MXPA01005274A - Compositions comprising cefuroxime axetil - Google Patents

Abstract

Cefuroxime axetil in a non-gelatinous form on contact with an aqueous liquid, e.g. in the form of a solid solution in a polymer or in the form of a solid dispersion on a carrier, e.g. useful for the production of pharmaceutical compositions comprising cefuroxime axetil as an active ingredient and the use of cefuroxime axetil in the manufacture of an oral dosage form which does not exhibit an adverse food effect.

Description

COMPOSITIONS THAT INCLUDE CEFUROXIMA-AXETIL The present invention relates to ß-lactam compositions, specifically with respect to cefuroxime-axetil, which is the cefuroxime 1-acetoxyethyl ester, and which is a well-known second generation cephalosporin antibiotic, for example useful in the treatment of microbial infections, for example described in The Merck Index, 12th edition, pages 234 and 325, No. 2002. The active ingredient in vivo in cefu-oxime-axetil is cefuroxime, because the carboxylic ester is separated. at position 4 of the ring system in vivo, the carboxylic acid is released, and the cefuroxime compound is formed. Cefuroxime axetil, for example in crystalline form or in amorphous form, for example, can be administered orally, for example in the form of, for example, film-coated tablets, or in the form of a dry powder, for example , it can be administered as such, for example, together with an aqueous liquid, or it can be reconstituted with an aqueous liquid, for example water, in the form of a suspension / syrup. However, cefuroxime axetil in crystalline or amorphous form may undergo gelatinization, for example it may form a gelatinous mass, in contact with an aqueous liquid, for example water or sage; for example, a gel can be formed on the surface of, for example, galenically-formulated cefuroxime-axetil particles. Gelatinization, for example gel formation on the surface of, for example, galenically-formulated cefuroxime-axetil particles, can result in a poor dissolution of cefuroxime-axetil, with, for example, the consequence that it can be reduce the adsorption of cefuroxime-axetil from the gastrointestinal tract. Surprisingly, it has now been found that the gelatinization of cefuroxime-axetil, for example the gel formation on the surface of, for example, galenically-formulated cefuroxime-axetil particles, after its contact with an aqueous liquid, example, it can be substantially avoided if the cefuroxime axetil is not in crystalline or amorphous form, but in a non-gelatinous form upon contact with an aqueous liquid. Although not intended to be bound by any theory, it is believed that, in a non-gelatinous form upon contact with an aqueous liquid according to the present invention, cefuroxime axetil can be incorporated into a polymer in the form of a molecular dispersion that is a solid solution of cefuroxime axetil in the polymer; and / or in the form of a solid (molecular) surface dispersion on an adsorbent. A non-gelatinous form, for example of galenically-formulated cefuroxime-axetil, for example that does not form a gel on the surface of the cefuroxime particles, on contact with an aqueous liquid according to the present invention, and as used herein , includes a form of cefuroxime-axetil, for example galenically formulated cefuroxime-axetil, for example a dosage form, for example solid, for example containing cefuroxime-axetil as an active ingredient, and pharmaceutically acceptable excipients, having a dissolution rate of active ingredient at 37 ° C in an aqueous medium, for example acid, for example acid with hydrochloric acid, for example regulated, which is higher, equal, or not lower: - than 5 percent at a pH of about 1 , for example at a pH of 1 after 10 to 15 minutes from the start of the dissolution test; and / or that 20 percent at a pH < 0 after 25 to 30 minutes from the start of the dissolution test, - that the rate of dissolution of the active ingredient at a pH of about 4, for example at a pH of 4. Cefuroxime-axetil in a non-gelatinous form , upon contact with an aqueous liquid, therefore, includes cefuroxime-axetil in a form, for example galenically formulated, having a dissolution rate which is substantially pH independent, eg at pH <0, at a pH of 1, and at a pH of 4. An appropriate method for determining the rate of dissolution includes, for example, a conventional method, for example determining the rate of dissolution of the cefuroxime-axetil, for example. in a dosage form, as stipulated in the USP (US Pharmacopaea) < 711 > in a USP-2 apparatus under at least as stringent conditions as the following: 900 milliliters of an aqueous medium, 37 ° C with the pads