JP2024524757A - Multiparticulate pharmaceutical compositions - Google Patents

Abstract

The present invention provides an oral solid pharmaceutical composition in the form of a multiparticulate composition comprising an immediate release core containing levetiracetam or a pharma- ceutically 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

FIELD OF THEINVENTION The present invention provides an oral solid pharmaceutical composition in the form of a multiparticulate composition comprising an immediate release core containing levetiracetam or a pharma- ceutically acceptable salt thereof coated with a release modifying layer, a process for preparing the composition of the invention and its use in therapy.

BACKGROUND OF THEINVENTION Levetiracetam has the IUPAC chemical name (S)-2-(2-oxopyrrolidin-1-yl)butanamide (formula (1)) and is a drug developed by UCB and sold under the trade name Keppra® for the treatment of epilepsy either as monotherapy or in combination.

The exact mechanism of action is not fully understood, but levetiracetam is thought to act via binding to the synaptic vesicle protein SV2A in the brain. Levetiracetam is rapidly and almost completely absorbed when administered orally, with maximum plasma concentrations achieved approximately 1 hour later, and is minimally bound to plasma proteins.

Epilepsy is a chronic condition characterized by epileptic seizures, i.e. clinical manifestations resulting from abnormal excessive discharges of neurons in the brain. Epileptic seizures can be classified into three categories: focal, generalized and unclassified epileptic seizures, which may cause convulsive or non-convulsive manifestations and may result in impaired consciousness (total or partial).

As a chronic condition, epilepsy requires lifelong drug therapy in many patients. In this regard, a single-dose regimen is advantageous to increase patient compliance as well as to maintain a steady level of drug in the body, thereby avoiding undesirable fluctuations in drug levels.

The standard initial dosing for levetiracetam is 500 mg twice daily, which can be increased to 1500 mg twice daily based on tolerance and clinical response. In Europe, levetiracetam is available in various tablet forms (in different strengths), as a solution for injection, and as an oral solution. An extended release formulation of levetiracetam is not available in Europe, even though it is available in the United States as Keppra® XR.

Keppra XR is available in strengths of 500 mg and 750 mg in the form of film-coated tablets in which the tablet core is a matrix tablet containing a hydrophilic rate-controlling polymer (such as high-viscosity hypromellose). However, these tablets do not allow easy subdivision of doses as they must not break or crumble, and their size may cause problems with patient compliance, for example in the pediatric population. Moreover, after oral administration of the tablets, a bitter taste of levetiracetam may be experienced due to the faint odor and bitter taste of the levetiracetam active drug itself.

International Publication WO 2006/088864 (A1) discloses controlled release compositions containing levetiracetam that are capable of producing a plasma profile similar to that produced by sequential administration of two or more levetiracetam dosage forms. However, no experimental results or examples are provided in this document.

International Publication WO 2009/069089 (A1) discloses a levetiracetam controlled release formulation in the form of a coated tablet. Various examples of tablets according to the disclosure are provided, in which it can be observed, however, that high dose tablets (e.g., 1000 mg) result in large tablets that may be an obstacle to patient compliance, especially in the pediatric population.

US Patent Application Publication No. 2011/0217374 (A1) discloses a composition that simultaneously has rapid and long-acting properties by including a sustained release portion coated with a hydrophobic polymer that contains a first active ingredient, and an immediate release portion that contains a second active ingredient.

US Patent Application Publication No. 2010/0172979 A1 discloses a controlled release formulation in which the core comprises an active ingredient (e.g., levetiracetam) and wax excipients, many of which require specific handling and/or processing conditions due to their physical properties (i.e., melting point).

International Publication WO 2011/107855 (A2) relates to a taste-masked sustained release oral liquid suspension dosage form comprising: a) an inert pellet surrounded by a seal coat; b) a drug layer surrounding the seal-coated inert pellet, the drug layer comprising a pharma- ceutical active ingredient together with one or more pharma- ceutical acceptable excipients; and c) a coating layer surrounding the drug layer, the coating layer comprising a rate-controlling polymer, wherein the sustained release pellets are suspended in a suspension medium at a suitable pH maintained with or without a buffer, together with a viscosity modifier or suspending agent or thickener or suspension stabilizer, in addition to other pharma- ceutical acceptable excipients.

International Publication No. WO 2014/025593 (A1) relates to an extended release levetiracetam pharmaceutical composition to enable a once-daily dosing regimen. The disclosed composition relies on reservoir microparticles having a release modifier, which may be further coated with a release modifier polymer.

Notwithstanding the above, there remains a need for the development of a pharmaceutical composition comprising levetiracetam that can improve patient compliance with a treatment regimen due to its easy administration and easy posology appropriateness, together with an easy administration schedule (e.g., once daily administration) while maintaining therapeutic levels of levetiracetam in the patient.

The inventors have developed a multiparticulate composition suitable for a once-daily treatment regimen, comprising an immediate release core containing levetiracetam or a pharma- ceutically acceptable salt thereof, said core being coated with a mixture comprising ethylcellulose and hydroxypropylmethylcellulose, the hydroxypropylmethylcellulose having a viscosity of about 1 mPa·s to about 1,000 mPa·s.

In a first aspect, the present invention provides a method for producing a composition comprising:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) a multiparticulate pharmaceutical composition, wherein at least 50% of said immediate release core a) is coated with a mixture comprising ethyl cellulose and hydroxypropyl methylcellulose having a viscosity of about 1 mPa·s to about 1,000 mPa·s.

In a second aspect, the present invention provides a method for preparing a solid pharmaceutical composition according to the first aspect.

In a third aspect, the present invention relates to a multiparticulate composition according to the first aspect for use in the treatment of epilepsy.

1 is a graph showing the mean plasma concentrations of the composition according to Example 1 compared to a reference treatment with Keppra®. 1 is a graph showing the mean plasma concentrations of the composition according to Example 4 compared to a reference treatment with Keppra®. 1 is a graph showing the mean plasma concentrations of the composition according to Example 5 compared to a reference treatment with Keppra®. 1 is a graph showing the mean plasma concentrations of the composition according to Example 6 compared to a reference treatment with Keppra®. 1 is a graph showing the mean plasma concentrations of the composition according to Example 1 compared to a reference treatment with Keppra®. Photographs of mini tablets obtained in Examples 1 to 6.

DEFINITIONS The term "about" as used herein indicates a statistically meaningful range of values (typically within 10%). Such ranges can be within the range of experimental error typical of the standard methods used to measure and/or determine a given value or range. In one embodiment, the range is within 5% of the stated value. In another embodiment, the range is within 1% of the stated value. In yet another embodiment, the range is within 0.5% of the stated value.

