WO2021099481A1

WO2021099481A1 - Solid composition containing rufinamide

Info

Publication number: WO2021099481A1
Application number: PCT/EP2020/082715
Authority: WO
Inventors: Montserrat Garcia Rovira; Marc Suñé Pou
Original assignee: Medichem, S.A.
Priority date: 2019-11-20
Filing date: 2020-11-19
Publication date: 2021-05-27

Abstract

The present invention relates to discrete units comprising rufinamide. The discrete units comprise a high load of rufinamide, are chemically and physically stable, and provides the characteristics that are desirable in order to be formulated as an oral solid pharmaceutical dosage form.

Description

Solid composition containing Rufinamide

This application claims the benefit of European Patent Application EP19383024.7 filed on November 20^th, 2019.

Technical field

The present invention refers to the field of pharmacy. Specifically, it relates to solid compositions comprising rufinamide.

Background of the invention

Rufinamide is the generic name of compound 1-[(2,6-difluorobenzyl)-1H-1,2,3-triazole-4- carboxamide, the chemical structure of which is the following:

Rufinamide, a process for its preparation, and its use as anticonvulsant was firstly disclosed in the European patent EP0199262.

EP0994863 discloses film-coated tablets each containing 100 mg, 200 mg or 400 mg of modification A of rufinamide. The non-coated core tablets disclosed therein are prepared by a wet granulation process and contain anhydrous colloidal silica, microcrystalline cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maize starch, sodium carboxymethylcellulose and sodium lauryl sulfate as excipients. Rufinamide is a triazole derivative and an anticonvulsant medication to treat seizure disorders associated with Lennox-Gastaut syndrome (LGS) in patients 1 year of age and older that is marketed by Eisai in the United States under the brand name Banzel® and in Europe under the brand name Inovelon®. The rufinamide authorized pharmaceutical dosage forms include immediate release film-coated tablets with strengths of 100 mg, 200 mg and 400 mg and an oral suspension of 40 mg/ml strength.

According to the FDA approved labelling text, the recommended starting daily dose of Banzel® in pediatric patients (1 year to less than 17 years) is approximately 10 mg/kg per day administered in two equally divided doses. The dose should be increased by approximately 10 g/kg increments every other day until a maximum daily dose of 45 mg/kg, not to exceed 3200 mg, administered in two equally divided doses, is reached. The recommended starting daily dose of Banzel® in adults (17 years and older) is 400 to 800 mg per day administered in two equally divided doses. The dose should be increased by 400-800 mg every other day until a maximum daily dose of 3200 mg, administered in two equally divided doses, is reached.

According to the Inovelon® summary of product characteristics, the recommended initial dose in children 1 to <4 years old is 10 mg/kg/day and the dose may be increased by up to 10 mg/kg/day every third day until a maximum dose of 45 mg/kg/day in patients not receiving valproate or until a maximum dose of 30 mg/kg/day in patients receiving valproate. The recommended initial dose in children ³4 years old and <30 kg not receiving valproate is 200 mg daily; the dose may be increased by 200 mg/day as frequently as every third day, to a maximum dose of 1000 mg/day in patients not receiving valproate or until a maximum dose of 600 mg/day in patients receiving valproate. An initial dose of 400 mg/day is recommended for adults, adolescents, and children ³4 years of age of 30 kg or over, with 400 mg/day dose increases, as frequently as every other day, up to a maximum daily dose based on body weight as follows: 1800 mg, 2400 mg, and 3200 mg in patients not receiving valproate with a body weight of 30.0-50.0 kg, 50.1-70.0 kg and ³70.1 kg, respectively, and up to a maximum recommended dose of 1200 mg, 1600 mg, and 2200 mg in patients also receiving valproate with a body weight of 30.0-50.0 kg, 50.1- 70.0 kg, and ³70.1 kg, respectively. Tablets and oral suspension should be taken twice daily in the morning and in the evening, in two equally divided doses. In the light of the above, patients requiring high doses of rufinamide should take, both in the morning and in the afternoon, several tablets at a time because the exact dose is not commercially available. It is known that regimens that require multiple pharmaceutical dosage forms administered simultaneously cause more discomfort and are associated with less medication compliance, usually defined as act of taking medication on schedule or taking medication as prescribed. Therefore, this is not desirable because patients that are not taking their medication properly at every appointment do not have the expected effects.