rotating at 55 rpm; determining an average dissolution rate of at least 6 samples, containing substantially the same amount of cefuroxime-axetil, and substantially the same excipients in substantially the same amount; at an appropriate pH, for example at (around) a pH of 4, at (around) a pH of 1, and at a pH < 0. Dosage forms that pass this test under more stringent conditions, for example a lower volume of the aqueous medium, a lower temperature, a lower paddle speed, are also included under the above definition. An appropriate aqueous medium useful for the determination at a pH of 4 comprises, for example, an acetate buffer (pH of 4), for example according to USP; and for the determination to (around) a pH of 1 and a pH < 0, an aqueous solution of acid with hydrochloric acid having the appropriate pH. The detection of the rate of dissolution of cefuroxime-axetil at the defined time point can be carried out according to a conventional method, for example by means of UV, HPLC. In one aspect, the present invention provides cefuroxime axetil in a non-gelatinous form in contact with an aqueous liquid, for example water, for example in the form of a solid solution in a polymer; for example in a weight ratio of the cefuroxime-axetil: polymer of 1: 0.1 to 1: 0.8, for example of 1: 0.15 to 1:08, such as of 1: 0.15 to 1:06, for example of 1: 0.35 to 1: 0.6, for example from 1: 0.35 to 1: 0.55, for example from 1: 0.35 to 1: 0.45; or in the form of a solid surface dispersion on an adsorbent, for example in a weight ratio of the cefuroxime axetil: adsorbent of 1: 0.1 to 1: 1.5; for example from 1: 0.3 to 1: 1.3, preferably in the form of a solid solution in a polymer. Cefuroxime-axetil in non-gelatinous form, for example in the form of a solid solution in a polymer or in a solid surface dispersion, for example, can be obtained as follows: A solution or suspension of cefuroxime axetil can be produced free form, for example in crystalline form, or in an amorphous form, for example in the form of a solvate or in the non-solvate form, and of a polymer and / or adsorbent, in an organic solvent, for example in the presence of water A polymer includes a polymer, for example one or more, which is capable of forming a solid solution of cefuroxime axetil in a polymer, for example according to the definition of cefuroxime axetil in a non-gelatinous form upon contact with an aqueous liquid. as indicated above, preferably a polymer that is soluble in the solvent (system) used. A polymer preferably includes a pharmaceutically acceptable polymer, for example a homo- and a copolymer, for example a homo- and a copolymer of a polyvinylpyrrolidone, for example as is commercially available under the tradename Kollidon®, for example a homopolymer such as a povidone, cross-linked povidone, for example crospovidone, polyplas- dona; and a polyvinyl pyrrolidone copolymer; polyethylene glycol, polyethylene oxide, cellulose. Cellulose includes alkyl celluloses, for example methyl-, ethyl-, propylcelluloses; hydroxyalkylcelluloses, for example hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; hydroxypropylmethylcellulose, and a cellulose which, for example, is chemically modified, for example, which carries carboxyl groups as substituents, such as a carboxymethylcellulose. A polyvinyl pyrrolidone is preferred, for example as commercially available under the tradename Kollidon®, for example povidone, crosslinked povidone, for example crospovidone or polyplasdone, copolymer of polyvinylpyrrolidone, celluloses, for example alkylcelluloses, hydroxyalkylcelluloses, hydroxymethylpropylcelluloses.; for example ethyl- and propylcelluloses, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, a cellulose which, for example, is chemically modified, for example carrying carboxyl groups as substituents, polyethylene oxide, crospovidone and polyplasdone, and a polyvinyl pyrrolidone copolymer . A polyvinyl pyrrolidone copolymer, such as vinyl pyrrolidone-vinyl acetate copolymer, for example consisting of N-vinyl-2-pyrrolidone and vinyl acetate, for example in a random ratio of 60:40, for example having units of the formula: for example as it is commercially available under the tradename Kollidon®, for example VA64) or Plasdone® (for example S-630). An appropriate weight ratio of the cefuroxime axetil and the polymer includes a ratio of 1: 0.1 to 1: 0.8, for example of 1: 0.15 to 1: 0.8, such as of 1: 0.15 to 1: 0.6, for example of 1: 0.35 to 1: 0.6, for example from 1: 0.35 to 1: 0.55, for example from 1: 0.35 to 1: 0.45. The appropriate adsorbent includes, for example, a pharmaceutically acceptable adsorbent, for example one or more, which can form a