The term "pharmacologically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for contact with the tissues of animals, particularly humans, without undue toxicity, irritation, allergic response or other problematic complications and which are commensurate with a reasonable benefit/risk ratio.

The term "treating," as used herein, unless otherwise indicated, includes ameliorating, curing, and/or maintaining cure of a disease or disorder (i.e., preventing or delaying the recurrence of the disease or disorder). After a disorder has developed, treatment aims to alleviate, relieve, ameliorate, or completely eliminate the disorder and/or its associated symptoms, prevent the disorder from getting worse, slow the rate of progression, or, once the disorder has been initially eliminated, prevent the disorder from reoccurring (i.e., preventing recurrence).

The term "extended release," as used herein, refers to a dosage form that is intentionally modified to extend the release rate of a drug substance compared to the release rate observed for an immediate release dosage form. The release pattern in an extended release dosage form 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 that releases at least 80% of the active pharmaceutical ingredient within 30 minutes in water at 25°C using a paddle test (50 rpm).

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 "pellets" as used herein refers to free-flowing, substantially spherical, particulates having a size between 90 micrometers and 2000 micrometers, preferably produced by agglomeration of fine powders or granules.

In an embodiment of the present invention, the term "mini-tablet" refers to a solid pharmaceutical dosage form that is produced by compression, i.e., can be produced on a conventional tablet press adapted for small size tablet pressing, typically having a diameter of ≦3 mm, preferably a diameter of 3 mm or less, more preferably a diameter of 2.5 mm or less, even more preferably between about 2.0 mm and at least 1.0 mm. Mini-tablets may be compressed in any common tablet shape selected from flat round, biconvex round, oval convex and cylindrical, preferably biconvex round. The shape of said mini-tablets is shown in FIG. 6.

In another embodiment of the invention, the term "minitablets" denotes solid forms produced by compression having a surface area of less than ²⁰ mm2, preferably between 16 and 18 ^mm2 , more preferably between 12 and ¹⁵ mm2, and a volume of less than ¹⁰ mm3, preferably between 7 and ¹⁰ mm3, more preferably ^between 4 and 6 mm3.

The term "granules," as used herein, refers to solid pharmaceutical dosage forms that are irregularly shaped and contain powder particles that have agglomerated to form larger particles that are sufficiently robust to withstand handling.

The term "coating" as used herein refers to the deposition and/or adsorption, preferably uniform deposition and/or adsorption, of at least one solution coating, dispersion coating or suspension coating onto a substrate. The coating on the substrate may be of any thickness. Preferably, the coating is a thin uniform film applied to the substrate. The thin uniform film can be of the type "film coating" or/and "isolated film coating" or/and "external film coating".

The term "hardening" as used herein refers to the process of physical or chemical hardening by whatever method, for example by cooling and/or drying. In particular, the physical hardening of the coating mixture (film coating) applied to the immediate release core of the multiparticulate pharmaceutical composition of the present invention.

The term "pharmaceutical acceptable salts" as used herein refers to relatively non-toxic inorganic and organic acid addition salts or base addition salts of a compound. These salts can be prepared in situ during the final isolation and purification of the compound or separately by 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 denotes a pharmaceutical product that is pharma- ceutical equivalent to or pharma- ceutical substitute for another pharmaceutical product(s) and whose bioavailability, in terms of rate (Cmax and tmax) and extent (area under the curve) of absorption after administration of the same molar dose under the same conditions, is similar to such an extent that their effects may be expected to be essentially the same. This is considered to be demonstrated if the 90% confidence interval of the ratio between AUC0 _-t and _Cmax between the products being compared lies in the range of 80-125%.

DETAILED DESCRIPTION OF THE PRESENT EMBODIMENT The inventors of the present invention have surprisingly found that by coating an immediate release core comprising levetiracetam or a pharma-ceutically acceptable salt thereof with a mixture comprising ethylcellulose and hydroxypropylmethylcellulose having a viscosity between about 1 mPa.s and about 1,000 mPa.s, it is possible to prepare an oral solid pharmaceutical composition with modified release that is suitable for a once-a-day dosing regimen.

Notably, the compositions of the present invention allow for the maintenance of plasma concentrations of levetiracetam with a once-daily dosing regimen that are identical to those achieved with the currently recommended twice-daily dosing of levetiracetam with Keppra®. Furthermore, the compositions of the present invention exhibit resistance to dose dumping when exposed to ethanol.

Thus, a first aspect of the present invention provides a method for producing a composition comprising:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) a multiparticulate pharmaceutical composition, wherein at least about 50% of said immediate release core a) is coated with a mixture comprising ethyl cellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s.

In an embodiment of the invention, the immediate release core is a solid.

In an embodiment of the present invention, the pharmaceutical composition of the present invention does not contain a wax excipient. More specifically, the pharmaceutical compositions of the present invention do not contain any excipients selected from the group consisting of carnauba wax, vegetable waxes, fruit waxes, microcrystalline waxes ("petroleum waxes"), beeswax (white or bleached, and yellow), hydrocarbon waxes, paraffin waxes, cetyl ester waxes, nonionic emulsifying waxes, anionic emulsifying waxes, candelilla wax, fatty alcohols (e.g., lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol, or cetostearyl alcohol), hydrogenated vegetable oils, hydrogenated castor oil, fatty acids (e.g., stearic acid, etc.), fatty acid esters (including fatty acid glycerides (monoglycerides, diglycerides, and triglycerides)), polyethylene glycols (PEGs) 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 combinations comprising at least one of the foregoing wax excipients.

In an embodiment of the present invention, the hydroxypropyl methylcellulose has a viscosity between 80 mPa·s and 120 mPa·s, preferably about 100 mPa·s.

In an embodiment of the present invention, the ethyl cellulose has a viscosity between 400 mPa·s and 1500 mPa·s.

In an embodiment of the invention, the coating mixture is used in an amount of coating solution (expressed as dry matter) comprised between 9 and 14 g per 100 g of immediate release cores.