Therefore, there is a need to provide alternative oral solid pharmaceutical dosage forms containing rufinamide to improve patients' medication compliance. The present invention fulfils this and related needs.

Summary of the invention The invention provides a discrete unit comprising: a) Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, b) At least a filler/diluent, c) At least a binder, d) Optionally, at least a disintegrant, and e) Optionally, at least a humectant.

The invention also provides a solid composition comprising one or more discrete units of the present invention, and optionally one or more pharmaceutically acceptable excipients or carriers.

The invention further provides the discrete unit as previously defined or the solid composition comprising one or more discrete units of the present invention, for use in the treatment of seizures (epilepsy), specially associated with Lennox-Gastaut syndrome (LGS).

The invention further provides a process for preparing the discrete unit of the present invention, which comprises: a. Mixing Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, with at least a filler/diluent and optionally at least a disintegrant, b. Mixing a binder, and optionally at least a humectant with a solvent, c. Wetting the mixture obtained in step (a) with the mixture obtained in step (b), d. Extruding the wet mixture obtained in step (c) to obtain an extrudate, e. Spheronizing the extrudate to obtain the discrete unit, f. Optionally, drying the discrete unit, g. Optionally, sieving the discrete unit, and h. Optionally, coating the dried discrete unit.

Detailed description of the invention

All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims. A first aspect of the present invention provides a discrete unit comprising: a) Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, b) At least a filler/diluent, c) At least a binder, d) Optionally, at least a disintegrant, and e) Optionally, at least a humectant.

The authors of the present invention have found that the discrete unit of the present invention surprisingly is stable while containing a high load of rufinamide and provide the characteristics that are desirable in order to be formulated as an oral solid pharmaceutical dosage form. Mainly, one or more discrete units of the present invention can be filled into a sachet, filled into a capsule (encapsulated) or compressed into a tablet and then administered to the patient.

All percentages referred herein are by weight. The term “percentage values (%)” refers to the percentage of each component with respect to the total weight of the discrete unit on a dry basis or to the total weight of the solid composition, such as tablet, capsule or sachet, unless otherwise indicated.

Rufinamide is present in the discrete unit of the present invention in an amount about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit.

The term "about" or “around” as used herein refers to a range of values ± 10% of a specified value. For example, the expression "about 10" or “around 10” includes ± 10% of 10, i.e. from 9 to 11.

Rufinamide can be in any crystalline form, salt or solvate, thereof. These forms may differ in some physical properties, but they are equivalent for the purposes of the present invention. Rufinamide used in the present invention can be subjected to mechanical size reduction, such as micronization, milling or any method known in the art for example cutting, chipping, grinding, crushing, trituration and the like. The forms thus obtained may differ in some physical properties, but they are equivalent for the purposes of the present invention.

Preferably, rufinamide used in the present invention has a d90 between about 30 mhi and about 70 mGh (i.e. 90% by volume of the particles have a diameter equal between about 30 mGh and about 70 mhi).

The particle size of rufinamide can be determined by laser light scattering for instance using a Malvern Mastersizer Apparatus MS 3000 equipped with a Hydro S dispersion unit and a mixture of water and Tween 20 may be used as dispersion medium.

In a preferred embodiment of the invention, the discrete unit comprises: a) Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, b) At least a filler/diluent, c) At least a binder, d) At least a disintegrant, and e) Optionally, at least a humectant.

In a preferred embodiment of the invention, the discrete unit comprises: a) Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, b) At least a filler/diluent, c) At least a binder, d) Optionally, a disintegrant, and e) At least a humectant.

In a preferred embodiment of the invention, the discrete unit comprises: a) Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, b) At least a filler/diluent, c) At least a binder, d) At least a disintegrant, and e) At least a humectant.

In a preferred embodiment of the invention, the filler/diluent is present in the discrete unit of the present invention at an amount between about 9% w/w and about 30% w/w, more preferably between about 13% w/w and about 29% w/w, and most preferably about 15% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit.

Non-limiting examples of fillers/diluents are cellulose derivatives (such as microcrystalline cellulose), starches (such as maize starch, potato starch, rice starch, wheat starch, pregelatinized starch), lactose, mannitol, sugar and the like, carmellose, sugar alcohols (such as mannitol, sorbitol and xylitol), calcium carbonate, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate and combinations or mixtures thereof.

In a preferred embodiment of the invention, the filler/diluent is microcrystalline cellulose.