solid surface dispersion with cefuroxime axetil, for example according to the definition of cefuroxime axetil in a non-gelatinous form upon contact with an aqueous liquid as indicated above, for example a material that can fix another material on its surface and form a solid (molecular) dispersion, such as silicon dioxide, for example colloidal, such as for example Aerosil®, for example Aerosil® 200, preferably colloidal silicon dioxide. Preferably, the adsorbent itself is biologically inactive. An appropriate weight ratio of the cefuroxime axetil: adsorbent includes, for example, from 1: 0.1 to 1: 1.5, for example from 1: 0.3 to 1: 1.3. A non-gelatinous form of cefuroxime axetil can comprise both polymer and adsorbent. A preferred weight ratio of cefuroxime axetil: polymer plus adsorbent includes, for example, a weight ratio of 1: 0.3 to 1: 1.8, for example 1: 0.3 to 1: 0.9. In another aspect, the present invention provides cefuro-xima-axetil in a non-gelatinous form upon contact with an aqueous liquid, comprising cefuroxime-axetil in the form of a solid solution in a polymer, in combination with cefuroxime-axetil in the form of a solid dispersion on an adsorbent; for example in a weight ratio of the cefuroxi-ma-axetil: adsorbent from 1: 0.1 to 1: 1.5, for example from 1: 0.3 to 1: 1.3. A suitable organic solvent includes one or more organic solvents, for example a solvent system, wherein the cefuroxime axetil and the polymer are soluble, and wherein the adsorbent is preferably insoluble, or only soluble to a slight degree, for example soluble in colloidal. For example, water may be present in an organic solvent, for example if the adsorbent, if present, is insoluble or only slightly soluble, for example colloidal, in water. The preferred organic solvent includes a single organic solvent or a mixture of organic solvents, for example in the presence of water, for example a ketone, for example acetone, an alcohol, for example ethanol; and a halogenated hydrocarbon, for example methylene chloride. The preferred organic solvent includes ketones, for example in the presence of water, for example up to (about) 30 percent by volume / volume of the organic solvent. A solution or suspension of cefuroxime-axetil and the polymer and / or adsorbent in an organic solvent, for example in the presence of water, can be obtained, for example, after (slight) heating of the mixture. A non-gelatinous form of cefuroxime-axetil on contact with an aqueous liquid can be obtained, for example by removing the solvent from the solution or suspension comprising cefuroxime axetil and the polymer and / or adsorbent in organic solvent, for example in the presence of water, by removal of the solvent, for example evaporation of the solvent, such as evaporation in a rotary evaporator, spray drying, spray granulation, such as fluidized bed granulation; preferably spray drying or spray granulation. A non-gelatinous form of cefuroxime-axetil on contact with an aqueous liquid, for example, is useful in the production of a granulate, whose granulate, for example, is useful for producing pharmaceutical formulations, for example tablets, or a powder, for example a dry powder, for example useful for oral administration, comprising cefuroxime-axetil as an active ingredient. In another aspect, the present invention provides a process for the production of cefuroxime axetil in a non-gelatinous form upon contact with an aqueous liquid, which comprises dissolving or suspending the cefuroxime axetil and a polymer, for example in a weight ratio of cefuroxime-axetil. -polymer from 1: 0.1 to 1: 0.8; or an adsorbent, for example in a weight ratio of the cefuroxime-axetil: adsorbent from 1: 0.1 to 1: 1.5; or a polymer plus an adsorbent in a weight ratio of the cefuroxime axetil-polymer plus an adsorbent of 1: 0.3 to 1: 1.3; in an organic solvent, for example in the presence of water, for example in ketone, for example acetone; or in an alcohol, for example ethanol, for example in the presence of a ketone and / or an alcohol as the sole organic solvent; and remove the solvent. Cefuroxime axetil in a non-gelatinous form contacted with an aqueous liquid, for example, is useful in the production of a pharmaceutical composition. A pharmaceutical composition, for example, can be produced according to a method as is conventional, using cefuroxime axetil in non-gelatinous form upon contact with an aqueous liquid as the active ingredient, or, for example, according to a method described in the present. In another aspect, the present invention provides a pharmaceutical composition, for example a dosage form, for example solid, for example oral, for example in the form