MXPA00008620A - Pharmaceutical composition of topiramate - Google Patents

Abstract

The invention is directed to a pharmaceutical composition of topiramate, an anticonvulsant which is useful for treating epilepsy. More specifically, the present invention provides a solid dosage formulation of topiramate intended primarily for use by pediatric patients, of for patients who have difficulty swallowing tablets. Processes for preparing the pharmaceutical composition are also described.

Description

PHARMACEUTICAL COMPOSITION OF TOPIRAMATO CROSS REFERENCE FOR RELATED APPLICATION This application claims priority of the provisional application for United States with serial number 60 / 076,770, filed March 4, 1998, the content of which is incorporated herein by reference.

FIELD OF THE INVENTION The present invention provides a solid dosage formulation of topiramate and a process for producing the solid dosage formulation. More particularly, the solid dosage formulation comprises core particles which are coated with a taste disguising coating to provide coated particles which can be sprinkled in the food to facilitate administration to patients having difficulty in swallowing tablets or capsules, for example, pediatric patients.

BACKGROUND OF THE INVENTION The pharmaceutical industry employs a variety of dosage formulations to orally administer medicinal agents to patients.

Typical formulations for oral administration include liquid solutions, emulsions, or suspensions, as well as solid forms such as capsules or tablets (as used herein, the term "tablets" means any solid and compressed solid dosage form, which includes tablets. ). Because these conventional solid dosage formulations are usually directed to adults who can not easily swallow large whole tablets, the frequent unpleasant taste of the active ingredient need not be taken into account in formulating the medicine, except for the provision of means to prevent the taste is evident during the short time the medicine is in the mouth. Such means may include the provision of a suitable coating on the tablet, the use of a capsule form (the outer gelatin shell of the capsule keeps the active ingredient in until the capsule has been swallowed), or simply compressing firmly a tablet so that it does not begin to disintegrate during the short time that it is intended to keep in the mouth. Children, the elderly and many others have difficulty swallowing whole tablets and even capsules. Therefore, it is often advisable to provide the medicine either in liquid form or in a chewable solid form or an alternative solid form, for example, small particles which can be sprinkled in soft foods and swallowed complete with the food, in addition to the entire tablet or capsule that you intend to swallow. Even when the medicine can be formulated as a liquid, it is convenient to provide a chewable solid form or an alternative solid form such as microspheres, which can be sprinkled in soft foods (eg, baby food) because it is often more convenient and easy to administer. A main requirement of any solid form is that it must be palatable, since an unappetizing formulation greatly increases the risk that a patient will refuse to take a medication. An additional requirement of any solid dosage form is that it must be bioavailable; that is, once the formulation reaches the stomach, the individual particles must release the active ingredient quickly and completely to ensure that substantially all of the active ingredient is absorbed. In cases where the active ingredient is not particularly appetizing and somewhat unstable, it can be difficult, if not impossible, to identify a solid form that meets both requirements (ie, palatable and bioavailable). A number of references are known which describe pharmaceutical compositions of non-palatable medicinal agents, which are coated with a taste disguising coating in order to hide the unpleasant taste. Julián et al., In the patent of E.U.A. No. 4,851, 266, describes tablets of chewable medicament made by coating granules of a medicament (especially, acetyl p-aminophenol) with a mixture of cellulose acetate or cellulose acetate-butyrate and polyvinylpyrrolidone (also known as "PVP" and hereinafter referred to by its name as United States Pharmacopeia (USP) as "povidone"). Mehta, in the patent of E.U.A. No. 5,084,278, describes a pharmaceutical composition comprising a pharmaceutical core of an active dose of a compound and a microencapsulated polymer, which covers the pharmaceutical core and is capable of disguising the taste of the active compound. Bhardway, et al., In the U.S. patent. No. 5,578,316, discloses drug cores coated with methacrylate ester copolymers, which disguise the bitter and unpleasant taste of the medicament. A variety of chlorosulfate and sulfamate esters of 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose, and their anticonvulsant activity in mammals, and therefore their usefulness in the treatment of diseases such as epilepsy and glaucoma, are described in the US patent No. 4, 513,006. More specifically, the sulfamate compound of 2,3,4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose referred to as "topiramate" is currently available for sale as a tablet product. in concentrations of 25, 50, 100, 200, 300 and 400 mg as an auxiliary therapy for the treatment of adults with partial initial sizes (TOPAMAX® tablets (topiramate)). Topiramate can be prepared by following the procedures described in the U.S. Patents. Nos. 4,513,006 and 5,387,700, and preferably, by the procedure described in examples 1 to 3 in the US patent. No. 5,387,700. The difficulty of identifying a chewable solid form of topiramate, due to the extremely bitter taste of topiramate and the problems associated with the stability of the active agent, especially by exposure to moisture and heat, which are known to cause degradation of the topiramate, has continued. topiramate. The degradation of topiramate is easily detected by changes in physical appearance, i.e., brown or black discoloration and by the formation of sulfate ions which can be easily detected by standard techniques known to those skilled in the art. (for example, CLAR). Accordingly, it is an object of the invention to provide a stable solid formulation of topiramate for use in children and other patients who have difficulty swallowing conventional solid forms (e.g., tablets, capsules) that is both palatable and bioavailable. It is a further object of the invention to provide an appetizing solid formulation of topiramate that can be sprinkled into soft foods before consumption (ie, a "sprayed formulation") and which provides immediate release of the active ingredient in the stomach.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a method for forming a pharmaceutical composition comprising: (a) preparing core particles comprising a topiramate active agent; (b) drying the core particles of step (a) to form dry core particles; (c) coating the dried core particles of step (b) with a taste disguising mixture to form coated particles; and (d) drying the coated particles of step (c) to form the pharmaceutical composition, wherein the amount of taste disguising mixture is in the range of about 7% by weight to about 15% by weight of the pharmaceutical composition, Preferably, about 9 to about 13% and preferably about 11% by weight of the pharmaceutical composition. In another aspect of the invention, it is a pharmaceutical composition comprising: (a) core particles containing a topiramate active agent, wherein the core particles have an initial particle size of between about 0.100 mm and 2.5 mm; and (b) a flavor disguising coating, wherein the taste disguising coating comprises from about 7 wt% to about 15 wt% of the pharmaceutical composition, preferably, about 9 to about 13% and preferably about 11. % by weight of the pharmaceutical composition and wherein the coated particles of the pharmaceutical composition have a final particle size of about 0.100 mm to about 2.5 mm.