In an embodiment of the invention, the immediate release core comprises levetiracetam or a pharma- ceutically acceptable salt, solvate, hydrate, crystalline or amorphous form thereof, preferably the immediate release core comprises crystalline levetiracetam. The final dosage form prepared for administration to a patient comprises a multiparticulate composition of the invention comprised of various particles (preferably minitablets) comprising levetiracetam that may be present in the final dosage form in an amount between 250 mg and about 3000 mg. For example, levetiracetam may be administered in the following dosage forms: about 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 12 Levetiracetam may be present in the final dosage form in any of the following amounts: 50mg, 1275mg, 1300mg, 1325mg, 1350mg, 1375mg, 1400mg, 1425mg, 1450mg, 1475mg, 1500mg, 1525mg, 1550mg, 1575mg, 1600mg, 1625mg, 1650mg, 1675mg, 1700mg, 1725mg, 1750mg, 1775mg, 1800mg, 1825mg, 1850mg, 1875mg, 1900mg, 1925mg, 1950mg, 1975mg, 2000mg, 2025mg, 2050mg, 2075mg, or 3000mg. In one embodiment, levetiracetam may be present in the final dosage form in an amount of about 1000mg. In one embodiment, levetiracetam may be present in the final dosage form in an amount of about 1500 mg. In one embodiment, levetiracetam may be present in the final dosage form in an amount of about 2000 mg. In one embodiment, levetiracetam may be present in the final dosage form in an amount of about 3000 mg.

Advantageously, the multiple individual immediate release cores comprising levetiracetam or a pharma-ceutically acceptable salt thereof of the present invention are preferably in the form of mini-tablets and exhibit good chemical and mechanical properties, such as good uniformity, friability, hardness (non-friable) and suitable disintegration time for successful coating application.

In addition, the dosage form will contain the multiparticulate composition of the present invention, preferably in the form of mini-tablets, such that said dosage form will contain several mini-tablets and the total amount of levetiracetam in the dosage form will be about 1000 mg, 1500 mg, 2000 mg or 3000 mg of levetiracetam. When levetiracetam is in the form of a dosage form containing several coated mini-tablets, it is possible to administer large amounts of levetiracetam, for example about 1000 mg, 1500 mg, 2000 mg or 3000 mg, by oral administration to a patient without the patient noticing a bitter, undesirable taste of levetiracetam and avoiding the need to add sweeteners or flavorings 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 core is coated with a mixture comprising ethylcellulose and hydroxypropylmethylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, preferably at least about 60%, more preferably at least about 65%, more preferably at least about 70%, more preferably at least about 75%, more preferably at least about 80%, more preferably at least about 85%, more preferably at least about 90%, more preferably at least about 95%, more preferably at least about 99%, and even more preferably all (100%) of the immediate release core is coated. Typically, the coating layer represents about 5% to about 20% by weight of the total composition, preferably about 7% to about 15% by weight of the total composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight. In an embodiment of the first aspect, the weight ratio of ethyl cellulose in the coating mixture to hydroxypropyl methyl cellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s is comprised between about 4:1 and about 20:1, preferably between about 5:1 and about 18:1, more preferably between about 8:1 and about 15:1, even more preferably between about 11:1 and about 15:1, and even more preferably about 12.5:1.

Those skilled in the art will recognize that ethylcellulose is available in various forms and under various trade names, such as Aqualon™, Aquacoat™, Ethocel™, Surelease™, and the like. Preferably, the ethylcellulose for the compositions of the present invention is an aqueous dispersion of ethylcellulose (e.g., Surelease™ E-7-19029, Surelease™ E-7-19030, Surelease™ E-7-19040, and the like, preferably Surelease™ E-7-19040) (the aqueous dispersion is a 25% (w/w) aqueous dispersion of ethylcellulose with medium chain triglycerides, oleic acid, and ammonium hydroxide). These preferred Surelease™ ethylcelluloses allow for a pH-independent drug release to be obtained.

In the context of the present invention, hydroxypropyl methylcellulose has a viscosity between about 1 mPa·s and about 1,000 mPa·s. Preferably, hydroxypropyl methylcellulose has a viscosity between about 5 mPa·s and about 400 mPa·s, more preferably between about 50 mPa·s and about 250 mPa·s, even more preferably between about 70 mPa·s and about 200 mPa·s, and most preferably between about 80 mPa·s and about 120 mPa·s. The viscosity values given correspond to the measured viscosity of a 2% (w/w) aqueous solution of hydroxypropyl methylcellulose at 20° C. measured according to the USP method. Preferred hydroxypropyl methylcelluloses are selected from the group consisting of cellulose ethers marketed as E5LV, E15LV, E50LV and K100LV (preferably K100LV) commercially available as Methocel™ (from Dow Chemicals) or Benecel™ (from Ashland).

In an embodiment of the first aspect, the hydroxypropyl methylcellulose has a viscosity (measured according to USP methods) of between about 80 mPa·s and about 120 mPa·s in a 2% (w/w) aqueous solution at 20°C.

In an embodiment of the first aspect, the coating mixture comprising ethyl cellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s further comprises I) 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, tartrate, 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 a plasticizer selected from medium chain triglycerides, oleic acid, and/or mixtures thereof, and II) a stabilizer selected from the group including ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, and/or mixtures thereof, preferably a stabilizer selected from ammonium hydroxide.

The term "medium chain triglyceride" or "MCT" refers to a triester of glycerol with _C6 - _C12 fatty acids, examples of which include caproic acid ( _C6 ), caprylic acid ( _C8 ), capric acid ( _C10 ) and lauric acid ( _C12 ). The three fatty acid residues of MCT can be the same or different, preferably there are two different fatty acid residues. A preferred medium chain triglyceride is caprylic/capric triglyceride (which is marketed as Stelliesters® 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 include sodium lauryl sulfate.

The multiparticulate composition of the present invention can be in the form of mini-tablets, pellets, granules and/or mixtures thereof, preferably in the form of mini-tablets. Mini-tablets, pellets, granules and/or mixtures thereof can be used for filling capsules or sachets and stick packs, preferably for filling sachets, which have a larger filling volume compared to stick packs and are therefore more suitable for packing a relatively large number of mini-tablets.

In an embodiment of the first aspect, the immediate release core of the multiparticulate pharmaceutical composition is a solid immediate release core, preferably in the form of a mini-tablet. The multiparticulate composition of the present invention may further comprise a pharma- ceutically acceptable excipient. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, sweeteners, colorants, flavoring agents or plasticizers.

Preferably, the multiparticulate composition does not contain either lactose or gluten. In a further embodiment of the first aspect, the weight percentage of levetiracetam or a pharma-ceutically 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 from about 73% to 78% by weight, based on the total weight of the composition.

In an embodiment of the first aspect, the weight percentage of levetiracetam in the composition of the present invention is about 60% to about 90% by weight, preferably about 70% to about 80% by weight, more preferably about 73% to 78% by weight, based on the total weight of the composition.

In an embodiment of the first aspect, the immediate release core comprising levetiracetam further comprises 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 core further comprises a diluent selected from the group consisting of cellulose derivatives, such as cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose, etc.; natural starches, such as corn starch and potato starch; pregelatinized starch and mixtures thereof; preferably, the diluent is a cellulose derivative selected from methylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose; pregelatinized starch and/or mixtures thereof; more preferably, the diluent is microcrystalline cellulose. Typically, the diluent may be present in an amount of about 4% to about 15% by weight, preferably about 7% to about 12% by weight, more preferably about 8% to about 10% by weight, based on the total weight of the composition.