of a tablet, dragee, powder (dry); Which comprises a pharmaceutically effective amount of cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid as an active ingredient, for example, wherein the active agent consists essentially of cefuroxime-axetil, for example in an amount that corresponds to an amount of cefuroxime of from 50 to 1000 milligrams, for example from 50 to 800 milligrams, such as from 100 to 600 milligrams, for example of 125 milligrams, for example of 250 milligrams, for example of 500 milligrams; in combination with, for example, conventional pharmaceutically acceptable excipients, for example that are suitable for the preparation of, for example, oral pharmaceutical compositions, for example compositions that are administered orally. It was found that pharmaceutical compositions according to the present invention, for example dosage forms, comprising cefuroxime axetil in a non-gelatinous form upon contact with an aqueous liquid according to the present invention, in combination with pharmaceutical excipients. acceptable, can satisfy the requirements of USP 23 (dissolution) and of USP 24 (in the understanding and assuming that it is in force since 2000), that is, these dosage forms effect at least a dissolution of 60 percent (value -Q) of the labeled amount of cefuroxime-axetil within 15 minutes, for example, and / or, at least a 75 percent (Q-value) solution of the labeled amount of cefuroxime-axetil within 45 minutes; when a dosage form of cefuroxime-axetil is tested as stipulated in the USP < 711 > in a USP-2 device under conditions as less astringent as the following: 900 milliliters of 0.07 N hydrochloric acid, 37 ° C, with the paddles rotating at 55 rpm. In another aspect, the present invention provides a pharmaceutical dosage form, for example solid, comprising cefuroxima axetil in a pharmaceutically effective amount in a non-gelatinous form upon contact with an aqueous liquid as an active agent, in combination with pharmaceutically acceptable excipients. , wherein this dosage form effects at least a 60 percent solution (va-lor-Q) of the labeled amount of cefuroxime-axetil within 15 minutes, for example and / or at least a 75 percent solution ( Q-value) of the labeled amount of cefuroximexetile within 45 minutes; when a dosage form of cefuroxime-axetil is tested as stipulated in the USP < 711 > in a USP-2 device under conditions as less astringent as the following: 900 milliliters of 0.07 N hydrochloric acid, 37 ° C, with the paddles rotating at 55 rpm. It has been found that cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid according to the present invention, it can be obtained in the form of a granulate comprising, in addition to cefuroxime-axetil, pharmaceutically acceptable excipients, for example components, which are useful in the production of a granulate. In another aspect, the present invention provides a granulate comprising cefuroxime axetil and a polymer and / or an adsorbent, wherein the cefuroxime axetil is in a non-gelatinous form upon contact with an aqueous liquid, for example wherein the cefuroxime-axetil is a solid solution in the polymer, and / or in a solid surface dispersion on an adsorben-te; and a pharmaceutically acceptable excipient; for example one or more, - for example a surface activity agent, for example a vehicle, for example a lubricant; for example containing cefuroxime-axetil in 25 to 95 weight percent; polymer in 0 to 75 weight percent, for example 5 to 75 weight percent, adsorbent in 0 to 60 weight percent; for example from 5 to 50 weight percent; surface activity agent in the 0 to 5 weight percent, for example 0.3 to 1.5 weight percent; vehicle in 0 to 50 weight percent, for example 5 to 50 weight percent; and / or lubricant in from 0 to 5 weight percent, for example from 0.1 to 5 weight percent. A granulate according to the present invention comprises agglomerated or aggregated particles of granule component substances. A granulate according to the present invention, for example may be in the form of a powder, grains or granules. A granulate according to the present invention can be obtained, for example, according to a method as is conventional, or, for example, as follows: From a solution or suspension containing cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid according to the present invention; for example previously prepared as described above in the process for the production of cefuroxime-axetil in a non-gelatinous form; or from a solution or suspension containing cefuroxime-axetil and a polymer and / or an adsorbent in an organic solvent, for example in the presence of water; comprising one or more pharmaceutically