the first aspect, the present invention refers to 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 hydroxide;
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 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.
In an embodiment of the first aspect, the present invention refers to 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

19 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 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.
In an embodiment of the first aspect, the present invention refers to 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 hydroxide;
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 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.
In an embodiment of the first aspect, the present invention refers to 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 mPas to about 1,000 mPas 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 5 ammonium hydroxide;
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 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.
In an embodiment of the first aspect, the present invention refers to 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 mPas 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 mPas in the coating mixture is comprised between about 8:1 to about 15:1, more preferably from about 11:1 to about 15:1.
In an embodiment of the first aspect, the present invention refers to 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 mPas to about 1,000 mPa-s, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPas to about 1,000 mPas in the coating mixture is about 12.5.

In an embodiment of the first aspect, the present invention refers to 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 mPas 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 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.
In an embodiment of the first aspect, the present invention refers to 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 12.5:1;
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 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.

In an embodiment of the first aspect, the present invention refers to 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 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.
In an embodiment of the first aspect, the present invention refers to 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 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_ In an embodiment of the first aspect, the present invention refers to 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 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 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.
In an embodiment of the first aspect, the present invention refers to 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; and II) stabilizers selected from ammonium hydroxide;
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 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.

In an embodiment of the first aspect, 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.
In an embodiment of the first aspect, the present invention refers to 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 hydroxypropylnnethyl 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 more preferably about 12.5:1, wherein the multiparticulate pharmaceutical composition is in the form of mini-tablets, pellets and/or granules, preferably mini-tablets.
In a second aspect, 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 with a glidant, preferably from about 5 min to about 30 min, more preferably from about 10 min to about 20 min, even more preferably for about 15 min;
5 vi) optionally, mixing the product resulting from step i) or from steps ii), iii), iv) or v) when these steps are present, with a lubricant from about 1 min to about 10 min, preferably from about 2 min to about 7 min, more preferably for about 5 min;
vii) optionally, compressing the product resulting from step i) or from steps ii), 10 iii), iv), V) and vi) when these steps are present;
viii) coating the product resulting from step i) or from steps ii), iii), iv), v), vi) and vii) when these steps are present, with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s;
15 ix) curing the coated product of step viii) at a temperature from about 15 C to about 30 C, preferably from about 20 C to about 25 C.
In an embodiment of the second aspect the process comprises:
i) providing levetiracetam or a pharmaceutically acceptable salt thereof ii) optionally, mixing levetiracetam or a pharmaceutically acceptable salt

20 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 25 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), iii), iv) or v) when these steps are present, with a lubricant for about 5 min;
vii) optionally, compressing the product resulting from step i) or from steps ii), iii), iv), v) and vi) when these steps are present;

viii) coating the product resulting from step i) or from steps ii), iii), iv), v), vi) and vii) when these steps are present, 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 coated product of step viii) at a temperature from about 20 C
to about 25 C.
In an embodiment of the second aspect, 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 vii) at a temperature from about 20 C to about C.
In an embodiment of the second aspect, 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_ In an embodiment of the second aspect, 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), iii), iv) or v) when these steps are present, with a lubricant from about 2 min to about 7 min;
vii) optionally, compressing the product resulting from step i) or from steps ii), iii), iv), v) and vi) when these steps are present;
viii) coating the product resulting from step i) or from steps ii), iii), iv), v), vi) and Vii) when these steps are present, with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPas to about 1,000 mPa-s 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, preferably from about 11:1 to about 15:1, more preferably about 12.5:1;
ix) curing the coated product of step viii) at a temperature from about 20 C
to about 25 C.
In an embodiment of the second aspect, 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), iii), iv) or v) when these steps are present, with a lubricant for about 5 min;
vii) optionally, compressing the product resulting from step i) or from steps ii), iii), iv), v) and vi) when these steps are present;
viii) coating the product resulting from step i) or from steps ii), iii), iv), v), vi) and vii) when these steps are present, with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s 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, preferably from about 11:1 to about 15:1, more preferably about 12.5:1;
ix) curing the coated product of step viii) at a temperature from about 20 C
to about 25 C.
In an embodiment of the second aspect, if uncoated immediate release cores are desired, steps viii) and ix) are not carried out.
In an embodiment of the second aspect, steps ii), iii), iv), v), vi) and vii) are carried Out (i.e. are present).
In an embodiment of the second aspect, steps ii) to ix) are carried out (i.e.
are present).
In an embodiment of the second aspect, 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.
In an embodiment of the second aspect, 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.
In an embodiment of the second aspect, 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.
In an embodiment of the second aspect, 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.
In an embodiment of the second aspect, the binder is copovidone, the diluent is microcrystalline cellulose, the glidant is talc, and the lubricant is magnesium stearate.
In an embodiment of the second aspect 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).
In an embodiment of the second aspect, 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, dibutylsebacate, acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and/or mixtures thereof, preferably selected from medium chain triglycerides, oleic acid, and/or mixtures thereof; and II) stabilizers selected from the group comprising ammonium hydroxide sodium hydroxide, lithium hydroxide, potassium hydroxide, caesium hydroxide, and/or mixtures thereof, preferably ammonium hydroxide, and/or mixtures thereof.