In a preferred embodiment of the invention, the binder is present in the discrete unit of the present invention at an amount between about 1% w/w and about 10% w/w, more preferably between about 2% w/w and about 6% w/w, and most preferably about 3% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit. Non-limiting examples of binders are gelatin, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), methylcellulose, povidone (polyvinylpyrrolidone), sucrose, starch, copovidone, powdered acacia, gelatin, guar gum, carbomer (e.g. carbopol), methylcellulose, polymethacrylates, starch and combinations or mixtures thereof.

In a preferred embodiment of the invention, the binder is copovidone.

The discrete unit of the present invention can optionally comprise at least a disintegrant. In a preferred embodiment of the invention, the disintegrant is present in the discrete unit of the present invention at an amount between about 0% w/w and about 30% w/w, more preferably between about 5% w/w and about 20% w/w, and most preferably about 9% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit.

Non-limiting examples of disintegrants are low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cellulose powdered, chitosan, docusate sodium, glycine, sodium alginate, croscarmellose sodium, crospovidone and the like, sodium starch glycolate, starch, alginic acid, calcium alginate, and combinations or mixtures thereof.

In a preferred embodiment of the invention, the disintegrant is low-substituted hydroxypropyl cellulose. The low-substituted hydroxypropyl cellulose (L-HPC) is available in a number of different grades which have different particle sizes and substitution levels, and which are classified on the basis of their % hydroxypropoxy content per glucose ring unit. Suitable grades of L-HPC include the following: 1) LH-11 having a hydroxypropoxy content of 11% and an average particle size of 50 microns; 2) LH-21 having a hydroxypropoxy content of 11% and an average particle size of 40 microns; 3) LH-31 having a hydroxypropoxy content of 11% and an average particle size of 25 microns; 4). LH-22 having a hydroxypropoxy content of 8% and an average particle size of 40 microns; 5) LH-32 having a hydroxypropoxy content of 8% and an average particle size of 25 microns; 6) LH-20 having a hydroxypropoxy content of 13%, and an average particle size of 40 microns; and 7) LH-30 having a hydroxypropoxy content of 13%, and an average particle size of 25 microns. Preferred L-HPCs are commercially available under the trade designation L-HPC Grade LH-21 and LH-11.

The discrete unit of the present invention can optionally comprise at least a humectant.

In a preferred embodiment of the invention, the humectant is present in the discrete unit of the present invention at an amount between about 0% w/w and about 30% w/w, more preferably between about 1% w/w and about 20% w/w, and most preferably about 3% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit.

Non-limiting examples of humectants are glycerin, polyoxyethylene polyoxypropylene ether, 1,3-butylene glycol, polyethylene glycol, diglycerin, dipropylene glycol, xylitol, trehalose, erythritol, hyaluronic acid, urea, and combinations or mixtures thereof. In a preferred embodiment of invention, the humectant is glycerin.

The discrete unit of the present invention may further comprise lubricant (s), anti-adherent agent(s), glidant(s), surfactant (s), plasticizer (s) and other suitable excipients well known in the formulation art.

Non-limiting examples of lubricants are stearic acid and stearic acid derivatives such as magnesium stearate, calcium stearate, zinc stearate, sucrose esters of fatty acid, polyethylene glycol, talc, sodium stearyl fumarate, zinc stearate, castor oils, waxes and combinations or mixtures thereof.

Non-limiting examples of anti-adherent agents are talc, silica derivatives, colloidal silicon dioxide, Syloid 244 FP and the like, and combinations or mixtures thereof. Non-limiting examples of glidants are colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, calcium phosphate tribasic, cellulose powdered, magnesium oxide, magnesium silicate, magnesium trisilicate, and bentonite, and combinations or mixtures thereof. Non-limiting examples of surfactants are sodium lauryl sulfate, triethyl citrate, alcohol, emulsifying wax, docusate sodium, phospholipids, bezethonium chloride, cetrimide, cetylpyridinium chloride, lauryl acid, myristyl alcohol, parabens and derivatives, sorbic acid, glyceril monooleate, polyoxyethylene derivatives, polysorbate 80, sorbitan esters and vitamin E polyethylene glycol succinate, and combinations or mixtures thereof.

Non-limiting examples of plasticizers are propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, acetyl tributyl citrate, glycerin, glyceryl monostearate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, diacetylated monoglyceride, cetyl alcohol, and combinations or mixtures thereof.