acceptable excipients, for example components, the solvent can be removed. The solvent of this solution or suspension, for example, can be removed according to a method as is conventional, or, for example, by mixing / stirring the solution or suspension of cefuroxime axetil, the polymer, and / or the adsorbent and the pharmaceutical excipient, for example under an elevated temperature, for example in a vacuum; under solvent removal, for example with the use of a rotary evaporator, spray drying, spray granulation, for example fluidized bed granulation, preferably spray drying or spray granulation. In the case of using a vehicle, for example, granulation in a fluidized bed, for example a solution of cefuroxime axetil containing a polymer and / or an adsorbent, for example, and one or more excipients, can be conveniently used. Pharmaceutically acceptable, it can be sprayed onto a fluid previously prepared from the solid carrier, for example whose fluid may comprise one or more additional pharmaceutically acceptable excipients, for example in solid form, for example lubricants. Spray drying and evaporation in the rotary evaporator can be carried out, for example, according to a conventional method. For example, the pharmaceutically acceptable excipient which is preferred in a granulate according to the present invention includes, for example, one or more of: surface active agent, for example having influence on the surface strengths of the agents. Chemicals, for example that reduce the surface tension of a liquid, for example whose use can result in easier wetting and / or easier emulsification of a solid in a liquid, for example including, for example, an ionic surfactant or nonionic, wetting agent, tenside; such as sulfonates and sulfates of fatty acid alcohols, for example sodium lauryl sulfate; Texapon®, which includes different types of raw material for washing, for example sulphates or ether sulfates of fatty acid alcohols, for example sodium and ammonium lauryl sulfate, for example a mixture of sodium lauryl sulfate and ammonium, preferably lauryl sulfate sodium, - a vehicle, for example an inert material that can be used as a core, for example in a fluidized bed granulation as a core for the active ingredient, for example such as a conventional core, for example sugar, including sugar alcohols, for example mannitol (mannitol), which includes mannitol granules, for example Pearlitol®, such as Pearlitol®SD 200; a lubricant, for example talcum, Mg stearates. A granulation of cefuroxime axetil in a non-gelatinous form upon contact with an aqueous liquid, comprising one or more pharmaceutically acceptable excipients, can be obtained after removing the solvent. For example, a granulate according to the present invention may contain, in percent by weight of the weight of the granulate: Cefuroxime axetil, from 25 to 95 percent, for example from 30 to 85 percent; Polymer, from 0 to 75 percent; if it is present from 5 to 75 percent, for example from 10 to 60 percent, such as from 15 to 60 percent; preferably from 15 to 60 percent if a granulate is obtained by spray granulation; and preferably from 25 to 45 percent if a granulate is obtained by spray drying; Adsorbent: from 0 to 60 percent, for example from 0 to 50 percent; if it is present from 5 to 50 percent; Surface activity agent: from 0 to 5 percent, for example from 0 to 2.5 percent, for example from 0.3 to 1.5 percent, - Vehicle: from 0 to 50 percent, for example from 0 to 40 percent, for example from 0 to 30 percent; if it is present, for example, from 5 to 50 percent, - Lubricant: from 0 to 5 percent, for example from 0 to 2. 5 percent, for example from 0 to 1.0 percent; if it is present, for example from 0.1 to 1.0 percent, for example from 0.1 to 0.5 percent; but containing at least one pharmaceutically acceptable excipient. In another aspect, the present invention provides a process for the production of a granulate, wherein the cefuroxime axetil is in a non-gelatinous form upon contact with an aqueous liquid, which comprises removing the solvent from the suspension or solution containing: cefuroxime axetil and a polymer and / or an adsorbent, which are capable of forming a non-gelatinous form upon contact with an aqueous liquid with cefuroxime axetil; or - cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid; for example prepared, for example, as described above; and a pharmaceutically acceptable excipient; for example one or more, - in an organic solvent, for example in the presence of water. A cefuroxime-axetil granulate can be obtained in a non-gelatinous form containing one or more pharmaceutically acceptable excipients, for example that is