In an embodiment of the second aspect 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;
5 and II) stabilizers selected from ammonium hydroxide.
In an embodiment, 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.
In an embodiment of the first and/or second aspect of the invention, the multiparticulate 10 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.
In an embodiment of the third aspect, the composition according to the first aspect is for use in the treatment of epilepsy in a once-a-day administration regime. In an 15 embodiment, 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.
EXPERIMENTAL
General methods 20 Multimedia Dissolution test Dissolution tests were carried out according to the basket method described in the Pharmacopea Europea, as follows:
= Apparatus Agilent Technologies 708-DS integrated with an 850-DS sampling station;
25 = Stirring speed: 100 rpm = Temperature: 37 C 0.5 C
The sample is placed in a basket, and then stirred at 100 rpm for 2 hours in 750 mL of HCI 0.1N, followed by 2 hours in 900 mL of pH 4.5 acetate buffer, and finally for 8 hours 30 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 6Ø
Phosphate buffer p/-i 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 0.1N 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 method The amount of active ingredient released in the dissolution test is determined by High Performance Liquid Chromatography (HPLC), as follows:
HPLC system: Agilent 1260 Infinity II, equipped with pump, a diode-array detector, and an auto-sampler.
Column: Kromasil C18 5 pnn, 150 x4.6 mm Oven temperature: 20 C
Wavelength: 230 nm Eluent: 85% buffer solution pH 5.5: 15% acetonitrile Flow: 1.0 mL/min Injection volume: 5 pL
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.
Standard solution: Prepare a levetiracetam solution in water containing a concentration exactly calculated of about 0.15 ring/mL.
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 levetiracetann.
Stir 30 minutes. Centrifuge.
Examples Examples 1 to 6.
Table 1. Immediate release cores composition for examples 1 to 6.
COMPONENT AMOUNT (MG) Levetiracetam 1000 Microcrystalline cellulose 120 Copovidone 23.53 Purified waterl q.s Talc 25.88 Magnesium stearate 7.06 Table 2. Physical parameters of mechanical properties of immediate release cores composition for examples 1 to 6. The parameters are determined by standard methods defined in the European Pharmacopoeia.
PARAMETERS VALUES
Diameter (mm) 2.00-2.06 Thickness (mm) 1.64-1.70 Weight (mg) 4.95-5.05 Hardness (N) 5.30-8.10 Friability (%) 0.10-0.52 Disintegration time (min) 4-9 min Water content by KF ((Yip) 0.30-0.50 Bulk density (g/ml) 0.7 Volume of mini-tablets (ml/g) 1.42 Content Uniformity (%) 98-102 AV Values 2.5 Table 3. Coating layer composition for examples 1 to 6 EX. 1 EX. 2 EX. 3 EX. 4 EX. 5 EX. 6 COMPONENT
COATING COMPOSITION (AMOUNTS IN MG) Ethyl cellulose 2 105.37 81.49 81.49 94.68 62.42 85.21 Medium chain triglycerides2 18.37 14.21 14.21 16.50 10.87 .. 14.85 Oleic Acid2 10.36 8.01 8.01 9.31 6.14 8.38 Ammonium hydroxide2 10.42 8.06 8.06 9.36 6.17 8.43 Hydroxypropylmethyl 8.41 5.88 11.14 7.43 10.03 cellulose3 Guar Gum 5.88 Purified water1'2 q.s q.s q.s. q.s.
q.s q.s Ethyl cellulose:
Hydroxypropylmethyl 12.5:1 13.85:1 13.85:1 8:5:1 8.4:1 8.5:1 cellulose (or guar gum) weight ratio 1. Evaporated during drying of the composition.
2. Ethyl cellulose, medium chain triglycerides, oleic acid, ammonium hydroxide and water are added in the form of the commercial product Surelease 8 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.
3. 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 stearate as added to the mixture resulting from step vii) in container mixer for 5 minutes;
ix) the mixture resulting from step viii) was compressed in a tablet compression machine using 2 mm multiunit punches obtaining 5 mg weight of each mini-tablet;
x) the mini-tablets resulting from step ix) were coated with a water suspension of ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between about 1 mPa-s to about 1,000 mPa-s, or guar gum in example 2;
Xi) the mini-tablets resulting from step x) were cured at room temperature.
The white or off-white round biconvex functional coated mini-tablets of 2 mm of diameter obtained as in examples Ito 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).
Example 6. Dissolution profiles Table 4.
Time (hours) Ex. 1 Ex.2 Ex.3 0 0.0 0.0 0.0 pH 0.5 1.0 6.0 1.0 1.2 1 3.0 32.0 5.0 2 5.0 64.0 15.0 pH 3 9.0 87.0 30.0 4.5 4 15.0 95.0 44.0 5 25.0 101.0 54.0 6 34.0 64.0 pH
8 48.0 71.0 6.8 10 59.0 79.0 12 70.0 88.0 As can be seen 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 XRO, the reference product on the market.
Example 7. Stability experiments 5 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 10 hours at HCl 0.1N, then 2 hours at pH 4.5 acetate buffer, followed by pH
6.8 phosphate buffer until complete dissolution).
Table 5.
RESULTS
Time ________________________________________________________________________ (hours) Day 0 3M 6M 12M
C/75%RH 40 C/75%RH 25 C/60%RH
0 0.0 0.0 0.0 0.0 1 1.0 1.0 2.0 2.0 2 5.0 6.0 7.0 6.0 4 15.0 26.0 27.0 23.0 8 48.0 56.0 59.0 55.0 12 70.0 74.0 79.0 75.0 15 81.0 84.0 87.0 85.0 The composition according to Ex. 1, was further evaluated for levetiracetam content, 15 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.
RESULTS
Sample Levetiracetam Impurity A Any unspecified Total Impurities impurity T=0 100.2 <0.1% 50.05 <0.1%