In an embodiment of the first aspect, the immediate release core further comprises 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, the binder may be present in an amount of about 0.5% to about 5% by weight, preferably about 1% to about 3% by weight, and even more preferably about 1.5% to about 2% by weight, based on the total weight of the composition.

In an embodiment of the first aspect, the immediate release core further comprises 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. Typically, the glidant may be present in an amount of about 0.5% to about 5% by weight, preferably about 1% to 3% by weight, more preferably about 2% by weight, based on the total weight of the composition.

In an embodiment of the first aspect, the immediate release core further comprises 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 a lubricant selected from magnesium stearate, calcium stearate, zinc stearate and/or mixtures thereof, more preferably magnesium stearate. Typically, the lubricant may be present in an amount of about 0.1% to about 2% by weight, preferably about 0.3% to about 1.5% by weight, more preferably about 0.5% to about 1.0% by weight, and even more preferably about 0.5% by weight, based on the total weight of the composition.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) a multiparticulate pharmaceutical composition, wherein at least about 50%, preferably at least about 60%, more preferably at least about 65%, more preferably at least about 70%, more preferably at least about 75%, more preferably at least about 80%, more preferably at least about 85%, more preferably at least about 90%, more preferably at least about 95%, more preferably at least about 99%, and even more preferably all (100%) of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is from 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.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) a multiparticulate pharmaceutical composition, wherein at least about 50%, preferably at least about 60%, more preferably at least about 65%, more preferably at least about 70%, more preferably at least about 75%, more preferably at least about 80%, more preferably at least about 85%, more preferably at least about 90%, more preferably at least about 95%, more preferably at least about 99%, and even more preferably all (100%) of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is 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 provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) at least about 50%, preferably at least about 60%, more preferably at least about 65%, more preferably at least about 70%, more preferably at least about 75%, more preferably at least about 80%, more preferably at least about 85%, more preferably at least about 90%, more preferably at least about 95%, more preferably at least about 99%, and even more preferably all (100%) of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa s and about 1,000 mPa s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa s and about 1,000 mPa s in said coating mixture is about 12.5:1.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) at least about 90% of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose in said coating mixture to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s is comprised between about 4:1 and about 20:1, preferably comprised between about 5:1 and about 18:1, more preferably comprised between about 8:1 and about 15:1, more preferably comprised between about 11:1 and about 15:1, and even more preferably about 12.5:1.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) at least about 90% of said individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethyl cellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is about 12.5:1.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) all of the individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose in the coating mixture to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s is between about 4:1 and about 20:1, preferably between about 5:1 and about 18:1, more preferably between about 8:1 and about 15:1, more preferably between about 11:1 and about 15:1, and even more preferably about 12.5:1;
The present invention relates to multiparticulate pharmaceutical compositions.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) all of said individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethyl cellulose to hydroxypropyl methyl cellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is about 12.5:1.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) at least 50%, preferably at least about 60%, more preferably at least about 65%, more preferably at least about 70%, more preferably at least about, more preferably at least about 75%, more preferably at least about 80%, more preferably at least about 85%, more preferably at least about 90%, more preferably at least about 95%, more preferably at least about 99%, and even more preferably all (100%) of said individual immediate release cores a) are ethyl cellulose and have a viscosity between about 1 mPa·s and about 1,000 mPa·s. and hydroxypropyl methylcellulose, wherein the weight ratio of ethyl cellulose in said coating mixture to hydroxypropyl methylcellulose having a viscosity of between about 1 mPa·s and about 1,000 mPa·s is between about 8:1 and about 15:1, more preferably between about 11:1 and about 15:1, and wherein said coating mixture further comprises I) a plasticizer selected from medium chain triglycerides, oleic acid, and/or mixtures thereof, and II) a stabilizer selected from ammonium hydroxide.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) at least 50%, preferably at least about 60%, more preferably at least about 65%, more preferably at least about 70%, more preferably at least about, more preferably at least about 75%, more preferably at least about 80%, more preferably at least about 85%, more preferably at least about 90%, more preferably at least about 95%, more preferably at least about 99%, and even more preferably all (100%) of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa s and about 1,000 mPa s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa s and about 1,000 mPa s in said coating mixture is about 12.5:1, and said coating mixture further comprises I) a plasticizer selected from medium chain triglycerides, oleic acid and/or mixtures thereof, and II) a stabilizer selected from ammonium hydroxide.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) at least 90% of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is between about 4:1 and about 20:1, preferably between about 5:1 and about 18:1, more preferably between about 8:1 and about 15:1, more preferably between about 11:1 and about 15:1, even more preferably about 12.5:1, and said coating mixture further comprises I) a plasticizer selected from medium chain triglycerides, oleic acid and/or mixtures thereof, and II) a stabilizer selected from ammonium hydroxide.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) all of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is between about 4:1 and about 20:1, preferably between about 5:1 and about 18:1, more preferably between about 8:1 and about 15:1, more preferably between about 11:1 and about 15:1, even more preferably about 12.5:1, and said coating mixture further comprises I) a plasticizer selected from medium chain triglycerides, oleic acid and/or mixtures thereof, and II) a stabilizer selected from ammonium hydroxide.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) a multiparticulate pharmaceutical composition, wherein at least 90% of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is between about 8:1 and about 15:1, more preferably between about 11:1 and about 15:1, and said coating mixture further comprises I) a plasticizer selected from medium chain triglycerides, oleic acid and/or mixtures thereof, and II) a stabilizer selected from ammonium hydroxide, and wherein said coating layer represents about 5% to about 20% by weight based on the total weight of the composition, preferably about 7% to about 15% by weight based on the total weight of the composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) a multiparticulate pharmaceutical composition, wherein at least 90% of said immediate release core a) is coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is about 12.5:1, said coating mixture further comprising I) a plasticizer selected from medium chain triglycerides, oleic acid and/or mixtures thereof, and II) a stabilizer selected from ammonium hydroxide, said coating layer representing about 5% to about 20% by weight based on the total weight of the composition, preferably about 7% to about 15% by weight based on the total weight of the composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) a multiparticulate pharmaceutical composition wherein all of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is between about 8:1 and about 15:1, more preferably between about 11:1 and about 15:1, and said coating mixture further comprises I) a plasticizer selected from medium chain triglycerides, oleic acid and/or mixtures thereof, and II) a stabilizer selected from ammonium hydroxide, and wherein said coating layer represents about 5% to about 20% by weight based on the total weight of the composition, preferably about 7% to about 15% by weight based on the total weight of the composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof,
b) a multiparticulate pharmaceutical composition wherein all of said immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is about 12.5:1, said coating mixture further comprising I) a plasticizer selected from medium chain triglycerides, oleic acid and/or mixtures thereof, and II) a stabilizer selected from ammonium hydroxide, said coating layer representing about 5% to about 20% by weight based on the total weight of the composition, preferably about 7% to about 15% by weight based on the total weight of the composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof and, optionally, one or more excipients selected from a diluent, a binder, a glidant, a lubricant;
b) at least about 90% of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is between about 8:1 and about 15:1, more preferably between about 11:1 and about 15:1.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof and, optionally, one or more excipients selected from a diluent, a binder, a glidant, a lubricant;
b) at least about 90% of said individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethyl cellulose to hydroxypropyl methyl cellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is about 12.5.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof and, optionally, one or more excipients selected from a diluent, a binder, a glidant, a lubricant;
b) a multiparticulate pharmaceutical composition, wherein at least about 90% of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is between about 8:1 and about 15:1, more preferably between about 11:1 and about 15:1, and said coating layer represents about 5% to about 20% by weight based on the total weight of the composition, preferably about 7% to about 15% by weight based on the total weight of the composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof and, optionally, one or more excipients selected from a diluent, a binder, a glidant, a lubricant;
b) a multiparticulate pharmaceutical composition, wherein at least about 90% of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is about 12.5:1, and said coating layer represents about 5% to about 20% by weight based on the total weight of the composition, preferably about 7% to about 15% by weight based on the total weight of the composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof and, optionally, one or more excipients selected from a diluent, a binder, a glidant, a lubricant;
b) a multiparticulate pharmaceutical composition wherein all of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is between about 8:1 and about 15:1, more preferably between about 11:1 and about 15:1, and said coating layer represents about 5% to about 20% by weight based on the total weight of the composition, preferably about 7% to about 15% by weight based on the total weight of the composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof and, optionally, one or more excipients selected from a diluent, a binder, a glidant, a lubricant;
b) a multiparticulate pharmaceutical composition wherein all of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is about 12.5:1, and said coating layer represents about 5% to about 20% by weight based on the total weight of the composition, preferably about 7% to about 15% by weight based on the total weight of the composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof and, optionally, one or more excipients selected from a diluent, a binder, a glidant, a lubricant;
b) a multiparticulate pharmaceutical composition wherein all of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is between about 8:1 and about 15:1, more preferably between about 11:1 and about 15:1, and said coating mixture further comprises I) a plasticizer selected from medium chain triglycerides, oleic acid and/or mixtures thereof, and II) a stabilizer selected from ammonium hydroxide, and wherein said coating layer represents about 5% to about 20% by weight based on the total weight of the composition, preferably about 7% to about 15% by weight based on the total weight of the composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight.