In one embodiment of the invention, the core particles comprise the topiramate active agent and at least one excipient; preferably, the core particles comprise the topiramate active agent, a binder and a diluent; Preferably, the core particles comprise the topiramate active agent, a binder and sugar spheres. In a class of the invention, it is a pharmaceutical composition comprising from about 85 to about 93% by weight of core beads and about 7 to about 15% by weight of a coating; wherein the core beads comprise from about 18 to about 21% by weight of topiramate, about 8 to about 11% by weight of povidone, and from about 58 to about 61% by weight of sugar spheres; and the coating comprises from about 6 to about 9% by weight of cellulose acetate and from about 2 to about 5% by weight of povidone. In a subclass of the invention, it is the pharmaceutical composition comprising about 89% by weight of core beads and about 11% by weight of coating, wherein the core beads comprise about 19.8% by weight of topiramate, about 9.9% in weight of povidone, and approximately 59.3% by weight of sugar spheres, and the coating comprises about 7.2% by weight of cellulose acetate and about 3.8% by weight of povidone. To illustrate the invention, methods are presented for treating seizures and / or epilepsy in a mammal in need thereof, which comprise administering to a mammal a therapeutically effective amount of any of the pharmaceutical compositions of the present invention. Also included in the invention are methods for treating a selected condition of neuropathic pain, amyotrophic lateral sclerosis, acute ischemia, obesity, diabetes, psoriasis or bipolar disorder (including manic depression) in a mammal in need thereof, which comprise the administration to the mammal of a therapeutically effective amount of any of the pharmaceutical compositions of the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a solid dosage formulation of topiramate which has the primary intention of pediatric use, or for patients who can not swallow tablets. More particularly, the solid dosage formulation is a sprayed formulation comprising core particles of the active agent, which is flavor disguised with a second layer to obscure the extremely bitter taste of topiramate. The core particles may comprise topiramate only, for example, in granular or crystalline form, or topiramate and one or more excipients, which are subsequently formed into granules or beads by techniques known to the person skilled in the art, for example, compaction and crushing with rolls, extrusion-spheronization or other methods to form granules or beads. The preferred solid dosage formulation of the present invention is the form of microspheres which can be sprinkled in soft foods (eg, baby food) and swallowed by the patient together with the food. In a preferred embodiment, three concentrations are obtained, , 25 and 50 mg, of a single sprayed formulation of topiramate coated on sugar spheres using povidone as a binder and flavor disguised with a coating of cellulose acetate and povidone to form coated beads. The concentrations are differentiated by means of different filling weights and proportional capsule sizes. That is, to assist in the delivery of the proper dosage to the patient, an amount of coated beads sufficient to deliver the desired dosage in a capsule can be encapsulated, for example, a gelatin capsule of size 0, size 1, or size 2 It consists of a white body with a natural cover. Black pharmaceutical ink can be used to provide identification information of the product in the capsules. For pediatric patients, the capsules can be opened and the contents of the capsules can be sprinkled in the food and ingested; however, mature patients can swallow the drug in whole capsules, if desired. In general, the process for the preparation of the sprayed formulation includes a step in which the core particles comprising granules, beads or topiramate crystals, alone or in combination with one or more excipients, are coated with a disguising mixture of taste and then dry. The term "particles" as used herein, refers to free-flowing substances of any form, which are larger than a powder including crystals, beads (smooth, round or spherical particles) and granules. A variety of methods known to those skilled in the pharmaceutical science art may be employed to prepare the core particles comprising the active agent of topiramate. In one method, granules or large single crystals of topiramate can be used as the core particles and can be coated with the taste disguising mixture. The coated material