MXPA99007514A - Oxacarbazepine film-coated tablets - Google Patents

Abstract

The invention relates to formulations, e.g. film-coated tablets containing oxacarbazepine and to processes for the production of said formulations. The film-coated tablets have a tablet core comprising a therapeutically effective dose of oxacarbazepine being in a finely ground form having a mean particle size of from 4 to 12&mgr;m (median value), and a hydrophilic permeable outer coating.

Description

OXACARBAZE INA TABLETS FILM COATINGS The present invention relates to oxacarbazepine formulations, in particular film-coated tablets, and to processes for the production of these formulations. Oxacarbazepine, 10,11-dihydro-10-oxo-5H-di-benz [b, f] azepine-5-carboxamide, such as RTegretol [(Novartis) carbamazepine: 5H-dibenz [b, f] azepine-5-carboxamide )], is an agent of first choice in the treatment of seizures. The known dosage forms, such as tablets and liquid dosage forms, for example suspensions, are suitable for ensuring a uniform concentration of the active ingredient in the blood, especially in the case of regularly recurrent administration over a prolonged period of treatment . However, it is always desirable to develop and improve existing formulations with respect to, for example, bioavailability and compliance. European Patent Number EP-0,646,374 discloses an oxacarbazepine formulation which is coated with two layers (an inner layer and an outer layer) containing pigments. The outer layer contains iron oxide. The doubly coated tablet eliminates inhomogeneous coloring of the formulation on storage. Despite the known forms of oxacarbazepine, it is always desirable to provide improved formulations.

We have now discovered oxacarbazepine formulations that are easily processed into dosage forms, and that can improve the bioavailability of oxacarbazepine, and increase compliance. According to the above, the invention provides, in one of its aspects, an oxacarbazepine formulation comprising oxacarbazepine, preferably in a finely ground form having an average particle size of about 2 to 12 microns, preferably 4 to 12 microns, more preferably 4 to 10 microns, and with a maximum residue on a sieve of 40 microns of up to 5 percent, for example 2 percent. The formulation according to the invention may contain pharmaceutically acceptable excipients commonly used in pharmaceutical formulations, for example, for oral administration. In a preferred embodiment according to the invention, the formulation may be in the form of a film coated tablet, which comprises: a) a tablet core comprising a therapeutically effective dose of the oxacarbazepine, preferably in a finely ground form, having an average particle size of about 2 to 12 microns, preferably 4 to 12 microns, more preferably 4 to 10 microns, with a maximum residue on a sieve of 40 microns of up to 5 percent, for example 2 percent, and other excipients that are suitable for the production of granules; and b) a permeable hydrophilic outer coating. The formulations, for example the pellet-coated tablets according to the present invention, utilize oxacarbazepine of fine particle size and narrow particle size distribution, and as such, can be formulated into dosage forms, for example, forms of solid oral dosing such as tablets with relative ease. In addition, fine particle size and narrow particle size distribution may also be beneficial in improving the bioavailability of oxacarbazepine. Still further, the formulations satisfy all customary requirements, such as storage stability and color stability. Color stability can be achieved by using only pigments containing a single coating, instead of requiring pigments containing double coating. This has the advantage of making the process of formulating the dosage forms relatively simple and efficient. In addition, for a given dosage size, for example, 300 milligrams or lower amounts of pigment, for example iron oxide (when used) in the coating. The invention provides, in another of its aspects, a process for the production of a film-coated tablet containing oxacarbazepine, which comprises the steps of forming oxacarbazepine, which has an average particle size of about 2 to 12 microns, preferably from 4 to 12 microns, more preferably from 4 to 10 microns, with a maximum residue on a sieve of 40 microns of up to 5 percent, for example, 2 percent, and optionally other excipients, in a central core , and coat this core with a permeable hydrophilic outer coating. In a preferred aspect of the invention, there is provided a process for the production of a film-coated tablet containing oxacarbazepine, which comprises finely grinding oxacarbazepine to an average particle size of about 2 to 12 microns, preferably 4 to 10 microns. 12 microns, more preferably 4 to 10 microns, with a maximum residue on a sieve of 40 microns of up to 5 percent, for example 2 percent, and, with the mixture of excipients that are suitable for the granulation processes , forming the oxacarbazepine into granules, compressing the granules to form tablet cores using conventional tabletting processes, and providing the cores with a permeable hydrophilic outer coating.

