Multiparticulate pharmaceutical compositions

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 pharma- ceutically acceptable salt thereof coated with a modified release layer, a process for the preparation of the composition of the present invention and its use in therapy.

Description

[Technical field]

[0001] 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 technology]

[0002] 2. Background of the Invention 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. [ka]

[0003] The exact mechanism of action is not fully understood, but it is believed that levetiracetam acts in the brain via binding to the synaptic vesicle protein SV2A. 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.

[0004] 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 (complete or partial) impairment of consciousness.

[0005] As a chronic condition, epilepsy requires lifelong drug therapy in many patients. In this regard, a single-dose regimen is advantageous for increasing patient compliance, as well as for maintaining a steady level of drug in the body, thereby avoiding undesirable fluctuations in drug levels.

[0006] The standard initial posology 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 an injection solution, 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.

[0007] Keppra XR is available in strengths of 500 mg and 750 mg in the form of film-coated tablets, the tablet core of which 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, the bitter taste of levetiracetam may be experienced due to the faint odor and bitter taste of the levetiracetam active drug itself.

[0008] International Publication WO2006 / 088864(A1) discloses a controlled release composition containing levetiracetam, which can produce a plasma profile similar to that produced by sequentially administering two or more levetiracetam dosage forms. However, no experimental results or examples are provided in this document.

[0009] International Publication WO2009 / 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, but it can be observed 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.

[0010] US Patent Application Publication No. 2011 / 0217374 (A1) discloses a composition that simultaneously has fast and long-acting properties by comprising a sustained release portion coated with a hydrophobic polymer containing a first active ingredient and an immediate release portion containing a second active ingredient.

[0011] US Patent Application Publication No. 2010 / 0172979 A1 discloses a controlled release formulation in which the core comprises an active ingredient (such as, for example, levetiracetam) and wax excipients, many of which require specific handling and / or processing conditions due to their physical properties (i.e., melting point).

[0012] International Publication WO 2011 / 107855(A2) relates to a taste-masked sustained release oral liquid suspension dosage form comprising: a) inert pellets surrounded by a seal coat; b) a drug layer surrounding the seal-coated inert pellets, the drug layer comprising an active pharmaceutical ingredient together with one or more pharma- ceutically 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 thickening agent or suspension stabilizer in addition to other pharma- ceutically acceptable excipients.

[0013] International Publication WO2014 / 025593(A1) relates to an extended release levetiracetam pharmaceutical composition to enable a once-daily dosing regimen. The disclosed composition relies on reservoir microparticles bearing a release modifier, which may be further coated with a release modifier polymer.

[0014] Notwithstanding the above, there remains a need for the development of a pharmaceutical composition comprising levetiracetam which 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. Summary of the Invention

[0015] The inventors have developed a multiparticulate composition suitable for a once-daily treatment regimen, comprising an immediate release core comprising 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.

[0016] In a 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 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.

[0017] In a second aspect, the present invention provides a method for preparing a solid pharmaceutical composition according to the first aspect.

[0018] In a third aspect, the present invention relates to a multiparticulate composition according to the first aspect for use in the treatment of epilepsy. [Brief description of the drawings]

[0019] [Figure 1] 1 is a graph showing the mean plasma concentrations of the composition according to Example 1 compared to a reference treatment with Keppra®. [Diagram 2]1 is a graph showing the mean plasma concentrations of the composition according to Example 4 compared to a reference treatment with Keppra®. [Diagram 3] 1 is a graph showing the mean plasma concentrations of the composition according to Example 5 compared to a reference treatment with Keppra®. [Figure 4] 1 is a graph showing the mean plasma concentrations of the composition according to Example 6 compared to a reference treatment with Keppra®. [Diagram 5] 1 is a graph showing the mean plasma concentrations of the composition according to Example 1 compared to a reference treatment with Keppra®. [Figure 6] 1 is a photograph of the mini-tablets obtained in Examples 1 to 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] definition 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 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.

[0021] 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 are commensurate with a reasonable benefit / risk ratio.

[0022] 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 a disease or disorder). Treatment after a disorder has occurred aims to alleviate, alleviate, 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 returning (i.e., preventing recurrence).