formed from the granules or crystals of topiramate can then be compressed into chewable tablets, if desired, or sprinkled in soft foods and can be swallowed. In a second method, the active agent of topiramate (in powder form) is first placed in a fluidized bed equipment and subsequently, a spray binder solution or suspension consisting of eg, povidone, starch, sugar, syrup, HPMC among other excipients known to those skilled in the art in a pharmaceutically acceptable solvent (e.g., water, ethanol, acetone, among others) is sprayed into the powder, formed into granules and dried until the solvent evaporates to provide the particles of core. The drying temperature can vary over a wide range, but it should not be so high to inactivate the active agent. As a slight modification of this second method, a suspension of topiramate and a binder in a pharmaceutically acceptable solvent is sprayed into the sugar spheres in a fluidized bed equipment and dried to provide core beads. In a third method for forming the core particles, a powder or granule active agent and diluent or volumetric agent is mixed with water or a pharmaceutically acceptable solvent (e.g., water, ethanol) to form a wet mass. The mixture is combined, for example in a Hobart mixer or other suitable mixer, until a wet paste or dough is formed. The wet mass is then placed in an extruder and extruded as a long thin filament. The mixture can then be dried and comminuted adequately or placed in a suitable spheronizer to make a pharmaceutical core that is round followed by drying. The drying temperature can vary over a wide range, but it should not be so high as to render the active agent inactive. Another method for forming the core particles is by roller compaction of topiramate, either alone or in combination with one or more excipients. For example, the powder topiramate or granulated form can be mixed with an excipient to provide suitable binding and lubricity, for example microcrystalline cellulose, magnesium stearate or talc among others, and then pass through a compactor to compact the mixture into a dough. The mass is then passed through a size reduction machine and reduced to a suitable particle size to provide the core particles. As used herein, the term "topiramate" and "active agent of topiramate" are synonyms and are used alternately throughout the specification to refer to the sulfamate compound of 2,3,4,4-bis-O- (1 -methylethylidene) -β-fructopyranose, which forms the active agent of the pharmaceutical compositions of the present invention. Topiramate and its use to treat epilepsy and glaucoma are described in the U.S. patent. No. 4,513,006. Topiramate can be synthesized according to the procedures described in the U.S. Patents. Nos. 4,513,006 and 5,387,700, and preferably, according to the procedure in Examples 1-3 in the US patent. No. 5,387,700. The term "therapeutically effective amount" as used herein, refers to the amount of active compound or pharmaceutical agent that produces the biological or medicinal response in a tissue, system, animal or human that is sought by a researcher, veterinarian, doctor or another clinician, which includes relief of the symptoms of the disease being treated. The term "excipient", as used herein, refers to any inert substance which may be combined with an active agent to prepare convenient dosage forms, including, for example, diluents, binders, lubricants, disintegrants, colors, flavors and sweeteners. Suitable diluents for use in the formulation and methods of the present invention include, but are not limited to dicalcium phosphate, calcium sulfate, lactose, sorbitol, microcrystalline cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and sugar spheres. In a preferred embodiment of the invention, sugar spheres (20-60 mesh, preferably 20-40 mesh, preferably 20-24 mesh) are used as a diluent in the core beads. In a particularly preferred embodiment, sugar spheres NF (20/25 mesh) available by Crompton &; Knowles Corporation as NU-PAREIL PG®. Suitable binders for use in the instant formulation and methods include, but are not limited to, synthetic gums such as hydroxypropylmethylcellulose ("HPMC"), povidone, carboxymethylcellulose, ethylcellulose and methylcellulose, starch, pregelatinized starch, gelatin, sugars (e.g., molasses) ) and natural gums (for example, acacia gum, sodium alginate, panwar gum). Preferably, povidone (especially povidone USP) is used as the binder. In a particularly preferred embodiment, the povidone is PLASDONE® (K29 / 32) supplied by ISP Technologies, Inc. as a manufacturer of GAF products.