Within the scope of the description of the invention, the terms used hereinbefore and hereinafter are defined as follows: The term "film-coated tablet" denotes a solid, single-dose, perorally administrable, dosage form; which can be produced by compressing oxacarbazepine with conventional tablet-forming excipients, to form a tablet core employing conventional tabletting processes, and subsequently coating the core. The tablet cores can be produced using conventional granulation methods, for example, wet or dry granulation; with an optional crushing of the granules, and with the compression and subsequent coatings. Granulation methods are described, for example, in Voigt, loe. clt pages 156-169. Suitable excipients for the production of granules are, for example, powdery fillers or having optionally flow conditioning properties, for example talcum, silicon dioxide, for example synthetic amorphous anhydrous silicic acid of the Syloid® type (Grace), for example SYLOID 244 FP, microcrystalline cellulose, for example of the Avicel® type (FMC Corp), for example of the AVICEL types PH101, 102, 105, RC581 or RC591, of the Emcocel® type (Mendell Corp.) or of the Elcema® type (Degussa); carbohydrates, such as sugars, sugar alcohols, starches or starch derivatives, for example lactose, dextrose, sucrose, glucose, sorbitol, mannitol, xylitol, potato starch, corn starch, rice starch, wheat starch or amylopectin, tricalcium triphosphate, calcium acid phosphate, or magnesium trisilicate; binders, such as gelatine, tragacanth, agar, alginic acid, cellulose ethers, for example methyl cellulose, carboxymethyl cellulose, or hydroxy-propylmethyl cellulose, polyethylene glycols or ethylene oxide homopolymers, having especially a degree of polymerization of about 2.0 x 103 to 1.0 x 105, and an approximate molecular weight of about 1.0 x 105 to 5.0 x 106, for example, the excipients known by the name of Polyox.RTM. (Union Carbide), polyvinyl pyrrolidone or povidones, having especially a molecular weight average of about 1000 and a degree of polymerization of about 500 to 2,500, and also agar or gelatin; substances of surface activity, for example anionic surfactants of the alkyl sulfate type, for example normal dodecyl sulphate, normal tetradecyl sulfate, normal hexadecyl sulfate, or normal octadecyl sulphate of sodium, potassium, or magnesium, of the alkyl ether sulfate type, for example normal dodecyloxyethyl sulfate, normal tetradecyloxyethyl sulfate, normal hexadecyloxyethyl sulfate, or normal octadecyloxyethyl sulfate sodium, potassium, or magnesium, or the type of alkane sulfonate, for example normal dodecane sulfonate, normal tetradecane sulfonate, normal hexadecane sulfonate, or octadecane sulphonate normal sodium, potassium, or magnesium, or nonionic surfactants of the fatty acid polyhydroxyalcohol ester type, such as monolaurate, mono-oleate, monostearate, or sorbitan monopalmitate, sorbitan tristearate or trioleate, polyoxyethylene adducts of fatty acid polyhydroxy alcohol esters, such as monolarate, mono-oleate, monostearate, monopalmitate, tristearate, or polyethylene sorbitan trioleate, fatty acid esters of polyethylene glycol, such as polyoxyethylstearylate, polyethylene glycol stearate 400, polyethylene glycol stearate 2000, especially ethylene oxide / propylene oxide block polymers of the Pluronics® type (BWC) or Synperonic® (ICI). The granules can be produced in a manner known per se, for example, using wet granulation methods known for the production of "built" granules or "decomposed" granules. The methods for the formation of constructed granules can operate continuously, and comprise, for example, simultaneously spraying the granulation mass with a granulation solution, and drying, for example, in a drum granulator, in tray granulators, in granulators of disc, in a fluidized bed, by spray drying or spray solidification, or operating discontinuously, for example in a fluidized bed, in a batch mixer, or in a spray drying drum.