[0023] The term "extended release," as used herein, refers to a dosage form that is purposefully 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 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.

[0024] 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).

[0025] The term "multiparticulate pharmaceutical composition" as used herein refers to a pharmaceutical composition in the form of multiple solid units, such as pellets, minitablets, granules and / or mixtures thereof.

[0026] The term "pellets" as used herein refers to free-flowing, substantially spherical, particulates having a size between 90 micrometers and 2000 micrometers and preferably produced by agglomeration of fine powders or granules.

[0027] In an embodiment of the present invention, the term "mini-tablet" refers to a solid pharmaceutical dosage form, 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, which can be produced by compression, i.e., on a conventional tablet press adapted for small size tablet pressing. 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 Figure 6.

[0028] In another embodiment of the present invention, the term "mini-tablet" refers to a tablet having a surface area of ​​20 mm 2 Less than 16 to 18 mm, preferably 2 More preferably, the thickness is 12 to 15 mm. 2 and the volume is 10 mm 3 Less than 7 to 10 mm, preferably 3 More preferably, the thickness is 4 to 6 mm. 3 FIG. 2 shows a solid form produced by compression,

[0029] The term "granules" as used herein refers to solid pharmaceutical dosage forms that are irregularly shaped and comprise powder particles that have agglomerated to form larger particles that are sufficiently firm to withstand handling.

[0030] 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 thin film applied to the substrate. The thin uniform thin film can be of the type "film coating" or / and "isolated film coating" or / and "external film coating".

[0031] The term "hardening" as used herein refers to the process of physical or chemical hardening by whatever means, for example by cooling and / or drying, etc. In particular, the physical hardening of the coating mixture (film coating) applied to the immediate release cores of the multiparticulate pharmaceutical composition of the present invention.

[0032] The term "pharmaceutical acceptable salts" as used herein refers to relatively non-toxic inorganic and organic acid addition or base addition salts of compounds. 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.

[0033] The term "bioequivalence," as used herein, refers to a pharmaceutical product that is pharma- ceutical equivalent to or pharma- ceutical substitute for another pharmaceutical product(s) and whose bioavailability is similar 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 to such an extent that their effects can be expected to be essentially the same. AUC 0-t and C. max This is considered to be proven if the 90% confidence interval for the ratio between is in the range 80 to 125%.

[0034] Detailed Description of the Invention 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 which is suitable for a once-a-day dosing regimen.

[0035] Notably, the compositions according to 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.

[0036] Thus, a first aspect of the present invention provides a method for producing a method for treating a pulmonary circulation 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% 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.

[0037] In an embodiment of the invention, the immediate release core is a solid.

[0038] In an embodiment of the invention, the pharmaceutical composition of the invention does not comprise a wax excipient. More specifically, the pharmaceutical compositions of the present invention do not comprise 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 a number average molecular weight Mn of greater than about 3000 (e.g., PEG3350, PEG4000, PEG4600, PEG6000, and PEG8000), or a combination comprising at least one of the foregoing wax excipients.

[0039] 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.

[0040] In an embodiment of the present invention, the ethyl cellulose has a viscosity between 400 mPa·s and 1500 mPa·s.

[0041] 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.

[0042] 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 composed of various particles (preferably minitablets) comprising levetiracetam which may be present in the final dosage form in an amount between 250 mg and about 3000 mg. For example, levetiracetam can be administered in the following doses: 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.

[0043] 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.

[0044] In addition, the dosage form preferably contains the multiparticulate composition of the present invention in the form of mini-tablets, so that said dosage form contains several mini-tablets and the total amount of levetiracetam in the dosage form will be about 1000mg, 1500mg, 2000mg or 3000mg of levetiracetam. When levetiracetam is in the form of a dosage form containing several coated mini-tablets, it is possible to take a large amount of levetiracetam, for example about 1000mg, 1500mg, 2000mg or 3000mg of levetiracetam, by oral administration to a patient without the patient noticing the 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.