In a preferred embodiment of the invention, the discrete unit comprises: a) Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, b) Microcrystalline cellulose, c) Copovidone, d) Low-substituted hydroxypropyl cellulose, and e) Glycerin.

In a preferred embodiment of the invention, the discrete unit of the present invention is in the form of pellet, granule, microsphere or spheroid.

In a preferred embodiment of the invention, the discrete unit is in the form of pellet.

In the present invention, the terms pellet, bead, and non-pareil are synonymous and may be used interchangeably.

Preferably, the discrete unit of the present invention range in size from about 0.5 mm to about 2.5 mm in diameter, more preferably from about 1 mm to about 2 mm, even more preferably at about 1.5 mm. Size in this respect is determined by whether a discrete unit passes through, or is retained, as a result of agitation on a sieve or screen having a mesh opening size as stated. If the discrete unit passes through the sieve or screen, it is described as having a size which is equal to or less than that of the mesh opening, and if the discrete unit is retained, it is described as having a size that is greater than the mesh opening. The discrete unit of the present invention may be coated with an appropriate material used for film coating for one or more purposes which include, without limitation, for further controlling the release properties of the active agent, for appearance, for taste masking and/or for moisture protection in order to improve their shelf-life. Coating agents may include polymers, for example cellulosic polymers such as HPMC, plasticizers, colourants, opacifiers and solvents or carriers. The coated discrete unit of the present invention can be prepared according to methods well known in the state of the art. The appropriate excipients and/or carriers, and their amounts of the coating can readily be determined by those skilled in the art. The discrete unit of the present invention may be formulated as a solid composition, preferably as an oral solid pharmaceutical dosage form especially suitable for the immediate, controlled and/or sustained release of the active ingredient, preferably for immediate release of rufinamide. Another aspect of the present invention is a solid composition comprising one or more discrete units of the present invention, and optionally one or more pharmaceutically acceptable excipients or carriers.

The expression "pharmaceutically acceptable excipients or carriers" refers to excipients that are compatible with the other ingredients of the pharmaceutical composition and are suitable for use in contact with the tissue or organ of humans without excessive toxicity, irritation, allergic response or other complications commensurate with a reasonable benefit/risk ratio.

In a preferred embodiment of the invention, the solid composition of the present invention is selected from a tablet, capsule or sachet.

Preferably, the discrete units of the present invention can be compressed into a tablet or any other compressed solid pharmaceutical dosage form. The compression step can be done without including any excipients (such as fillers/diluents, lubricants, anti-adherents and/or glidants) or with excipients, for example in an amount up to 30% w/w based on the total weight of the tablet or any compressed solid pharmaceutical dosage form.

The solid compositions of the present invention can be prepared according to methods well known in the state of the art. The appropriate excipients and/or carriers, and their amounts, can readily be determined by those skilled in the art according to the type of composition being prepared.

In a preferred embodiment of the invention, the discrete units of the present invention can be compressed without including any excipient. The resulting compressed tablet exhibits excellent hardness and minimal friability even in the absence of additional excipients.

The tablets obtained can be, for example, round or oval, preferably oval.

Preferably, the tablet is an immediate release tablet. Immediate release tablets are those where the active ingredient, such as rufinamide, is released from the tablet immediately or very soon after ingestion.

In a preferred embodiment of the invention, the solid composition of the present invention is selected from a tablet which contains 200 mg or 400 mg or 800 mg of rufinamide.

The tablets of the present invention with 800 mg of rufinamide are, despite the high load of rufinamide, tablets with a similar size than the commercially available 400 mg tablets. Therefore, tablets with a dosage strength of 800 mg of rufinamide provide a more convenient dosage form to deliver the recommended dose of rufinamide, while at the same time reducing the total number of tablets to achieve the required daily dose and without increasing significantly the size of the tablet. Therefore, the tablets of the present invention lead to a better patients' medication compliance. The oval 800 mg tablets are between about 15 m and about 22 mm in length, preferably between about 16 mm and about 19.5 mm, most preferably about 17 mm; between about 5 mm and about 12 mm in width, preferably between about 6 mm and about 10 mm, most preferably about 8.5 mm; and between about 4 mm and about 12 mm in thickness, preferably between about 6 mm and about 10 mm, most preferably about 9 mm.

The tablets of the present invention with 200 mg of rufinamide or 400 mg of rufinamide are tablets with a smaller size than the commercially available tablets.