suitable in the production of pharmaceutical compositions, for example oral, for example after further processing, such as the production of a powder, for example dry, for oral administration which is, for example, suitable to be administered as such, or suitable in the preparation of an Arabian suspension. A dry powder according to the present invention can be obtained, for example, by a conventional method, or, for example, as follows: a granulate according to the present invention, for example after further processing, for example including processing through a sieve, grinding; it can be mixed with one or more pharmaceutically acceptable excipients, for example auxiliaries, for example that are useful in the production of a dry powder for oral administration. The mixture can be made, for example according to a conventional method. A dry powder for oral administration may be, for example, in the form of powder, grains, granules, for example having a desired particle size. A mixture obtained, for example a final mixture of powder / grains / granules, or an intermediate mixture of powder / grains / granules obtained, can be further processed, for example granular, compact, break, grind, sieve, for example , to obtain any desired particle size, for example according to a conventional method. The pharmaceutically acceptable excipients which are useful in the production of a dry powder for oral administration according to the present invention include, for example: sugar, for example chemically modified, for example fructose, glucose, sucrose, sugar alcohol, chemically modified example, - sweetener, for example nutritious and artificial, as-pártame; filling, including modified starches, for example starch 1500 (previously gelatinized starch); thickener, for example guar flour; - binder, for example polyvinyl pyrrolidones, celluloses; flavoring agent, preservative, surface activity agent, dye material; preferably sugar and / or sweetener and / or filler and / or fatliquor and / or preservative. In another aspect, the present invention provides a dry powder, for example in the form of powder, grains, granules, for example having a desired particle size, for oral administration, for example suitable for administration as such, for example together with an aqueous liquid, for example water, and, for example, suitable for the preparation of a suspension / syrup, which comprises an effective amount of cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid as an active ingredient, example which can be reconstituted with an aqueous liquid, for example water, to obtain a suspension / syrup; for example in a dosage form, for example comprising a desired amount of cefuroxime-axetil in a desired volume; and a pharmaceutically acceptable excipient; for example that is suitable in the production of a dry powder, for example sugar and / or sweetener and / or filler and / or thickener and / or preservative. A dry powder according to the present invention can be provided in a pharmaceutical dosage form, for example in a container, for example sachet, bottle, for example containing cefuroxime-axetil corresponding to a desired quantity of cefuroxime, for example in a unit dosage form. A desired amount of cefuroxime axetil includes an amount corresponding to an amount of cefuroxime of from 50 to 1000 milligrams, for example from 50 to 800 milligrams, such as from 100 to 800 milligrams, for example from 100 to 600 milligrams, for example from 125 milligrams, for example 250 milligrams, for example 500 milligrams per unit dosage form. In another aspect, the present invention provides a dosage form comprising a dry powder according to the present invention in a container, for example a bottle, a small envelope, for example containing cefuroxime-axetil corresponding to a desired amount of cefuroxime, for example by dosage form. The dried powder in a container, for example containing cefuroxime-axetil corresponding to a desired amount of cefuroxime, for example, can be administered in the form of an Arabian suspension. The dry powders in small envelopes, for example containing cefuroxime axetil according to the present invention, corresponding to a desired amount of cefuroxime, for example 50 to 1000 milligrams, for example 50 to 800 milligrams, such as 100 to 800 milligrams, for example 100 to 600 milligrams, for example 125 milligrams, for example - 250 milligrams, for example 00 milligrams, for example in a unit dosage form, for example, can be administered as such, for example together with an aqueous liquid, for example water, or as a suspension in an aqueous liquid, for example water, for example a small envelope may contain