[0045] In an embodiment of the first aspect, at least about 55% of the immediate release core is coated with a mixture containing 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 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 first aspect, the weight ratio of ethyl cellulose in the coating mixture to hydroxypropyl methyl cellulose having a viscosity of 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, even more preferably between about 11:1 and about 15:1, and even more preferably about 12.5:1.

[0046] 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™, etc. 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, etc., 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 pH-independent drug release to be obtained.

[0047] In the context of the present invention, the hydroxypropyl methylcellulose has a viscosity between about 1 mPa·s and about 1,000 mPa·s. Preferably, the 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. A preferred hydroxypropyl methylcellulose is selected from the group consisting of cellulose ethers standardized as E5LV, E15LV, E50LV and K100LV (preferably K100LV), commercially available as Methocel™ (from Dow Chemicals) or Benecel™ (from Ashland).

[0048] 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.

[0049] 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) a medium chain triglyceride, 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 laurate, sorbitol lauryl ether ... and II) a plasticizer selected from the group comprising ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide and / or mixtures thereof, preferably 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 selected from ammonium hydroxide.

[0050] The term "medium chain triglyceride" or "MCT" refers to glycerol and C6-C 12 Triesters with fatty acids are shown. Examples of the fatty acids are caproic acid (C6), caprylic acid (C8), capric acid (C 10 ) and lauric acid (C 12The 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).

[0051] In an embodiment of the first aspect, the coating mixture does not include sodium lauryl sulfate.

[0052] The multiparticulate composition of the present invention can be in the form of minitablets, pellets, granules and / or mixtures thereof, preferably in the form of minitablets, which can be used to fill capsules or sachets and stick packs, preferably sachets, which have a larger filling volume compared to stick packs and are therefore more suitable for packing a relatively large number of minitablets.

[0053] In an embodiment of the first aspect, the immediate release core of the multiparticulate pharmaceutical composition is a solid immediate release core, preferably a solid immediate release core 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, flavorings or plasticizers.

[0054] 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 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.

[0055] In an embodiment of the first aspect, the weight percentage of levetiracetam in the composition of the present invention is about 60% by weight to about 90% by weight, preferably about 70% by weight to about 80% by weight, more preferably about 73% by weight to about 78% by weight, based on the total weight of the composition.

[0056] 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.

[0057] 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, etc.; 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 can 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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 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 having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is about 4:1 to about 20:1, preferably about 5:1 to about 18:1, more preferably about 8:1 to about 15:1, more preferably about 11:1 to about 15:1, and even more preferably about 12.5:1.

[0062] 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 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 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.

[0063] 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 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 having a viscosity between about 1 mPa·s and about 1,000 mPa·s in said coating mixture is about 12.5:1.

[0064] 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 hydroxypropylmethylcellulose having a viscosity of between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose in said coating mixture to hydroxypropylmethylcellulose having a viscosity of 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.

[0065] 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 90% of the 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 the coating mixture is about 12.5:1.

[0066] 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 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 in the coating mixture to hydroxypropyl methyl cellulose 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.

[0067] 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, 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.

[0068] 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 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 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.

[0069] 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 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, 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 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.

[0070] 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 hydroxypropylmethylcellulose 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 hydroxypropylmethylcellulose 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, 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.

[0071] 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 of 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 of 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, even more preferably about 12.5:1, 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.

[0072] 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 hydroxypropylmethylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and wherein the weight ratio of ethylcellulose in said coating mixture to hydroxypropylmethylcellulose having a viscosity 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 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.

[0073] 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 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 wherein the weight ratio of ethylcellulose in said coating mixture to hydroxypropylmethylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s 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 corresponding to 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.

[0074] 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 hydroxypropylmethylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and wherein the weight ratio of ethylcellulose in said coating mixture to hydroxypropylmethylcellulose having a viscosity 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 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.

[0075] 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 corresponding to 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.

[0076] 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 hydroxypropylmethylcellulose having a viscosity of between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose in said coating mixture to hydroxypropylmethylcellulose 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.

[0077] 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 the 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 the coating mixture is about 12.5.

[0078] 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 hydroxypropylmethylcellulose having a viscosity of between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose in said coating mixture to hydroxypropylmethylcellulose 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 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.