The methods for the production of decomposed granules are preferred, which can be carried out in a discontinuous manner, and wherein the granulation mass forms first a wet aggregate with the granulation solution, the aggregate of which is then crushed or formed into granules of size of the desired particles, and then the granules are dried. The equipment suitable for the granulation step are planetary mixers, low and high shear mixers, wet granulation equipment, including extruders and spheronizers that include, for example, equipment from the companies Loedige, Glatt, Diosna, Fielder, Collette, Aeschbach, Alexanderwerk, Ytron, Wyss & Probst, Werner & Pfleiderer, HKD, Loser, Fuji, Nica, Caleva and Gabler. The granulation mass consists of crushed oxacarbazepine, preferably milled, and the excipients mentioned above, for example powdery fillers, such as microcrystalline cellulose of the AVICEL type. AVICEL PH 102 is especially suitable. Depending on the method used, the granulation mass may be in the form of a premix, or it may be obtained by mixing oxacarbazepine in one or more excipients, or the mixture of excipients in the oxacarbazepine. The wet granules are preferably dried, for example, in the manner described by drying in a tray or in a fluidized bed. According to a variant of the alternative process, tablet cores are produced using the so-called compacting or dry granulation method, wherein the active ingredient is compressed with the excipients to form relatively large molded articles, for example ingots or battens, which are crushed by grinding, and the material ground is compressed to form the tablet cores. The excipients suitable for the compaction method are preferably those which are suitable for conventional direct compression methods, for example dry binders, such as starches, for example potato, wheat, and corn starch, microcrystalline cellulose, example the commercial products available under the registered trademarks Avicel®, Filtra R, Heweten® or Pharmacel®, highly dispersed silicon dioxide, for example Aerosil®, mannitol, lactose, and also polyethylene glycol, having especially a molecular weight of 4000 to 6000, cross-linked polyvinyl pyrrolidone (Polyplasdone® XL or Kollidon® CL), cross-linked carboxymethyl cellulose (Acdisol® CMC-XL), carboxymethyl cellulose [Nymcel®, for example ZSB-10, (Nymcel®, eg ZSB-10, (Nyma)], hydroxypropylmethyl cellulose, example HPMC 603 quality carboxymethyl starch [ExplotabR (Mendell) or PrimojelR (Scholtens)], microcrystalline cellulose, by axis mplo Avicel® PH 102, dicalcium phosphate for example, Emcompress®, or talc. The addition of small amounts of, for example, lubricants, such as magnesium stearate, is also convenient.

The compression to form tablet cores can be carried out in conventional tabletting machines, for example EK-0 Korsch eccentric tablet forming machines, or rotary tablet forming machines. The tablet cores can be of different shapes, for example round, oval, oblong, cylindrical, etc., and of different sizes, depending on the amount of oxacarbazepine. Oxacarbazepine is known. Its manufacture and its therapeutic use as an anticonvulsant are described in German Patent Number 2,011,087, which is incorporated herein by reference. A commercially convenient process for the preparation of this active ingredient is described in European Patent Application Number 0,028,028, which is incorporated herein by reference. Commercially available dosage forms are provided for peroral administration, for example, tablets comprising 300 and 600 milligrams of active ingredient. These dosage forms are known by the registered trademark RTrileptal (Novar-tis), and have been introduced in a large number of countries, such as Denmark, Finland, Austria, and Belgium. The average particle size of the oxacarbazepine is from about 2 to 12 microns, preferably from 4 to 12 microns, more preferably from 4 to 10 microns, with a maximum residue over a sieve of 40 microns of up to 5 percent, by example 2 percent. In a preferred form of the process, the The average particle size of oxacarbazepine is about 4 to 12 microns, normally 6 to 8 microns, with a maximum residue on a sieve of 40 microns, up to 5 percent, for example 2 percent. The known particle size analysis methods are suitable for determining the average particle size, for example, the measurement of particle size using light, for example, light scattering methods or turbidimetric methods, sedimentation methods, eg analysis pipetting using an Andreassen pipette, sedimentation scales, photosedimentometers, or sedimentation in a centrifugal force field, pulse methods, for example using a Coulter counter, or selection by means of gravity or centrifugal force. These methods are described, among other things, in Vo? Gt, loe. cit. pages 64-79. In order to produce oxacarbazepine particles, for example crystals having the desired particle size, conventional crushing and deagglomeration techniques can be employed, for example grinding in an air jet mill or in an impact mill, a mill of balls, a vibrating mill, mortar mill, or a pin mill. The permeable hydrophilic external coating b) comprises a film-forming material that is permeable to water and intestinal juice, and that can be swollen, and that is soluble or at least to some extent soluble, in these fluids Water-permeable film-forming materials are, for example, hydrophilic mixtures of polyvinyl pyrrolidone, or a copolymer of polyvinyl pyrrolidone and polyvinyl acetate with hydroxypropylmethyl cellulose, mixtures of shellac with hydroxypropylmethyl cellulose, polyvinyl acetate or copolymers thereof with pyrrolidone. polyvinyl, or mixtures of water soluble cellulose derivatives, such as hydroxypropylmethyl cellulose, and water insoluble ethyl cellulose. The coating compositions, if desired, can be used in admixture with other additional excipients, such as talc or silicon dioxide, for example synthetic amorphous silicic acid of the Syloid® type (Grace), for example SYLOID 244 FP, or wetting agents, for example sorbates or plasticizers, for example the aforementioned polyethylene glycols. Elastic film-like materials are especially hydrophilic partially etherified cellulose derivatives. Hydrophilic partially etherified cellulose derivatives are, for example, lower alkyl ethers of cellulose having an average degree of molar substitution (MS) that is greater than one and less than three, and an average degree of polymerization of about 100 to 5,000.