Disintegrants that can be used in the formulation and methods of the present invention include, but are not limited to, methylcellulose, cellulose, carboxymethylcellulose, croscarmellose sodium, magnesium aluminum silicate, povidone, starch, sodium starch glycolate, starch. pregelatinized, alginic acid and guar gum. Preferably, the disintegrant is povidone. In a particularly preferred embodiment, the povidone is PLASDONE® (K29 / 32) supplied by ISP Technologies, Inc. as a manufacturer of GAF products. Suitable taste disguising agents that can be used in the formulation and processes include, but are not limited to cellulose acetate, cellulose acetate butyrate, ethyl cellulose, methyl cellulose (including combinations of ethyl cellulose and methyl cellulose) and a broad scale of copolymers available under the trade name Eudragits (Rohm Pharma of Darmstadt, Germany). In a preferred embodiment, the taste disguising agent is cellulose acetate (Cellulose Acetate, NF). A variety of solvents can be used as the first and second solvents in the processes for preparing the pharmaceutical composition. Suitable solvents include, but are not limited to water, acetone, alcohols (e.g., methanol, ethanol, isopropanol), methylene chloride, ethyl acetate, methyl ethyl ketone, and mixtures thereof. In a preferred embodiment, the first solvent used to form the core beads is water, and the second solvent used to coat the beads of the core with the taste disguising mixture is a mixture of acetone-alcohol, preferably a mixture of acetone- ethanol, preferably a mixture of acetone-dehydrated alcohol. In a preferred embodiment, a suspension of topiramate and a binder in a first solvent is spread on the sugar spheres (20-25 mesh) and dried to provide core beads. The core beads are then selected to remove fines and agglomerates. The core beads are coated again with a taste disguising mixture and then dried. The taste disguising mixture, which is sprayed into the core beads, comprises a taste disguising agent and a disintegrant dissolved or suspended in a second solvent, which may be the same as or different from the first solvent. The coated beads are sifted to remove fines and agglomerates, before encapsulation. In a particularly preferred embodiment of the process for preparing the sprayed formulation, a suspension of topiramate in a solution of povidone in purified water is sprayed on sugar spheres (20-25 mesh) and dried in a fluid bed processor equipped with a column of Wurster. The ratio of topiramate: povidone used in the suspension can be 50:25, 50:30 or 50:35. Preferably, a 50:25 ratio of topiramate: povidone is used. The core beads are then selected to remove fines and agglomerates, so that the core beads have a particle size between about 0.100 mm and about 2.5 mm, preferably between about 0.5 mm and about 1.5 mm, preferably, between about 0.710 mm and approximately 1.18 mm. The core beads are coated again with a taste-disguising mixture of cellulose acetate and povidone suspended in a mixture of acetone / alcohol in a fluid bed unit equipped with a Wurster column, and dried. The ratio of cellulose acetate / povidone in the taste disguising mixture can be 60/40, 50/50, 65/35 or 55/45; preferably, a 65/35 ratio of cellulose acetate / povidone is used. Coated beads are sifted to remove fines and agglomerates to provide a final particle size of between about 0.100 mm and about 2.5 mm, preferably between about 0.5 mm and about 1.5 mm, preferably between about 0.850 mm and about 1.18 mm. The coated beads are packaged (for example, in capsules, small pouches or other methods known to those skilled in the art) to deliver the desired amount of active ingredient to the patient. When a particle size scale is specified for the coated and / or core particles (e.g., between about 0.100 mm and about 2.5 mm), it is intended that at least 75%, preferably 85% and preferably 95% of the particles have a particle size that is within the specified scale (e.g., about 0.100 mm and about 2.5 mm). The invention will be described more specifically in terms of its preferred embodiment, which is the preparation of a sprayed formulation of topiramate. In the first step of the procedure, the core beads are prepared by coating sugar spheres (20-25 mesh) with a suspension of topiramate and povidone in water. More specifically, the sugar spheres are placed in a fluidized bed coater and fluidized by a flow of hot air. The temperature of the air has not been found to be narrowly decisive and can vary over a wide range, however, the temperature should not be high enough to cause decomposition, sintering or melting of the sugar spheres. When the sugar spheres are coated with the topiramate / povidone suspension (preferably a 50:25 ratio), it has been found that a temperature of about 50 ° to 75 ° C is adequate. The speed of the air flow is adjusted to fluidize the sugar spheres. Said flow will vary depending on factors, such as the specific equipment used, the size of the individual sugar spheres, the size of the sugar spheres load, the apparent specific gravity of the spheres and other factors known to the skilled artisan. of fluidized bed coating. After the sugar spheres have been fluidized, a previously prepared suspension of topiramate is spread in a solution of povidone in water in the fluidized bed to provide the core beads. The air flow through the bed continues until the amount of water remaining in the beads of the topiramate core has been substantially reduced. The core beads are in fact dry to the touch within a very short time after the suspension of topiramate has been spread in the sugar spheres. However, the total drying time required to ensure that the water content has been reduced to the desired level, can take much longer, depending on air temperature, lot size and the like. Routine experimentation will be sufficient to determine the appropriate air temperatures and the total times required in the fluid bed coaters in individual cases. The core beads are measured through a screen using 16 mesh and 25 mesh screens. In the second step of the process, the core beads are coated with a taste disguising mixture to provide the beads coated with the sprayed formulation. More specifically, the core beads are placed in a fluidized bed coater and fluidized by a flow of hot air. The air temperature has not been found to be narrowly decisive and can vary over a wide range, keeping in mind the fact that the temperature should not be so high to cause decomposition, sintering or melting of the core beads of topiramate. When the beads of the topiramate core are coated, it has been found that a temperature of 30 ° to 75 ° C is adequate. The air flow rate is adjusted so as to fluidize the core beads. Said flow will vary depending on factors such as the specific equipment used, the size of the charge of the core beads, the size of the individual core beads, the apparent specific gravity of the core beads and other factors known to those skilled in the art. the fluidized bed coatings techniques. After the core beads have been fluidized, a taste disguising coating mixture is spread in the fluidized bed. The taste disguising coating mixture comprises a solution of cellulose acetate / povidone (preferably in a 65:35 ratio) in a solvent mixture of acetone-alcohol (preferably acetone-dehydrated alcohol). The air flow through the bed continues until the amount of solvent remaining in the coating has been reduced to parts per million levels. The coated beads are in fact dry to the touch within a very short time after the coating solution has spread on the beads of the topiramate core. However, the total drying time required to ensure that the solvent content of the coating has been reduced to the desired level can take much longer, depending on air temperature, lot size and the like. Routine experimentation will be sufficient to determine the appropriate air temperature and the total times required in the fluidized bed coaters in individual cases. The coated beads are then measured through a screen using 16 mesh and 20 mesh screens. A sprayed formulation having satisfactory bioavailability and taste disguising properties is obtained when the taste disguising coating comprises about 7 to about 15% in weight of the final pharmaceutical composition. Preferably, the taste disguising coating comprises about 9% by weight to about 13% by weight, preferably about 11% by weight of the pharmaceutical composition when dried. The results of water dissolution indicators of bioavailability for the pharmaceutical composition having between 7 and 15% by weight of taste disguising coating, are shown below in Table 1.