In an embodiment of the first aspect, the present invention provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof and, optionally, one or more excipients selected from a diluent, a binder, a glidant, a lubricant;
b) a multiparticulate pharmaceutical composition wherein all of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is about 12.5:1, and said coating mixture further comprises I) a plasticizer selected from medium chain triglycerides, oleic acid and/or mixtures thereof, and II) a stabilizer selected from ammonium hydroxide, and wherein said coating layer represents about 5% to about 20% by weight based on the total weight of the composition, preferably about 7% to about 15% by weight based on the total weight of the composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight.

In an embodiment of the first aspect, the optional one or more excipients are present, 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 provides a method for producing a composition comprising the steps of:
a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof and one or more excipients selected from a diluent, a binder, a glidant and a lubricant;
b) at least about 90% of said individual immediate release cores, preferably all (100%) of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropylmethylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropylmethylcellulose is between about 4:1 and about 20:1, preferably between about 5:1 and about 18:1, more preferably between about 8:1 and about 15:1, more preferably between about 11:1 and about 15:1, even more preferably about 12.5:1, said multiparticulate pharmaceutical composition in the form of minitablets, pellets and/or granules, preferably in the form of minitablets.

In a second aspect, the present invention provides a method for preparing a multiparticulate composition of the first aspect, comprising the steps of:
i) providing levetiracetam or a pharma- ceutically acceptable salt thereof;
ii) optionally mixing levetiracetam or a pharma- ceutically acceptable salt thereof with a diluent for about 1 minute to about 10 minutes, preferably about 2 minutes to about 7 minutes, more preferably about 5 minutes;
iii) optionally granulating the mixture resulting from step ii) with a solution containing a binder;
iv) optionally drying the product resulting from step i) or, when present, the product resulting from steps ii) and iii), preferably at a temperature of about 55° C. to 70° C., preferably at a temperature of about 60° C. to about 65° C., more preferably at a temperature of about 60° C.;
v) optionally mixing the product resulting from step i), or, when present, the product resulting from steps ii), iii) and iv), with a glidant, preferably for a period of about 5 minutes to about 30 minutes, more preferably for about 10 minutes to about 20 minutes, even more preferably for about 15 minutes;
vi) optionally mixing the product resulting from step i), or, when present, from step ii), step iii), step iv) or step v), with a lubricant for a period of about 1 minute to about 10 minutes, preferably about 2 minutes to about 7 minutes, more preferably about 5 minutes;
vii) optionally compressing the product resulting from step i) or, when steps are present, the product resulting from steps ii), iii), iv), v) and vi);
viii) coating the product resulting from step i), or, when steps are present, the product resulting from steps ii), iii), iv), v), vi) and vii), with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s;
ix) curing the coated product of step viii) at a temperature of about 15°C to about 30°C, preferably at a temperature of about 20°C to about 25°C.

In an embodiment of the second aspect, the method comprises:
i) providing levetiracetam or a pharma- ceutically acceptable salt thereof;
ii) optionally mixing levetiracetam or a pharma- ceutically acceptable salt thereof with a diluent for about 5 minutes;
iii) optionally granulating the mixture resulting from step ii) with a solution containing a binder;
iv) optionally drying the product resulting from step i), or, when present, the product resulting from steps ii) and iii), at a temperature of about 60° C. to about 65° C.;
v) optionally mixing the product resulting from step i), or, when present, the product resulting from steps ii), iii) and iv), with a glidant for about 10 minutes to about 20 minutes;
vi) optionally mixing the product resulting from step i) or, when present, from step ii), step iii), step iv) or step v) with a lubricant for about 5 minutes;
vii) optionally compressing the product resulting from step i) or, when steps are present, the product resulting from steps ii), iii), iv), v) and vi);
viii) coating the product resulting from step i), or, when present, the product resulting from steps ii), iii), iv), v), vi) and vii), with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s;
ix) curing the coated product of step viii) at a temperature of about 20°C to about 25°C.