The degree of substitution is a measure of the substitution of the hydroxyl groups by the lower alkoxy groups per glucose unit.

The average degree of molar substitution (MS) is an averaged value, and indicates the number of lower alkoxy groups per glucose unit in the polymer. The average degree of polymerization (DP) is also an averaged value, and indicates the average number of glucose units in the cellulose polymer. The lower alkyl ethers of cellulose are, for example, cellulose derivatives which are substituted in the hydroxymethyl group (primary hydroxyl group) of the glucose unit which forms the cellulose chains, and where appropriate, in the second and third group secondary hydroxyl by alkyl groups of 1 to 4 carbon atoms, especially methyl or ethyl, or by alkyl groups of 1 to 4 carbon atoms substituted, for example 2-hydroxyethyl, 3-hydroxypropyl normal, carboxymethyl or 2-carboxyethyl. Suitable lower alkyl ethers of cellulose are preferably cellulose derivatives which are substituted in the hydroxymethyl group (primary hydroxyl group) of the glucose unit by the alkyl groups of 1 to 4 carbon atoms mentioned, or by alkyl groups of 1 to 4 carbon atoms substituted, and in the second, and where appropriate, third secondary hydroxyl group, by methyl or ethyl groups, Suitable cellulose lower alkyl ethers are special These include methyl cellulose, ethyl cellulose, methylhydroxyethyl cellulose, mefcylhydroxypropyl cellulose, ethylhydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose (in the form of a salt, for example in the form of a sodium salt), or methylcarboxymethyl cellulose (also in salt form, for example in the sodium salt form). Preferred lower alkyl cellulose ethers are ethyl cellulose (degree of polymerization: from about 150 to 1000; molar substitution: from about 1.2 to 1.8), for example of the Aquacoat® type (FMC Corp.), hydroxyethyl cellulose (degree of polymerization: from about 120 to 1,200, molar substitution: from about 1.2 to 2.5), and hydroxypropyl cellulose (degree of polymerization: from about 200 to 3,000, molar substitution: from about 1.0 to 3.0). Water permeable film forming materials also include cellulose acetate trimellitate (CAT), and methacrylic acid / methacrylate copolymer, 1: 1 or 1: 2, for example EUDRAGIT L and S, for example EUDRAGIT L 12.5 or S 12.5 . The film-forming material can be sprayed on in the form of an aqueous dispersion of redispersible cellulose acetate phthalate - CAP - (Aquateric®: FMC), of polyvinyl acetate phthalate - PVAP - (Coateric®: Colorcon), of phthalate hydroxypropylmethyl cellulose - HPMCP - (Aquacoat® HP 50 or HP 55: Shin-Etsu) or also, in particular, acrylic acid / methacrylic acid copolymer partially esterified by groups alkyl of 1 to 4 carbon atoms. Also suitable is a copolymer of acrylic acid / methacrylic acid, 1: 1, partially esterified by methyl and / or ethyl groups of the type EUDRAGIT L 30 D or EUDRAGIT L 100-55 dispersed in water. The film-forming materials may comprise additional excipients, such as, for example, plasticizers, for example triethyl citrate, for example Citroflex® (Pfizer) triacetin, different phthalates, for example diethyl or dibutyl phthalate, mono- or diglycerides mixtures of the Myvacet® type (Eastman) for example MYVACET 9-40, the polyethylene glycols mentioned hereinabove, having, for example, a molecular weight of about 6,000 to 8,000, and also ethylene oxide block copolymers / propylene oxide of the Pluronic.RTM. type (BASF) or Synperonic.RTM. (II), powdery mold release agents, for example magnesium trisilicate, starch, or synthetic amorphous silicic acid of the SYLOID type, for example SYLOID 244 FP. The permeable hydrophilic external coating b) comprises white pigments, for example titanium dioxide pigments, preferably combined with iron oxide pigments. The iron oxide may be ferric or ferrous iron oxide, preferably Fe203 optionally in hydrated form. When iron oxide is used, the amounts used in the coating will depend on the size of the dosage form particular. Preferably, the amount of