TABLE 1 Dissolution results in water Coating (%) 10 min 20 min 30 min 45 min 60 min (%) Dissolved 7 35.0 72.9 91.2 98.4 99.2 9 26.8 58.1 84.3 97.7 100.8 11 21.7 52.3 79.1 97.3 99.7 13 15.5 40.9 66.3 91.4 98.8 15 12.5 35.3 59.7 85.6 96.6 To help provide adequate dosing to the patient, a machine can be used to encapsulate a quantity of coated beads to provide concentrations of 15 mg, 25 mg and 50 mg of topiramate in a gelatin capsule of size 2, 1 or 0, respectively . Although the use of fluidized bed coating has been described in detail as a preferred method for making the core beads and coated beads, other techniques for making the core beads and coated beads known to those skilled in the art can be used. . These other techniques include different microencapsulation techniques, such as coacervation and solvent evaporation. In a particularly preferred embodiment, the ingredients and amounts of each ingredient used to prepare the sprayed topiramate bead formulation are provided in Table 2.

TABLE 2 Component / objective composition Unit dosage concentration (mg) Ingredient Reference Function 50 mg 25 mg 15 mg Topiramate Activa 50.0 25.0 15.0 Povidona USP Link agent 25.0 12.5 7.5 Purified water1 USP Auxiliary of - - - procedure NF Spheres Core Pearl 150.0 75.0 45.0 Sugar Mesh 20-25 NF Acetate Coating 18,076 9,038 5,423 cellulose film Povidona USP Coating of 9,733 4.8665 2.9199 movie Acetone1 NF Auxiliary of - - - procedure USP Alcohol Auxiliary of - - - dehydrated1 procedure Type IV capsules Carrier of a unit I a unit I a unit gelatin drug (size (size (size 0) 1) 2) ink of printing identifier 1. Essentially removed during drying Spray capsule concentrations of topiramate, 15, 25 and 50 mg are obtained from a unique formulation of beads coated with topiramate by encapsulating the amounts provided from beads coated in properly sized and labeled capsules. Table 3 provides a batch formula for a batch of pearl formulation sprayed with topiramate.