In an embodiment of the second aspect, the method comprises:
i) providing levetiracetam or a pharma- ceutically acceptable salt thereof;
ii) mixing levetiracetam or a pharma- ceutically acceptable salt thereof with a diluent for about 5 minutes;
iii) granulating the product resulting from step i) with a solution containing 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 minutes;
vi) mixing the product resulting from step iv) with a lubricant for about 5 minutes;
vii) compressing the product resulting from step v);
viii) coating the product from step vi) with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s;
ix) curing the product of step vii) at a temperature of about 20°C to about 25°C.

In an embodiment of the second aspect, the coating layer represents about 5% to about 20% by weight of the total weight of the composition, preferably about 7% to about 15% by weight of the total weight of the composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight.

In an embodiment of the second aspect, the method comprises:
i) providing levetiracetam or a pharma- ceutically acceptable salt thereof;
ii) optionally mixing levetiracetam or a pharma- ceutically acceptable salt thereof with a diluent for about 2 minutes to about 7 minutes;
iii) optionally granulating the mixture resulting from step ii) with a solution containing a binder;
iv) optionally drying the product resulting from step i), or, when present, the product resulting from steps ii) and iii), at a temperature of about 60° C. to about 65° C.;
v) optionally mixing the product resulting from step i), or, when present, the product resulting from steps ii), iii) and iv), with a glidant for about 10 minutes to about 20 minutes;
vi) optionally mixing the product resulting from step i), or, when present, from step ii), step iii), step iv) or step v), with a lubricant for about 2 minutes to about 7 minutes;
vii) optionally compressing the product resulting from step i) or, when steps are present, the product resulting from steps ii), iii), iv), v) and vi);
viii) coating the product resulting from step i) or, when present, the product resulting from steps ii), iii), iv), v), vi) and vii) with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, wherein the weight ratio of ethyl cellulose in said coating mixture to hydroxypropyl methyl cellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s is comprised between about 8:1 and about 15:1, preferably between about 11:1 and about 15:1, more preferably about 12.5:1,
ix) curing the coated product of step viii) at a temperature of about 20°C to about 25°C.

In an embodiment of the second aspect, the method comprises:
i) providing levetiracetam or a pharma- ceutically acceptable salt thereof;
ii) optionally mixing levetiracetam or a pharma- ceutically acceptable salt thereof with a diluent for about 5 minutes;
iii) optionally granulating the mixture resulting from step ii) with a solution containing a binder;
iv) optionally drying the product resulting from step i) or, when present, the product resulting from steps ii) and iii) at a temperature of about 60° C.;
v) optionally mixing the product resulting from step i), or, when present, the product resulting from steps ii), iii) and iv), with a glidant for about 15 minutes;
vi) optionally mixing the product resulting from step i) or, when present, from step ii), step iii), step iv) or step v) with a lubricant for about 5 minutes;
vii) optionally compressing the product resulting from step i) or, when steps are present, the product resulting from steps ii), iii), iv), v) and vi);
viii) coating the product resulting from step i) or, when present, the product resulting from steps ii), iii), iv), v), vi) and vii) with a mixture comprising ethylcellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, wherein the weight ratio of ethylcellulose in said coating mixture to hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s is comprised between about 8:1 and about 15:1, preferably between about 11:1 and about 15:1, more preferably about 12.5:1,
ix) curing the coated product of step viii) at a temperature of about 20°C to about 25°C.

In an embodiment of the second aspect, if an uncoated immediate release core is desired, steps viii) and ix) are not performed.

In an embodiment of the second aspect, steps ii), iii), iv), v), vi) and vii) are performed (i.e., are present).

In an embodiment of the second aspect, steps ii) to ix) are performed (i.e., are present).

In an embodiment of the second aspect, the diluent in step ii) is selected from cellulose derivatives, such as cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose, etc.; natural starches, such as corn starch and potato starch; pregelatinized starch and mixtures thereof; preferably, the diluent is a cellulose derivative selected from methylcellulose, 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 in step iii) is selected from povidone, copovidone, polyethylene glycol, gelatin, polyethylene oxide, alginic acid, modified maize starch and/or mixtures thereof, preferably selected from povidone, copovidone and/or mixtures thereof, preferably copovidone.

In an embodiment of the second aspect, the glidant in 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 in 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 hydroxypropyl methylcellulose has a viscosity (measured according to USP methods) of between about 80 mPa·s and about 120 mPa·s in a 2% (w/w) aqueous solution at 20°C.

In an embodiment of the second aspect, the coating mixture of step vii) comprising ethyl cellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s further comprises I) 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, A plasticizer selected from the group including 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 a plasticizer selected from medium chain triglycerides, oleic acid, and/or mixtures thereof, and II) a stabilizer selected from the group including ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, and/or mixtures thereof, preferably a stabilizer selected from ammonium hydroxide and/or mixtures thereof.

In an embodiment of the second aspect, the coating mixture of step vii) comprising ethyl cellulose and hydroxypropyl methylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s further comprises I) a plasticizer selected from the group comprising medium chain triglycerides, oleic acid and/or mixtures thereof, and II) a stabilizer selected from ammonium hydroxide.

In one embodiment, the coating mixture of step viii) may be applied by a perforated pan coating method or a fluidized bed coating method, preferably by a fluidized bed coating method, which is a commonly used technique for coating small particles.

In an embodiment of the first and/or second aspect of the invention, the multiparticulate composition is in the form of a mini-tablet. In a third aspect, the invention relates to a 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 treating epilepsy on a once-daily dosing regimen. In one embodiment, the multiparticulate composition of the invention comprises levetiracetam in dosage strengths of about 1000 mg, 1500 mg, 2000 mg or 3000 mg for once-daily administration to treat epilepsy.

experiment
General Method
Multimedia Dissolution Tests Dissolution tests were performed according to the basket method described in the European Pharmacopoeia as follows:
Equipment: Agilent Technologies 708-DS, integrated with 850-DS sampling station;
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 HCl (0.1 N), followed by 2 hours in 900 mL acetate buffer pH 4.5, and finally 8 hours in 900 mL phosphate buffer pH 6.8 or pH 6.0. Alternatively, the last step can be carried out until complete dissolution.

Preparation of phosphate buffer (pH 6.0) : Dissolve 6.8 g of potassium dihydrogen phosphate and 0.2 g of sodium hydroxide in 1000 mL of deionized water. If necessary, adjust to pH 6.0 with 1 N sodium hydroxide.
Preparation of phosphate buffer (pH 6.8) : 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 Binge Release Assay: Samples are placed in baskets and then stirred at 100 rpm in 750 mL HCl (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 min.