The oval 200 mg tablets are between about 8 mm and about 16 mm in length, preferably between about 9 mm and about 15 mm, most preferably about 10 mm; between about 4 mm and about 10 mm in width, preferably between about 5 mm and about 8 mm, most preferably about 6 mm; and between about 2 mm and about 8 mm in thickness, preferably between about 4 mm and about 6 mm, most preferably 5 mm.

The oval 400 mg tablets are between about 12 mm and about 20 mm in length, preferably between about 14 mm and about 18.5 mm, most preferably about 15.5 mm; between about 4 mm and about 12 mm in width, preferably between about 6 mm and about 10 mm, most preferably about 9.5 mm; and between about 2 mm and about 8 mm in thickness, preferably between about 4 mm and about 6 mm, most preferably about 5 mm.

Optionally, the tablet may be coated for one or more purposes which include, without limitation, for further controlling the release properties of the active agent, for appearance, for taste masking and for moisture protection in order to improve the shelf-life.

Optionally, the tablet of the present invention may have one or more score lines on one or both sides. The in vitro dissolution behavior of the tablets of the present invention is similar to that of the reference product Banzel®.

Alternatively, the discrete units of the present invention can be filled into a sachet or encapsulated (e.g. in hydroxypropyl methylcellulose or hard gelatine capsules). Both solid pharmaceutical dosage forms can be sprinkled onto food, for example, applesauce, yogurt, cottage cheese, custard, or pudding, at the time of administration in patients with difficulty swallowing, e.g., paediatric patients and geriatrics. Also, the discrete units of the present invention can be administered through a feeding tube in a long-term care setting to critically ill patients. Optionally, the discrete units of the present invention can be lubricated before filling the capsule or sachet. In a preferred embodiment of the invention, the solid composition of the present invention is selected from a capsule which contains 200 mg or 400 mg or 800 mg of rufinamide.

The capsule filled with the discrete units of the present invention offers the advantage that it is a smaller capsule than would be used with other alternative and offers a manufacturing advantage because there is no need for further processing steps (such as a compression step) apart from a standard encapsulation.

In a preferred embodiment of the invention, the solid composition of the present invention is selected from a sachet which contains 200 mg, 400 mg or 800 mg of rufinamide.

The sachet filled with the discrete units of the present invention offers the advantage that allows higher doses than tablets or capsules, and more considering that some patients need to take higher doses of rufinamide, such as 1600 mg, 2400 mg, and 3200 mg of rufinamide.

The solid compositions comprising one or more discrete units of the present invention can be packaged in any type of container and/or packaging component that prevents water absorption and degradation. Non-limiting examples of containers include bottles, flasks, plastic bags, and blister packs.

In a further aspect, the invention relates to the discrete unit or the solid composition of the present invention, for use in the treatment of seizures (epilepsy), specially associated with Lennox-Gastaut syndrome (LGS). This embodiment of the invention relates to the use of the discrete unit as defined above or the solid composition as defined above, such as a tablet or capsule or sachet, for the manufacture of a medicament for the treatment of seizures (epilepsy), specially associated with Lennox-Gastaut syndrome (LGS).

It may also be formulated as a method for the treatment of seizures (epilepsy), specially associated with Lennox-Gastaut syndrome (LGS), comprising administering an effective amount of the previously defined discrete units or the solid composition as defined above, such as a tablet or capsule or sachet, and optionally one or more pharmaceutically acceptable excipients or carriers, in a subject in need thereof, including a human. Another aspect of the invention is a process for preparing the discrete unit of the present invention, which comprises: a. Mixing Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, with at least a filler/diluent and optionally at least a disintegrant, wherein the percentages are expressed with respect to the total weight of the discrete unit, b. Mixing a binder, and optionally at least a humectant with a solvent, c. Wetting the mixture obtained in step (a) with the mixture obtained in step (b), d. Extruding the wet mixture obtained in step (c) to obtain an extrudate, e. Spheronizing the extrudate to obtain the discrete unit, f. Optionally, drying the discrete unit, g. Optionally, sieving the discrete unit, and h. Optionally, coating the dried discrete unit.

Preferably, rufinamide, the filler/diluent and disintegrant, if used, are sieved before mixed.

The mixing step (a) can be done using different types of mixers like twin shell blender, high shear mixer, tumbler mixer and planetary mixer.

Preferably, the mixture obtained in step (b) is a solution.