TABLE 3 Formulation by batch PLANNED FORMULATION TARGET INGREDIENT (kg) SCALE (kg) SCALE (%) NUCLEUS PEARLS Topiramate 37.5 - - Povidone, USP 18.75 ± 0.09375 ± 0.5% Purified water, USP1 93.75 ± 0.9375 ± 1.0% Sugar sphere, NF mesh 20-25 112.50 - - Lot size of core pearl 168.75 COATED PEARLS core 150.00 Cellulose acetate, NF 12,051 ± 0.12051 ± 1.0% Povidone, USP 6.489 ± 0.06489 ± 1.0% Acetone, NF1 120.00 ± 1.2% ± 1.0% Dehydrated alcohol, USP1 30.00 ± 0.3% ± 1.0% Coated peda batch size 168.54 GELATIN CAPSULES Gelatin Printing ink 1. Essentially removed during drying Table 4 below shows a comparison of dissolution rates in water between TOPAMAX® 100 mg tablets and topiramate sprayed capsule formulations, dosages of 25 and 50 mg (according to the specifications in Table 2 ).

TABLE 4 Comparison of dissolution Dissolved label% (average) Product 10 min 20 min 30 min 45 min 100 mg 85.0 92.6 96.4 _ Tablet (79-89) (89-96) (93-99) 25 mg 19.7 51.4 75.0 94.7 Spray (17-22) (48-55) (71-80) (90-99) 50 mg 17.8 48.1 71.3 93.5 Spray (17-19) (45-50) (69-73) (91-96) The stability of the sprayed formulation of the present invention was compared with TOPAMAX® tablets (topiramate) by storing both formulations in controlled stability chambers for the purpose of determining the stability profile for the two products. The samples were stored at 30 ° C. Sprays were stored at 60% relative humidity (RH); the relative humidity for the tablet batches was controlled at either 35% RH or not controlled, but in any case, it was well below 60% RH. Data were collected for analysis (amount of remaining drug), sulfate and sulfamate, physical appearance at selected time intervals for example, 18 months, 24 months. Physical appearance, ie brown or black discoloration and detected sulfate amount, are good indicators of degradation of the active agent (topiramate). For every mole of topiramate that degrades, a molar equivalent of inorganic impurity (sulfate / sulfamate) is formed. The presence of inorganic impurity is easily determined by one skilled in the art using standard techniques, for example, CLAR. At 18 months, some instability was detected by appearance data for the tablets, while the sprayed formulation showed no signs of stability / degradation. Clear signs of degradation were manifested by appearance and sulfate data for the tablets at 24 months. After 24 months of storage at 30 degrees 60% RH, concentrations of 25 and 50 mg of sprayed capsules remained stable, while the 15 mg concentration showed instability. At a storage of 25 degrees 60% RH for 24 months, the three concentrations of the sprayed formulation remained stable. It is known that moisture accelerates the degradation of topiramate. It has now been unexpectedly discovered that the coating used to disguise the taste of the topiramate core beads also provides a barrier to moisture absorption, and therefore, improves the stability of the sprayed formulation. For the storage of the tablets, it was necessary to place a desiccant in the bottles to stabilize the tablet formulation. However, there is no need for a desiccant for the sprayed formulation. In addition, the capsules which were used to facilitate the supply of the appropriate dosage of sprays contain more than 10% moisture by weight, and even this moisture does not accelerate the degradation of topiramate due to the taste disguising coating for sprays. The following examples are provided to further define the invention without limiting it to the details of these examples.

EXAMPLE 1 Preparation of core beads Ingredient Amount per lot Topiramate 37.50 Povidone, USP 18.75 Sugar spheres, NF (20-24 mesh) 112.50 Purified water, USP 93.70 The batch quantities of each of the core pearl ingredients were accurately weighed. In a boiler with a heating jacket (approximately 227.11 liters) equipped with a sweeper, a homogenizer (Silverson or equivalent) and a mixer (LIGHTNIN'® or equivalent) was placed the amount per adequate batch of purified water, UPS. The amount per pound of Povidone, USP was added and the resulting mixture was mixed for a minimum of 15 minutes to disperse the povidone in the purified water. Topiramate (37.50 kg) was added and the mixture was incorporated for a minimum of 15 minutes for dispersion. The water was passed through the heating jacket. Using the mixer and homogenizer, the topiramate suspension was homogenized for approximately 90 minutes (scale: 80-100 minutes). Agitation continued through the steps that follow to prepare the core beads. A pump (Masterflex or equivalent) was prepared with three pump heads for spraying. The quantity per batch of sugar spheres, NF was charged to a fluid bed (Glatt Fluid Bed equipped with a Wurster column of 81.28 cm, three guns with a 2.2 mm nozzle or equivalent). The sugar spheres were fluidized and the topiramate suspension was spread through the nozzles (approximate spray speed: 1 kg / min, approximate spray time: 2.25 hours) according to the parameters shown in table 5.