[0079] 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 hydroxypropylmethylcellulose having a viscosity of between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose to hydroxypropylmethylcellulose having a viscosity of 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 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.

[0080] 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 hydroxypropylmethylcellulose having a viscosity of between about 1 mPa·s and about 1,000 mPa·s, and further wherein the weight ratio of ethylcellulose in said coating mixture to hydroxypropylmethylcellulose 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 said 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.

[0081] 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 of 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 of 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 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.

[0082] 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 hydroxypropylmethylcellulose having a viscosity of between about 1 mPa·s and about 1,000 mPa·s, and wherein the weight ratio of ethylcellulose in said coating mixture to hydroxypropylmethylcellulose 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 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.

[0083] 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 hydroxypropylmethylcellulose having a viscosity between about 1 mPa·s and about 1,000 mPa·s, and wherein the weight ratio of ethylcellulose to hydroxypropylmethylcellulose 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.

[0084] 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.

[0085] 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 of 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, wherein the multiparticulate pharmaceutical composition is in the form of minitablets, pellets and / or granules, preferably in the form of minitablets.

[0086] 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 steps are present, the products 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 a period of about 10 minutes to about 20 minutes, and 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 ii), iii), iv), v) and vi), viii) coating the product resulting from step i), or, when steps i), 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. The present invention relates to a method comprising the steps of:

[0087] 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 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, 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 ii), iii), iv), v) and vi), viii) coating the product resulting from step i), or, when steps i), 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. The present invention relates to a method for producing a semiconductor device comprising the steps of:

[0088] 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 methylcellulose 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. The present invention relates to a method for producing a semiconductor device comprising the steps of:

[0089] In an embodiment of the second aspect, the coating layer corresponds to about 5 wt % to about 20 wt % of the total weight of the composition, preferably about 7 wt % to about 15 wt % of the total weight of the composition, more preferably about 8 wt % to about 13 wt %, more preferably about 9 wt % to about 12 wt %, and most preferably about 11.5 wt %.

[0090] 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 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 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 between about 1 mPa·s and about 1,000 mPa·s, wherein 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 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. The present invention relates to a method for producing a semiconductor device comprising the steps of:

[0091] 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 steps ii), iii) and iv), with a glidant for about 15 minutes; vi) optionally mixing the product resulting from step i) or, when present, 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 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 between about 1 mPa·s and about 1,000 mPa·s, wherein 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 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. The present invention relates to a method for producing a semiconductor device comprising the steps of:

[0092] In an embodiment of the second aspect, if an uncoated immediate release core is desired, steps viii) and ix) are not performed.

[0093] In an embodiment of the second aspect, steps ii), iii), iv), v), vi) and vii) are performed (ie are present).

[0094] In an embodiment of the second aspect, steps ii) to ix) are performed (ie, present).

[0095] In an embodiment of the second aspect, the diluent in step ii) is selected from a cellulose derivative, such as cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose, etc; a natural starch, 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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 medium chain triglyceride, 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) a stabilizer selected from the group comprising ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, and / or mixtures thereof, preferably selected from ammonium hydroxide and / or mixtures thereof.

[0102] 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.

[0103] In one embodiment, the coating mixture of step viii) may be applied by perforated pan coating method or fluidized bed coating method, preferably by fluidized bed coating method, which is a commonly used technique for coating small particles.

[0104] In an embodiment of the first and / or second aspect of the invention, the multiparticulate composition is in the form of minitablets.In a third aspect, the present invention relates to a multiparticulate composition according to the first aspect for use in the treatment of epilepsy.

[0105] 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. EXAMPLES

[0106] experiment General method Multi-media dissolution test 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℃±0.5℃

[0107] The samples are placed in a basket and then stirred at 100 rpm for 2 hours in 750 mL of HCl (0.1 N), followed by 2 hours in 900 mL of acetate buffer pH 4.5, and finally 8 hours in 900 mL of phosphate buffer pH 6.8 or pH 6.0. Alternatively, the last step can be carried out until complete dissolution.

[0108] 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.

[0109] Alcohol Binge Release Assay: The samples are placed in baskets and then stirred at 100 rpm in 750 mL of HCl (0.1 N) or 900 mL of phosphate buffer (pH 6.0) in the presence of the corresponding ethanol % (v / v), and samples are taken every 15 min.