iron oxide used can be selected from about 0.1 milligrams per dosage form, eg, tablets, up to 1.6 milligrams per dosage form, eg, tablet, more preferably 0.3 milligrams per dosage form, per tablet example, at 0.9 milligrams per dosage form, for example tablet. The tablet cores can be coated with the permeable hydrophilic coating composition in a manner known per se, using conventional coating methods. For example, the coating composition is dissolved or suspended in water in the desired amount ratio. If desired, excipients, such as polyethylene glycol, are added. The solution or dispersion is sprayed onto the tablet cores together with other excipients, for example talc or silicon dioxide, for example SYLOID 244 FP, for example using known methods, such as spray coating in a fluidized bed, for example using the Aeromatic, Glatt, Wurster or Hüttlin system (ball coater), or also in a coating tray according to the methods known by the names Accela Cota, or dip coating. Preferably, an aqueous dispersion comprising hydroxypropylmethyl cellulose (HPMC cellulose) is sprayed on, and pigments The formulations, for example the film-coated tablets according to the invention, are useful for their anticonvulsant action, and are useful as a monotherapy or as an auxiliary therapy in the control, prevention, or treatment of attacks, for example resulting from the establishment of epilepsy, status epilepticus, cerebrovascular disorders, head injury, and alcohol withdrawal. The exact dose of oxacarbazepine, and the particular formulation to be administered, depends on a number of factors, e.g., the condition to be treated, the desired duration of treatment, and the rate of release of oxacarbazepine. . For example, the amount of oxacarbazepine required, and the rate of release thereof, can be determined by in vitro or in vivo techniques, determining the time during which a particular concentration of the active agent remains in the blood plasma, at a level acceptable for a therapeutic effect. Preferred regimens include for monotherapy, from 150 to 600 milligrams, for example 300 milligrams twice a day. Doses of 1, 200 to 2,400 milligrams per day can be tolerated. Preferred regimens for auxiliary therapy include an initial dose of 300 milligrams per day.

Doses from 600 to 2,400 milligrams per day can be tolerated. The following examples illustrate the invention.

Example 1 Formulations Example 1 The TRILEPTAL, the cellulose HPM 603 (binder), and the AVICEL PH 102 (binder, filler, excipient promoter of the disintegration) are mixed in a mixer, preferably in a high speed mixer (DIOSNA, LOEDIGE, FIELDER, GLATT and so on). ). Water is added as the granulation liquid to the mixture, and it is kneaded in a mixer, preferably in a high speed mixer, until a suitable consistency is achieved. In an alternative way, the cellulose binder HPM can be dissolved in water in the granulation liquid beforehand. The wet granules are granulated using a suitable device (ALEXANDER Reibschnitzler, QUADRO-COMILL) and dried in a fluidized bed (AEROMATIC, GLATT). AVICEL PH 102, AEROSIL 200 (flow conditioner), and polyvinyl pyrrolidone PXL (disintegrator) are added to the dry granules, and they are crushed and mixed in a crusher (FREWITT, QUADRO-COMILL, FITZMILL). Finally, magnesium stearate (lubricant) is added and mixed (STOECKLIN container mixer, VRIECO mixer). In an alternative way, the lubricant can be added directly to the crushed material. The final mixture is compressed to form TRILEPTAL tablets (eccentric press, rotary press: KILIAN, KORSCH, FETTE, MANESTY). The tablets are coated with an aqueous preparation consisting of cellulose HPM 603 (film former), yellow iron oxide 17268 (pigment), PEG 8,000 (plasticizer for the film former), talc (anti-adhesive agent, coating), and titanium dioxide (covering agent), in a rotating coating tray (ACCELA-COTA, GLATT, DRIACOATER, DUMOULIN). Alternatively, it is possible to use, for example, a fluidized bed or air suspension apparatus for the coating process (AEROMATIC, GLATT, FREUND, HUETTLIN).