25 C/60%RH 100.3 <0.1% 50.05 <0.1%

40 C/75%RH 100.3 <0.1% 50.05 <0.1%

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.
Example 8. Alcohol-induced dose dumping The 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.
Table 7.
Ex. 1 Time (min) 0% Et0H 5% Et0H 10% Et0H 20%
Et0H

pH 1.2 45 0 0 1 pH 6.0 45 0 1 1 As can be seen in table 7, 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, Keppra0.
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. For immediate release tablets, Keppra0 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.
The results are shown in Fig. 1, 2, 3 and 4. As can be seen in the graphs, the average mean plasmatic concentrations of levetiracetam obtained with a single dose of the formulations according to Ex.1, 4, 5 and 6, respectively, maintain and/or achieve levetiracetam levels in plasma of the subjects comparable to the ones achieved with twice-daily intake with Keppra0.
This clearly shows that the compositions according to the invention are suitable for a single-dose posology regime for levetiracetam.
Example 10. In vivo Multiple Dose Bioequivalence Study An in Vivo study was performed in healthy human volunteers to demonstrate the steady state bioequivalence between the extended release levetiracetam formulated according to Ex. 1 (test=Levetiracetam 1000 mg prolonged-release mini-tablets in sachets, taken as 3000 mg dose in the morning, in fasting conditions) and a corresponding dose of the reference medicinal product (Keppra0 500 mg immediate release film-coated tablets, administered twice daily on each treatment day, in fasting conditions: the first dose in the morning ¨3 tablets of Keppra0 500 mg - and the second one in the evening 12 hours after the morning dose ¨ 3 tablets of Keppra0 500 mg).
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.
The results are shown in Table 8 and Fig. 5. As can be seen, a dose of 3000 mg of Levetiracetam formulation according to Ex.1 and a corresponding dose of the reference formulation are bioequivalent with respect to Levetiracetam extent of absorption (AUCO-tau) after multiple dosing in fasting conditions.
Table 8. Bioequivalence comparison (based on primary PK parameters) Test Parameter Geo Mean 90% Confidence Acceptance Infra-name Ratio Interval range subject (Test!
CV (%) Reference) Lower Upper Lower Upper 90% CL 90% CL limit limit (`)/0) (%) Classic AUCO-tau 89.669 86.099 93.387 80.00 125.00 10.808 90% Cl Classic Cmax.ss 69.259 65.320 73.434 80.00 125.00 15.623 90% Cl Classic Cmin,ss 98.505 90.005 107.809 80.00 125.00 24.287 90% Cl If the lower and upper CL (Confidence Interval limits) lie within accepted regulatory criteria, then we may conclude for bioequivalence.