TABLE 5 Operating function Operating parameter Air flow 2400 CFM (scale: 1900-2900 CFM) Inlet air temperature 60 ° C (scale: 50 ° C-70 ° C) Bed temperature 40 ° C (scale: 38 ° C-45 ° C) Air atomization 3 bar (scale: 2.7-3.5 bar) Core beads were dried at 60 ° C for at least 15 minutes (scale 15-18 minutes) after the bed temperature was reached 60 ° C (scale: 55 ° C-65 ° C) according to the parameters provided in table 6.

TABLE 6 Operating function Operating parameter Air flow 2100 CFM (scale: 1800-2200 CFM) Inlet air temperature 60 ° C (scale: 50 ° C-70 ° C) Atomizing air 1 bar (scale: 1-2 bar) Then, the core beads were measured through a 121.92 cm screen (Sweco or equivalent), using 16 mesh and 25 mesh screens to remove fines and agglomerates.

EXAMPLE 2 Preparation of coated beads Inqredient Quantity per lot Topiramate-core beads 150.00 Cellulose acetate, NF 12,051 Povidone, USP 6,489 Acetone, NF 120.00 Dehydrated alcohol, USP 30.00 The batch quantities of Acetone, NF and Dehydrated Alcohol, USP were transferred to a stainless steel tank adequate and mixed. The batch quantity of Povidone, USP was added using a suitable mixer (LIGHTNIN'® or equivalent). The amount per lot of NF Cellulose Acetate was added to the vortex while mixing with a suitable mixer and the clarity of the coating solution visually verified. The beads of the maya topiramate core 16/25 (150 kg) of Example 1 were fluidized in a Glatt Fluid Bed processor equipped with a Wurster column (or equivalent). The core beads were spread with the coating solution until the entire amount of coating solution was exhausted. The coated beads were dried at approximately 60 ° C for a minimum of 30 minutes (scale: 28-32 minutes). The operating parameters are shown in table 7.

TABLE 7 Operational scales for sprinkling / drying Parameter Operating scale Inlet air flow 1500-3000 CFM Inlet air temperature 30 ° C - 70 ° C Atomization air 1 - 4 baria Bed temperature 30 ° C - 70 ° C A Sweco sieve (or equivalent equipment) adapted in the upper part with a sieve of 16 mesh and in the bottom with a sieve of 20 mesh. The complete batch of coated beads was sifted and the coated beads were discarded outside the 16-20 mesh scale.