[0110] 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 5μm, 150×4.6mm Oven temperature: 20℃ Wavelength: 230nm Eluent: 85% buffer solution (pH 5.5): 15% acetonitrile Flow rate: 1.0mL / min Injection volume: 5 μL

[0111] 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 solutions : 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 homogenous powder. Prepare a solution of the powder in the solvent at a concentration of approximately 0.15 mg / mL of levetiracetam. Stir for 30 minutes. Centrifuge.

[0112] Working Example Examples 1 to 6 [Table 1]

[0113] [Table 2]

[0114] [Table 3]

[0115] All examples were prepared in the form of minitablets with an uncoated core weight of 5 mg. For example 6, 10% of the minitablet cores were left uncoated, resulting in a combination of 90% coated and 10% uncoated minitablets. The resulting minitablets have a biconvex circular shape.

[0116] 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 weighing 5 mg. x) The mini-tablets resulting from step ix) are 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.

[0117] The functional coated mini-tablets of white or off-white circular biconvex shape 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 gram of mini-tablets).

[0118] Example 6. Dissolution Profiles [Table 4]

[0119] 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®.

[0120] Example 7. Stability Studies Stability data for the composition according to Example 1 at the time of preparation (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.

[0121] 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).

[0122] [Table 5]

[0123] 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 (according to general method) of levetiracetam content and related impurities after stability study.

[0124] [Table 6]

[0125] 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 excellent ability to prevent levetiracetam degradation as shown in Table 6.

[0126] Example 8. Alcohol-induced binge-eating 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.

[0127] [Table 7]

[0128] As can be seen in Table 7, the composition of Example 1 is able to tolerate increasing alcohol concentrations up to 20% without significant release of levetiracetam into the medium (less than 50% release of the active ingredient).

[0129] Example 9. In vivo Pharmacokinetic Assay 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 immediate release levetiracetam tablets Keppra®.

[0130] 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 were given 1000 mg of levetiracetam orally. 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 Example 1, Example 4, Example 5 and Example 6 were given in the morning as a single dose.

[0131] Mean plasma levels of levetiracetam were determined from blood samples drawn from each participant using a validated HPLC method with MS / MS detection.

[0132] 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 formulations according to Example 1, Example 4, Example 5 and Example 6, respectively, maintain and / or achieve levetiracetam levels in the plasma of subjects comparable to the levetiracetam levels achieved by twice daily intake with Keppra®.

[0133] This clearly indicates that the composition according to the invention is suitable for a single dose posology strategy for levetiracetam.

[0134] Example 10. In vivo multiple dose bioequivalence study The in vivo study was carried out on 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) and a corresponding dose of the reference drug product (Keppra® 500 mg immediate release film-coated tablets taken twice a day under fasting conditions on each treatment day: first dose in the morning (3 tablets of Keppra® 500 mg tablets) and second dose in the evening 12 hours after the morning dose (3 tablets of Keppra® 500 mg tablets). A study was conducted in healthy human volunteers to determine the steady-state bioequivalence between levetiracetam and eppra® 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.

[0135] 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.

[0136] [Table 8]

Claims

1. a) A multi-particle pharmaceutical composition comprising 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, b) at least 50% of said individual immediate-release cores a) being coated with a mixture comprising ethylcellulose and hydroxypropylmethylcellulose having a viscosity between 1 mPa·s and 1,000 mPa·s in a 2% (w / w) aqueous solution at 20°C, the weight ratio of ethylcellulose to hydroxypropylmethylcellulose being from 11:1 to 15:1, and said composition being in the form of minitablets and free of wax excipients. A multi-particle pharmaceutical composition characterized by this.

2. The multi-particle composition according to claim 1, wherein at least 90%, preferably 100%, of all the individual immediate-release cores are coated with said mixture comprising ethylcellulose and hydroxypropylmethylcellulose.

3. The multi-particle composition according to claim 1 or 2, characterized in that the weight ratio of ethylcellulose to hydroxypropylmethylcellulose is 12.5:

1.