Claims

39

1. 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 90%, preferably 100% of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between 1 mPa.s to 1,000 mPa.s in a 2% w/w aqueous solution at 20 C, wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose is comprised between 11 :1 to 15:1, and wherein the multiparticulate pharmaceutical composition is in the form of mini-tablets and wherein the multiparticulate pharmaceutical composition does not comprise wax excipients.

2. The multiparticulate composition according to any one of the preceding claims, wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose is 12.5:1.

3. The multiparticulate composition according to any one of the preceding claims wherein, the coating mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose further comprises 0 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, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and/or mixtures thereof, preferably selected from medium chain triglycerides, oleic acid, and/or mixtures thereof; and II) stabilizers selected from the group comprising ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, caesium hydroxide, and/or mixtures thereof, preferably ammonium hydroxide.

4. The multiparticulate composition according to any one of the preceding claims, wherein the coating layer represents from 5% to 20% weight of the total weight of the composition, preferably from 7% to 15%, more preferably from 8% to 13%, more preferably from 9% to 12%, most preferably 11.5% by weight of the total weight of the composition.

5. The multiparticulate composition according to any one of the preceding claims, wherein the diluent 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, more preferably, microcrystalline cellulose.

6. The multiparticulate composition according to any one of the preceding claims, wherein the binder 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; more preferably copovidone.

7. The multiparticulate composition according to any one of the preceding claims, wherein the lubricant 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.

8. The multiparticulate composition according to any one of the preceding claims 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 the group consisting of diluents, binders, glidants, and lubricants;
wherein b) all the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose, further wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose in the coating mixture is comprised between 11:1 to 15:1;

wherein the coating layer represents from 5% to 20% weight of the total weight of the composition, preferably from 7% to 15%, more preferably from 8% to 13%, more preferably from 9% to 12%, most preferably 11.5% by weight of the total weight of the composition.

9. The multiparticulate pharmaceutical composition according to any preceding claim, in the form of a dosage form to be administered to the patient which comprises several of the composition's particles in an amount sufficient to provide a dosage form containing levetiracetam in an amount of 1000 mg, 1500 mg, 2000 mg, or 3000 mg.

10.The multiparticulate pharmaceutical composition according to any preceding claim, packaged into sachets.

11. Process for the preparation of a multiparticulate pharmaceutical composition as defined in any one of the preceding claims comprising:
1) providing levetiracetam or a pharmaceutically acceptable salt thereof ii) optionally mixing said levetiracetam or pharmaceutically acceptable salt thereof with a diluent from 1 min to 10 min, more preferably from 2 min to 7 min, even more preferably for 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 55 QC to 70 QC, preferably from 60 QC to 65 QC, more preferably 60 QC;
v) optionally, mixing the product resulting from step (i) or from steps (ii), (iii) and (iv) when these steps are present with a glidant, preferably from 5 min to 30 min, more preferably from 10 min to 20 min, even more preferably for 15 min;
vi) optionally, mixing the product resulting from step (i) or from steps (ii), (iii), (iv) and (v) when these steps are present, with a lubricant, preferably from 1 min to 10 min, more preferably from 2 min to 7 min, even more preferably for 5 min;
vii) optionally, compressing the product resulting from step (i) or from steps (ii), (iii), (iv), (v) and (vi) when these steps are present;

viii) coating the product resulting from step (i) or from steps (ii), (iii), (iv), (v), (vi) and (vii) when these steps are present with a mixture comprising ethyl cellulose and hydroxypropylmethyl cellulose having a viscosity comprised between 1 mPa.s to 1,000 mPa-s in a 2% w/w aqueous solution at 20 C;
wherein the weight ratio of ethyl cellulose to hydroxypropylmethyl cellulose is comprised between 11:1 to 15:1; and ix) curing the coated mixture resulting from step viii) preferably at a temperature from 15 C to 302C, more preferably from 202C to 25 C
wherein the multiparticulate pharmaceutical composition is in the form of mini-tablets and does not comprise wax excipients.

12. The process according to claim 11, wherein steps ii), iii), iv), v), vi) and vii) are carried out.

13. A multiparticulate pharmaceutical composition as defined in any one of claims 1 to 10 for use in the treatment of epilepsy.

14. The multiparticulate pharmaceutical composition for use according to claim 13, in a once-a-day administration regime.

15. Use of a multiparticulate pharmaceutical composition as defined in any one of claims 1 to 10 for the manufacture of a medicament for the treatment of epilepsy.

16. Use according to claim 15, wherein the medicament is for a once-a-day administration regime.