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, diode array detector and autosampler.
Column: Kromasil C18 5 μm, 150 × 4.6 mm
Oven temperature: 20°C
Wavelength: 230 nm
Eluent: 85% buffer solution (pH 5.5): 15% acetonitrile Flow rate: 1.0 mL/min Injection volume: 5 μL

Buffer solution (pH 5.5) : Dissolve 0.26 g of potassium dihydrogen phosphate in 1000 mL of water. Adjust to pH 5.5 with 0.1 M potassium hydroxide. Filter through a 0.45 μm filter.
Standard solution : Prepare an aqueous solution of levetiracetam containing an accurately calculated concentration of approximately 0.15 mg/mL.
Test solution : Select at least 5 sachets, weigh and calculate the average weight. Crush the mini-tablets to a fine uniform powder. Prepare a solution of powder in solvent at a concentration of approximately 0.15 mg/mL of Levetiracetam. Stir for 30 minutes. Centrifuge.

Examples <br/> Examples 1 to 6

All examples were prepared in the form of mini-tablets with an uncoated core weight of 5 mg. For example 6, 10% of the mini-tablet cores were left uncoated, thereby resulting in a combination of 90% coated and 10% uncoated mini-tablets. The resulting mini-tablets have a biconvex circular shape.

The minitablets were prepared as follows:
i) Microcrystalline cellulose PH101 and levetiracetam were sieved through a 0.8 mm sieve.
ii) Microcrystalline Cellulose PH101 and Levetiracetam were mixed in a high shear granulator for 5 minutes.
iii) Copovidone was dissolved in purified water with propeller stirring.
iv) The mixture resulting from step ii) was granulated in a high shear granulator using the Copovidone solution resulting from step iii).
v) The granules resulting from step iv) were dried in a fluid bed dryer at a temperature of about 60°C to 65°C.
vi) The dried granules resulting from step v) were sieved using a screening mill through a 0.8 mm stainless steel sieve.
vii) Talc was added to the granules resulting from step vi) in a container mixer for 15 minutes.
viii) Magnesium stearate was added to the mixture resulting from step vii) in a container mixer for 5 minutes.
ix) The mixture resulting from step viii) was compressed in a tablet press using 2 mm multi-unit punches yielding individual mini-tablets of 5 mg weight.
x) The mini-tablets resulting from step ix) were coated with a suspension in water of ethylcellulose and hydroxypropylmethylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, or, in Example 2, guar gum.
xi) The mini-tablets resulting from step x) were allowed to harden at room temperature.

The white or off-white circular biconvex coated functional mini-tablets with a diameter of 2 mm obtained in Examples 1 to 6 showed a bulk density of 0.71 to 0.75 g/ml and an apparent volume of 1.33 to 1.41 ml/g. The apparent volume was calculated taking into account the bulk density of the mini-tablets (i.e. in ml per 1 g of mini-tablets).

Example 6. Dissolution Profiles

As can be seen, Example 2, which contains guar gum instead of hydroxypropylmethylcellulose with a viscosity comprised between about 1 mPa·s and about 1,000 mPa·s, exhibits a pH-dependent release of levetiracetam, whereas Examples 1 and 3 exhibit a pH-independent release profile, which is consistent with the dissolution profile observed for the commercial reference product, Keppra XR®.

Example 7. Stability Studies Stability data for the composition according to Example 1 at the conditions of as-prepared (day 0), and after 3 and 6 months at 40° C./75% relative humidity (RH), and after 12 months at 25° C./60% RH are shown below.

Dissolution test according to the general method described above (multi-media dissolution test: HCl (0.1N) for 2 hours, then acetate buffer pH 4.5 for 2 hours, followed by phosphate buffer pH 6.8 until complete dissolution).

The composition according to Example 1 was further evaluated for levetiracetam content and impurities or degradation products that may have arisen during storage conditions. HPLC analysis (following general methods) of levetiracetam content and related impurities after stability testing.

As can be seen from Table 5, the tablets according to the present invention show good stability even after 6 months of storage under accelerated storage conditions as the dissolution profile is almost the same as on day 0. In addition, the composition showed good prevention of levetiracetam degradation as shown in Table 6.

Example 8. Alcohol-induced Excessive Release The compositions according to the present invention were tested to determine their resistance to unintended rapid release of all or a significant portion of levetiracetam over a short period of time. The tests were carried out in the presence of various percentages of ethanol and at different pH levels.

As can be seen in Table 7, the composition of Example 1 is able to withstand increasing alcohol concentrations up to 20% without significant release of levetiracetam into the medium (less than 50% release of the active ingredient).

Example 9. In vivo Pharmacokinetic Assays An in vivo study was conducted in healthy human volunteers to evaluate the plasma concentrations of levetiracetam formulated according to Examples 1, 4, 5 and 6 compared to a reference treatment with Keppra® immediate release levetiracetam tablets.

The study was designed as an open-label, four-period, four-way crossover, block-randomized, single-dose bioequivalence study in healthy human (male and female) volunteers by oral administration under fasting conditions. Participants received 1000 mg of levetiracetam by oral administration. For immediate release tablets, Keppra® tablets were given according to the recommended posology of 500 mg twice a day (once in the morning and once in the evening, i.e., 12 hours after the morning dose). Extended release formulations according to Examples 1, 4, 5 and 6 were administered in the morning as a single dose.

Mean plasma levels of levetiracetam were determined from blood samples drawn from each participant using a validated HPLC method with MS/MS detection.

The results are shown in Figures 1, 2, 3 and 4. As can be seen in the graphs, the mean plasma concentrations of levetiracetam obtained by single doses of the formulations according to Examples 1, 4, 5 and 6, respectively, maintain and/or achieve levetiracetam levels in the subjects' plasma comparable to the levetiracetam levels achieved by twice daily intake of Keppra®.

This clearly indicates that the composition according to the present invention is suitable for single dose dosing policy for levetiracetam.

Example 10. In vivo multiple dose bioequivalence study An in vivo study was carried out comparing extended release levetiracetam formulated according to Example 1 (Test = 1000 mg extended release mini tablets of levetiracetam in a sachet taken as a 3000 mg dose in the morning under fasting conditions) with a corresponding dose of a reference drug product (Keppra® 500 mg immediate release film coated tablets taken twice a day under fasting conditions on each treatment day: a first dose in the morning (3 Keppra® 500 mg tablets) and a second dose in the evening 12 hours after the morning dose). A study was conducted in healthy human volunteers to determine the steady-state bioequivalence between levetiracetam and a dose of 3 Keppra® 500 mg tablets. The study was designed as an open-label, two-period, two-way crossover, block-randomized, multiple-dose pivotal bioequivalence study in human volunteers, administered under fasting conditions for 5 consecutive days. Bioequivalence assessment was based on plasma drug levels of levetiracetam determined from blood samples drawn from each participant using a validated HPLC method with MS/MS detection.