The wetting step (c) can be done using planetary mixer or sigma blade mixer or high shear mixer and Horbat mixer.

Non-limiting examples of solvents used in step (b) are water, methanol, ethanol, 1- propanol, /sopropanol and combinations or mixtures thereof. In a preferred embodiment of the invention, the solvent is water.

Preferably, the amount of water used is from about 60% w/w to less or equal than about 99% w/w, more preferably about 90% w/w, in relation to the total amount of the mixture obtained in step b).

The extrusion step (d) can be done, for example by employing a radial extruder, an axial extruder or other type of extruder. The spheronization step (e) comprises three stages: breaking of cylindrical segments or extrudates, agglomeration of broken segments and smoothing of particles.

Optionally, a drying step can be done to dry the discrete unit. The drying step can be done, for example by try drying or by fluid bed drying.

Optionally, a sieving step can be done in order to retain the discrete unit with the desirable size. Sieving is a technique well known by those skilled in the art. Optionally, a coating step can be done with an appropriate material used for film coating.

Coating agents may include polymers, for example cellulosic polymers such as HPMC, plasticizers, colourants, opacifiers and solvents or carriers. The coated discrete unit of the present invention can be prepared according to methods well known in the state of the art. The appropriate excipients and/or carriers, and their amounts of the coating can readily be determined by those skilled in the art.

A preferred embodiment of the invention is that the process for preparing solid composition as previously defined comprises: a) Mixing Rufinamide in an amount between about 60% and about 90%, more preferably between about 65% and about 85%, and most preferably about 70%, wherein the percentages are expressed with respect to the total weight of the discrete unit, with at least a filler/diluent and optionally at least a disintegrant, b) Mixing a binder and optionally at least a humectant with a solvent, c) Wetting the mixture obtained in step (a) with the mixture obtained in step (b), d) Extruding the wet mixture obtained in step (c) to obtain an extrudate, e) Spheronizing the extrudate to obtain the discrete unit, f) Optionally, drying the discrete unit, g) Optionally, sieving the discrete unit, h) Optionally, coating the dried discrete unit, and

Wherein: when a tablet is prepared, the process further comprises: i) a compression step after step h) to produce a tablet, and j) optionally coating the tablet; when a capsule is prepared, the process further comprises an encapsulation step after step h) to produce a capsule; and when a sachet is prepared, the process further comprises a filling step after step h) to produce a sachet. The compression step i) can be done with or without any excipients. The tablets thus obtained can be optionally coated. Preferably, the tablet is coated.

Coating agents may include polymers, for example cellulosic polymers such as HPMC, plasticizers, colourants, opacifiers and solvents or carriers. The coated tablets of the present invention can be prepared according to methods well known in the state of the art. The appropriate excipients and/or carriers, and their amounts of the coating can readily be determined by those skilled in the art.

Examples

Example 1: Pellets of rufinamide

The following pellets were prepared:

Manufacturing procedure:

1. Rufinamide, microcrystalline cellulose and low-substituted hydroxypropyl cellulose were sifted through suitable mesh and mixed.

2. Copovidone and glycerin were mixed with about 90% w/w of water, under stirring. The amount of water is expressed in relation to the total amount of the mixture copovidone, glycerin and water,

3. The mixture obtained in step (1) was wetted with the mixture obtained in step (2).

4. The mixture obtained in step (3) was extruded using an axial extrusor in order to obtain an extrudate. 5. The extrudate obtained in step (4) was spheronized to obtain pellets. 6. The pellets obtained in step (5) were dried.

7. The dried pellets obtained in step (6) were sifted through suitable mesh.

Example 2: Tablet formulation

Tablets of 200 g, 400 mg and 800 mg strength were prepared by direct compression of the pellets obtained in Example 1 without adding any additional excipients using a rotary tablet press with the suitable punches for every strength. The compressed tablets were coated in a coating drum with the HPMC based film-coating dispersion.

The final developed compositions per strength are the following:

Claims

1. A discrete unit comprising: a) Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, b) At least a filler/diluent, c) At least a binder, d) Optionally, at least a disintegrant, and e) Optionally, at least a humectant.

2. The discrete unit according to claim 1, wherein said discrete unit comprises: a) Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, b) At least a filler/diluent, c) At least a binder, d) At least a disintegrant, and e) Optionally, at least a humectant.

3. The discrete unit according to claim 1 wherein said discrete unit comprises: a) Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, b) At least a filler/diluent, c) At least a binder, d) Optionally, a disintegrant, and e) At least a humectant.