EXAMPLE 3 Encapsulation of coated beads An encapsulating machine (H &K capsule or equivalent) was prepared with a capsule filling attachment and the coated capsules of example 2 were encapsulated. The objective filling weights were determined by analysis of the coated beads before encapsulation. The variability of the filling weights was controlled by weight classification, which is required for the 15 mg concentration, but which is optional and is used as necessary for concentrations of 25 to 50 mg. A KKE sorting machine (or equivalent) was used to weigh the filled capsules when the weight classification was used. The filled capsules that did not reach the acceptable weight scale were discarded by the classifier. Although the above specification shows the principles of the present invention, with examples provided for purposes of illustration, it will be understood that the practice of the invention encompasses all variations, adaptations and / or normal modifications that fall within the scope of the following claims and its equivalents.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS 1. - A method for forming a pharmaceutical composition comprising: (a) preparing core particles comprising a topiramate active agent; (b) drying the core particles of step (a) to form dried core particles; (c) coating the dried core particles of step (b) with a taste disguising mixture to form coated particles; and (d) drying the coated particles of step (c) to form the pharmaceutical composition, wherein the amount of taste disguising mixture is in the range of about 7% by weight about 15% by weight of the pharmaceutical composition. 2. The process according to claim 1, further characterized in that the core particles comprise the topiramate active agent and at least one excipient. 3. The process according to claim 2, further characterized in that the core particles comprise the active agent of topiramate, a binder and a diluent wherein the diluent are sugar spheres. 4. The process according to claim 3, further characterized in that the taste disguising mixture comprises about 9 to about 13% by weight of the pharmaceutical composition. 5. The process according to claim 4, characterized in that the dried core particles of step (b) are measured between approximately 0.100 mm and approximately 2.5 mm before coating with the taste disguising mixture. 6. The process according to claim 5, further characterized in that the coated particles of step (d) are measured between about 0.100 mm and about 2.5 mm. 7. The process according to claim 6, further characterized in that the core particles are prepared by spreading a suspension of topiramate and the binder in a solvent in the sugar spheres. 8. The method according to claim 7, further characterized in that the binder is selected from povidone, HPMC, acacia gum, sugar, molasses, sodium alginate, panwar gum, starch, pregelatinized starch, carboxymethylcellulose, ethylcellulose or methylcellulose. 9. The process according to claim 8, further characterized in that the binder is povidone. 10. The method according to claim 8, further characterized in that the taste disguising mixture comprises a flavor disguising agent selected from cellulose acetate, cellulose acetate butyrate, methylcellulose, ethylcellulose or an Eudragit; and a selected disintegrant of povidone, methylcellulose, starch, sodium starch glycolate, pregelatinized starch, cellulose, carboxymethylcellulose, croscarmellose sodium, magnesium aluminate silicate, alginic acid or guar gum. 11. The process according to claim 10, further characterized in that the taste disguising mixture comprises cellulose acetate and povidone. 12. The method according to claim 11, further characterized in that it comprises the encapsulation of the coated bead. 13. A pharmaceutical composition made by the method of claim 1. 14. A pharmaceutical composition comprising: (a) core particles containing a topiramate active agent, wherein the core particles have an initial particle size between approximately 0.100 mm and 2.5 mm; and (b) a taste disguising coating, wherein the taste disguising coating comprises between about 7% by weight and about 15% by weight of the pharmaceutical composition and wherein the coated particles of the pharmaceutical composition have a final particle size. from about 0.100 mm to about 2.5 mm. 15. - The pharmaceutical composition according to claim 14, further characterized in that the core particles comprise the active agent of topiramate and at least one excipient. 16. The pharmaceutical composition according to claim 15, further characterized in that the core particles comprise the active agent of topiramate, a binder and a diluent wherein the diluent is sugar spheres. 17. The pharmaceutical composition according to claim 16, further characterized in that the taste disguising coating comprises between about 9% by weight and about 13% by weight of the pharmaceutical composition. 18. The pharmaceutical composition according to claim 17, further characterized in that the taste disguising coating comprises approximately 11% by weight of the pharmaceutical composition. 19. The pharmaceutical composition according to claim 18, further characterized in that the core particles have an initial particle size of between about 0.5 mm and 1.5 mm and the coated particles of the pharmaceutical composition have a final particle size of between approximately 0.5 mm and 1.5 mm. 20. The pharmaceutical composition according to claim 19, further characterized in that the core particles have an initial particle size of between about 0.710 mm and

1. 18 mm and the coated particles of the pharmaceutical composition have a final particle size of between about 0.850 mm and 1.18 mm. 21. The pharmaceutical composition according to claim 20, further characterized in that the binder is selected from povidone, HPMC, sodium alginate, panwar gum, acacia gum, gelatin, sugar, molasses, starch, pregelatinized starch, methylcellulose, ethylcellulose or carboxymethylcellulose; and the taste disguising coating comprises a taste disguising agent and a disintegrant, wherein the taste disguising agent is selected from cellulose acetate, methylcellulose, ethylcellulose, an Eudragit or cellulose acetate-butyrate; and the disintegrant is selected from povidone, cellulose, carboxymethylcellulose, croscarmellose sodium, magnesium aluminate silicate, sodium starch glycolate, pregelatinized starch, alginic acid or guar gum. 2

2. The pharmaceutical composition according to claim 21, further characterized in that the binder is povidone, the taste disguising agent is cellulose acetate and the disintegrant is povidone. 2

3. The pharmaceutical composition according to claim 22, further characterized in that the coated particles of the pharmaceutical composition are encapsulated. 2

4. A pharmaceutical composition comprising about 85 to about 93% by weight of core particles and about 7 to about 15% by weight of a coating; wherein the core beads comprise about 18 to about 21% by weight of topiramate, about 8 to about 11% by weight of povidone, and about 58 to about 61% by weight of sugar spheres; and the coating comprises about 6 to about 9% by weight of cellulose acetate and about 2 to about 5% by weight of povidone. 2

5. The pharmaceutical composition according to claim 24, comprising about 89% by weight of core particles and about 11% by weight of coating, further characterized in that the core beads comprise approximately 19.8% by weight of topiramate, approximately 9.9 % by weight of povidone and approximately 59.3% by weight of sugar spheres; and the coating comprises about 7.2% by weight of cellulose acetate and about 3.8% by weight of povidone. 2

6. The use of the pharmaceutical composition as claimed in claim 14 for the preparation of a medicament for treating seizures in a mammal. 2

7. The use of the pharmaceutical composition as claimed in claim 14 for the preparation of a medicament for treating epilepsy in a mammal. 28.- The use of topiramate in the preparation of a medication to treat diabetes.