The results are shown in Table 8 and Figure 5. As can be seen, the 3000 mg dose of the levetiracetam formulation according to Example 1 and the corresponding dose of the reference formulation are bioequivalent in terms of the extent of absorption of levetiracetam (AUC0-tau) after multiple doses in fasting conditions.

Claims (15)

a) a multiparticulate pharmaceutical composition comprising a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof and one or more excipients selected from diluents, binders, glidants and lubricants,
b) a multiparticulate pharmaceutical composition, wherein at least about 50% of said individual immediate release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropylmethylcellulose having a viscosity in a 2% (w/w) aqueous solution at 20° C. between about 1 mPa·s and about 1,000 mPa·s, wherein the weight ratio of ethylcellulose to hydroxypropylmethylcellulose is about 4:1 to about 20:1, and said composition is in the form of minitablets, pellets and/or granules, preferably in the form of minitablets. The multiparticulate composition of claim 1, wherein at least about 90%, preferably about 100%, of all individual immediate release cores are coated with the mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose. The multiparticulate composition of claim 1 or 2, wherein the weight ratio of ethyl cellulose to hydroxypropyl methyl cellulose is from about 5:1 to about 18:1, 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 coating mixture comprising ethyl cellulose and hydroxypropyl methylcellulose further comprises I) 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 A multiparticulate composition according to any one of claims 1 to 3, comprising a plasticizer selected from the group comprising butyl sebacate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and/or mixtures thereof, preferably a plasticizer selected from medium chain triglycerides, oleic acid, and/or mixtures thereof, and II) a stabilizer selected from the group comprising ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, and/or mixtures thereof, preferably a stabilizer selected from ammonium hydroxide. The multiparticulate composition according to any one of claims 1 to 4, wherein the coating layer represents about 5% to about 20% by weight of the total composition, preferably about 7% to about 15% by weight of the total composition, more preferably about 8% to about 13% by weight, more preferably about 9% to about 12% by weight, and most preferably about 11.5% by weight. A multiparticulate composition according to any one of claims 1 to 5, wherein the diluent is selected from cellulose derivatives, such as cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose, etc.; natural starches, such as corn starch and potato starch; pregelatinized starch and mixtures thereof, preferably the diluent is a cellulose derivative selected from methylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose; pregelatinized starch and/or mixtures thereof, more preferably microcrystalline cellulose. The multiparticulate composition according to any one of claims 1 to 6, wherein the binder is selected from povidone, copovidone, polyethylene glycol, gelatin, polyethylene oxide, alginic acid, modified maize starch and/or mixtures thereof, preferably selected from povidone, copovidone and/or mixtures thereof, more preferably copovidone. The multiparticulate composition according to any one of claims 1 to 7, wherein the lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, mineral oil, stearic acid and/or mixtures thereof, preferably magnesium stearate, calcium stearate, zinc stearate and/or mixtures thereof, more preferably magnesium stearate. a) a plurality of individual immediate release cores comprising levetiracetam or a pharma- ceutically acceptable salt thereof and, optionally, one or more excipients selected from the group consisting of diluents, binders, glidants and lubricants;
b) all of the individual immediate release cores a) are coated with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose, and further wherein the weight ratio of ethyl cellulose to hydroxypropyl methyl cellulose in the coating mixture is from about 8:1 to about 15:1;
9. A multiparticulate composition according to any one of claims 1 to 8, wherein the coating layer represents from about 5% to about 20% by weight, based on the total weight of the composition, preferably from about 7% to about 15% by weight, more preferably from about 8% to about 13% by weight, more preferably from about 9% to about 12% by weight, and most preferably about 11.5% by weight, based on the total weight of the composition. A multiparticulate pharmaceutical composition according to any one of claims 1 to 9, in the form of a dosage form for administration to a patient, comprising some of the particles of the composition in an amount sufficient to provide a dosage form containing levetiracetam in an amount of about 1000 mg, about 1500 mg, about 2000 mg or about 3000 mg. The multiparticulate pharmaceutical composition according to any one of claims 1 to 10, which is packaged in a sachet. A method for preparing a multiparticulate pharmaceutical composition according to any one of claims 1 to 11, comprising the steps of:
i) providing levetiracetam or a pharma- ceutically acceptable salt thereof;
ii) optionally mixing the levetiracetam or a pharma- ceutically acceptable salt thereof with a diluent for about 1 minute to about 10 minutes, more preferably about 2 minutes to about 7 minutes, and even more preferably about 5 minutes;
iii) optionally granulating the mixture resulting from step ii) with a solution containing a binder;
iv) optionally drying the product resulting from step (i), or, when present, the product resulting from steps (ii) and (iii), preferably at a temperature of about 55° C. to 70° C., preferably at a temperature of about 60° C. to about 65° C., more preferably at a temperature of about 60° C.;
v) optionally mixing the product resulting from step (i), or, when steps (ii), (iii) and (iv) are present, with a glidant, preferably for a period of about 5 minutes to about 30 minutes, more preferably 10 minutes to 20 minutes, even more preferably about 15 minutes;
vi) optionally mixing the product resulting from step (i), or, when steps are present, the products resulting from steps (ii), (iii) and (iv) with a lubricant, preferably for a period of from about 1 minute to about 10 minutes, more preferably from about 2 minutes to about 7 minutes, even more preferably for about 5 minutes;
vii) optionally compressing the product resulting from step (i) or, when steps (ii), (iii), (iv), (v) and (vi),
viii) coating the product resulting from step (i), or, when steps are present, the products resulting from steps (ii), (iii), (iv), (v), (vi) and (vii) with a mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose having a viscosity in a 2% (w/w) aqueous solution at 20° C. of from about 1 mPa·s to about 1,000 mPa·s, and further comprising a weight ratio of ethyl cellulose to hydroxypropyl methyl cellulose of from about 4:1 to about 20:1;
ix) curing the coated mixture resulting from step viii), preferably at a temperature of about 15°C to about 30°C, more preferably at a temperature of 20°C to 25°C. The method according to claim 12, wherein steps ii), iii), iv), v), vi) and vii) are carried out. A multiparticulate pharmaceutical composition according to any one of claims 1 to 11 for use in the treatment of epilepsy. 15. A multiparticulate pharmaceutical composition according to claim 14 in a once daily dosing regimen.

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