4. The discrete unit according to any of claims 1 to 3, wherein said discrete unit comprises: a) Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, b) At least a filler/diluent, c) At least a binder, d) At least a disintegrant, and e) At least a humectant.

5. The discrete unit according to any of claims 1 to 4, wherein the filler/diluent is present at an amount between about 9% w/w and about 30% w/w, more preferably between about 13% w/w and about 29% w/w, and most preferably about 15% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit.

6. The discrete unit according to any of claims 1 to 5, wherein the filler/diluent is microcrystalline cellulose.

7. The discrete unit according to any of claims 1 to 6, wherein the binder is present at an amount between about 1% w/w and about 10% w/w, more preferably between about 2% w/w and about 6% w/w, and most preferably about 3% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit.

8. The discrete unit according to any of claims 1 to 7, wherein the binder is copovidone.

9. The discrete unit according to any of claims 1 to 8, wherein the disintegrant is present at an amount between about 0% w/w and about 30% w/w, more preferably between about 5% w/w and about 20% w/w, and most preferably about 9% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit.

10. The discrete unit according to any of claims 1 to 9, wherein the disintegrant is low- substituted hydroxypropyl cellulose.

11. The discrete unit according to any of claims 1 to 10, wherein the humectant is present at an amount of between about 0% w/w and about 30% w/w, more preferably between about 1% w/w and about 20% w/w, and most preferably about 3% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit.

12. The discrete unit according to any of claims 1 to 11, wherein the humectant is glycerin.

13. The discrete unit according to any of claims 1 to 12, wherein said discrete unit comprises: a) Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, b) Microcrystalline cellulose, c) Copovidone, d) Low-substituted hydroxypropyl cellulose, and e) Glycerin.

14. The discrete unit according to any of claims 1 to 13, wherein said discrete unit is in the form of pellet, granule, microsphere or spheroid.

15. The discrete unit according to claim 14, wherein said discrete unit is in the form of pellet.

16. A solid composition comprising one or more discrete units according to any of claims 1 to 15, and optionally one or more pharmaceutically acceptable excipients or carriers.

17. The solid composition according to claim 16, which is selected from a tablet, a capsule, and a sachet.

18. The solid composition according to any of claims 16 to 17, which contains 200 mg or 400 mg or 800 mg of rufinamide.

19. The discrete unit as defined in any of claims 1 to 15, or the solid composition as defined in any of claims 16 to 18, for use in the treatment of seizures (epilepsy), specially associated with Lennox-Gastaut syndrome (LGS).

20. A process for preparing the discrete unit as defined in any of claims 1 to 15, which comprises: a) Mixing Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w , and most preferably about 70% w/w, wherein the percentages are expressed with respect of the total weight of the discrete unit, with at least a filler/diluent and optionally at least a disintegrant, b) Mixing a binder, and optionally at least a humectant with a solvent, c) Wetting the mixture obtained in step (a) with the mixture obtained in step (b), d) Extruding the wet mixture obtained in step (c) to obtain an extrudate, e) Spheronizing the extrudate to obtain the discrete unit, f) Optionally, drying the discrete unit, g) Optionally, sieving the discrete unit, and h) Optionally, coating the dried discrete unit.

21. The process according to claim 20, wherein the solvent is water.

22. A process for preparing the solid composition as defined in any of claims 17 to 18, which comprises: a) Mixing Rufinamide in an amount between about 60% w/w and about 90% w/w, more preferably between about 65% w/w and about 85% w/w, and most preferably about 70% w/w, wherein the percentages are expressed with respect to the total weight of the discrete unit, with at least a filler/diluent and optionally at least a disintegrant, b) Mixing a binder, and optionally at least a humectant with a solvent, c) Wetting the mixture obtained in step (a) with the mixture obtained in step (b), d) Extruding the wet mixture obtained in step (c) to obtain an extrudate, e) Spheronizing the extrudate to obtain the discrete unit, f) Optionally, drying the discrete unit, g) Optionally, sieving the discrete unit, h) Optionally, coating the dried discrete unit, and Wherein: when a tablet is prepared, the process further comprises: i) a compression step after step h) to produce a tablet, and j) optionally coating the tablet; when a capsule is prepared, the process further comprises an encapsulation step after step h) to produce a capsule; and when a sachet is prepared, the process further comprises a filling step after step h) to produce a sachet.