Example 2 Oxacarbazepine, cellulose HPM 603, and Avicel PH 102 are mixed together in a planetary mixer (Aeschbach). Alcohol is added to this mixture before it is kneaded in a planetary mixer until the desired consistency is achieved. Subsequently, the methodology according to Example 1 is followed to provide coated tablets. 3 "The same methodology as Example 1 is carried out on the formulation, to provide coated tablets.

Claims (10)

1. A formulation comprising oxacarbazepine having an average particle size of about 2 to 12 microns, preferably 4 to 12 microns, more preferably 4 to 10 microns, and with a maximum residue on a 40 micron sieve of up to 5 microns. percent, for example 2 percent.

2. A film coated tablet comprising oxacarbazepine, having an average particle size of about 2 to 12 microns, preferably 4 to 12 microns, more preferably 4 to 10 microns, and with a maximum residue on a sieve of 40 microns of up to 5 percent, for example 2 percent.

3. A film-coated tablet, comprising: a) a tablet core comprising a therapeutically effective dose of oxacarbazepine, which is preferably in a finely ground form, having an average particle size of about 4 to 12 microns , preferably from 4 to 10 microns, with a maximum residue on a sieve of 40 microns of up to 5 percent, for example 2 percent, and other excipients that are suitable for the production of granules; and b) a permeable hydrophilic outer coating.

4. A film coated tablet according to claim 3, which comprises: a) a tablet core comprising a therapeutically effective dose of oxacarbazepine, which is preferably in a finely ground form, having an average particle size of about 6 to 8 microns, with a maximum residue on a sieve of 40 microns of 2 percent, and other excipients that are suitable for the production of dry granules. A film coated tablet according to claim 3 or claim 4, which comprises as component b), a permeable hydrophilic outer coating comprising white pigments, iron oxide pigment, and optionally other excipients. 6. A process for the production of a film coated tablet containing oxacrbazepine, which comprises forming the oxacarbazepine, which has an average particle size of about 2 to 12 microns, preferably 4 to 12 microns, more preferably 4 at 10 microns, with a maximum residue on a sieve of 40 microns of up to 5 percent, for example 2 percent, and optionally other excipients, in a central core, and to coat this core with a permeable hydrophilic outer coating. 7. A process for the production of a film coated tablet according to claim 3, the which comprises grinding oxacarbazepine finely to an average particle size of about 2 to 12 microns, preferably 4 to 12 microns, more preferably 4 to 10 microns, with a maximum residue on a sieve of 40 microns up to 5 microns percent, for example 2 percent, and with the mixture of excipients that is suitable for the granulation processes, form the active ingredient into granules, compress the granules to form tablet cores using conventional tabletting processes, and provide the nuclei a permeable hydrophilic outer coating. A process according to claim 7, which comprises forming the finely ground oxacarbazepine in wet granules with the mixture of excipients that are suitable for the granulation processes, and compressing the wet granules to form tablet cores, employing processes of formation of conventional tablets. 9. * Oxacarbazepine having an average particle size of about 2 to 12 microns, preferably 4 to 12 microns, more preferably 4 to 10 microns. 10. Oxacarbazepine having an average particle size of about 2 to 12 microns, preferably 4 to 12 microns, more preferably 4 to 10 microns, and with a maximum residue on a 40 micron sieve of up to 5 percent , for example 2 percent.