4. The coating mixture comprising ethyl cellulose and hydroxypropyl methyl cellulose further comprises I) a plasticizer selected from the group consisting of 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 a plasticizer selected from medium-chain triglycerides, oleic acid, and / or mixtures thereof, and II) a stabilizer selected from the group consisting of ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide and / or mixtures thereof, preferably a stabilizer selected from ammonium hydroxide. The multi-particle composition according to claim 1 or 2, characterized in that it comprises the above.

5. The multi-particle composition according to claim 1 or 2, characterized in that the coating layer corresponds to 5% to 20% by weight, preferably 7% to 15% by weight, more preferably 8% to 13% by weight, more preferably 9% to 12% by weight, most preferably 11.5% by weight based on the total weight of the composition.

6. The multi-particle composition according to claim 1 or 2, characterized in that 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, etc.; alpha-starches and mixtures thereof, preferably the diluent is a cellulose derivative selected from methyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl cellulose; alpha-starch and / or mixtures thereof, more preferably microcrystalline cellulose.

7. The multi-particle composition according to claim 1 or 2, wherein the binder is selected from povidone, copovidone, polyethylene glycol, gelatin, polyethylene oxide, alginic acid, modified corn starch and / or mixtures thereof, preferably selected from povidone, copovidone and / or mixtures thereof, more preferably copovidone.

8. The multi-particle composition according to claim 1 or 2, 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.

9. a) comprising 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; b) all of the individual immediate-release cores a) are coated with a mixture comprising ethylcellulose and hydroxypropylmethylcellulose, and further, the weight ratio of ethylcellulose to hydroxypropylmethylcellulose in the coating mixture is 11:1 to 15:1; The multi-particle composition according to claim 1 or 2, wherein the coating layer corresponds to 5% to 20% by weight, preferably 7% to 15% by weight, more preferably 8% to 13% by weight, more preferably 9% to 12% by weight, most preferably 11.5% by weight based on the total weight of the composition.

10. A multi-particle pharmaceutical composition according to claim 1 or 2, which is 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 1000 mg, 1500 mg, 2000 mg or 3000 mg.

11. The multi-particle pharmaceutical composition according to claim 1 or 2, characterized in that it is filled in a sachet.

12. A method for preparing the multi-particle pharmaceutical composition according to claim 1 or 2, comprising: i) providing levetiracetam or a pharmaceutically acceptable salt thereof; ii) optionally, mixing the levetiracetam or a pharmaceutically acceptable salt thereof with a diluent for 1 to 10 minutes, more preferably 2 to 7 minutes, even more preferably 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 steps are present, the product resulting from steps (ii) and (iii), preferably at a temperature of 55°C to 70°C, more preferably at a temperature of 60°C to 65°C, even more preferably at a temperature of 60°C; v) optionally, mixing the product resulting from step (i), or when steps are present, the product resulting from steps (ii), (iii) and (iv) with a flow promoter, preferably for 5 to 30 minutes, more preferably for 10 to 20 minutes, even more preferably for 15 minutes; vi) optionally, mixing the product resulting from step (i), or when steps are present, the product resulting from steps (ii), (iii) and (iv) with a lubricant, preferably for 1 to 10 minutes, more preferably for 2 to 7 minutes, even more preferably for 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) and (vi) with a mixture comprising ethylcellulose and hydroxypropylmethylcellulose having a viscosity of 1 mPa·s to 1,000 mPa·s in a 2% (w / w) aqueous solution at 20°C, and further, the weight ratio of ethylcellulose to hydroxypropylmethylcellulose is 11:1 to 15:1; ix) curing the coated mixture resulting from step viii) preferably at a temperature of 15°C to 30°C, more preferably at a temperature of 20°C to 25°C comprising, wherein the composition is in the form of a mini-tablet and does not contain a wax excipient.

13. The method according to claim 12, characterized in that steps (ii), (iii), (iv), (v), (vi) and (vii) are carried out.

14. The multi-particle pharmaceutical composition according to claim 1 or 2 for use in the treatment of epilepsy.

15. The multi-particle pharmaceutical composition according to claim 14 in a once-daily dosing regimen.

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