a unit dosage form, for example, and an indication of how much. Aqueous liquid should be used for reconstitution, for example to obtain a suspension / syrup. The dry powder may be in a bottle, for example having a mark, which indicates the necessary amount of aqueous liquid, for example water, to be filled into the bottle to obtain a desired amount of cefuroxime in a given volume; for example an amount of cefuroxime-axetil corresponding to an amount of cefuroxime of 50 to 1000 milligrams, for example 50 to 800 milligrams, such as 100 to 800 milligrams, for example 100 to 600 milligrams, for example of 125 milligrams, for example 250 milligrams, for example 500 milligrams for a desired volume, for example 3 to 10 milliliters, for example 5 milliliters of aqueous liquid. In another aspect, the present invention provides a pharmaceutical dosage form, for example a unit dosage form, comprising a dry powder according to the present invention in a small envelope, containing cefuroxime-axetil corresponding to a quantity of cefuroxime of 50 to 1000 milligrams, for example 50 to 800 milligrams, such as 100 to 800 milligrams, for example 100 to 600 milligrams, for example 125 milligrams, for example 250 milligrams, for example 500 milligrams. In another aspect, the present invention provides a pharmaceutical dosage form comprising a dry powder according to the present invention in a bottle, this bottle having a mark, indicating the necessary amount of aqueous liquid to be filled into the bottle, to obtain a amount of cefuroxime-axetil corresponding to a described amount of cefuroxime, for example 50 to 1000 milligrams, for example 50 to 800 milligrams, such as 100 to 800 milligrams, for example 100 to 600 milligrams, for example 125 milligrams, for example 250 milligrams, for example 500 milligrams, for a given volume of suspension / syrup, for example 3 to 10 milliliters, for example 5 milliliters of suspension / syrup. A dry powder according to the present invention can effect a dissolution of at least 60 percent (Q-value) of the labeled amount of cefuroxime-axetil within 15 minutes, for example, and / or a solution of at least 75 percent (Q value) of the labeled amount of cefuroxima-axetil within 45 minutes; when a dosage form of cefuroxime-axetil is tested as stipulated in the USP < 711 > in a USP-2 device under at least as stringent conditions as the following: 900 milliliters of hydrochloric acid 0.07N 37 ° C, with the paddles rotating at 55 rpm. A dry powder according to the present invention can be reconstituted with an aqueous liquid, for example water. In another aspect the present invention provides a syrup / suspension for oral administration, which comprises a dry powder according to the present invention, which is reconstituted with an aqueous liquid. In a preferred embodiment of the present invention, a dry powder according to the present invention, containing fructose and glucose, or a mixture thereof, in an amount such that upon reconstitution of the dry powder with an aqueous liquid, for example water, for example containing a quantity of cefuroxime-axetil corresponding to a desired amount of cefuroxime, for example from 50 to 1000 milligrams, for example from 50 to 800 milligrams, such as from 100 to 800 milligrams, for example from 100 to 600 milligrams, for example example of 125 milligrams, for example of 250 milligrams, for example of 500 milligrams, for example a desired volume, for example by 3 to 10 milliliters, for example 5 milliliters of aqueous liquid, a suspension / syrup is obtained, wherein the glucose and / or fructose are in a highly concentrated, saturated solution, for example supersaturated. In another aspect, the present invention provides cefuroxime axetil for example in a non-gelatinous form upon contact with an aqueous liquid, in the form of a dry powder, containing such an amount of fructose and / or glucose that, after reconstitution , in an aqueous liquid, for example water, an amount of cefuroxime-axetil corresponding to a desired amount of cefuroxime, for example in a desired volume, a suspension / syrup is obtained, wherein the glucose and / or fructose are in a solution highly concentrated, for example saturated or supersaturated; for example containing from 3 to 10 milliliters of the highly concentrated solution an amount of cefuroxime-axetil, for example in a non-gelatinous form upon contact with an aqueous liquid, for example corresponding to 500 to 1000 mi-ligramos of cefuroxime; and an oral suspension / syrup comprising an effective amount of cefuroxime-axetil, for example in a non-gelatinous form upon contact with an aqueous liquid, wherein the glucose and / or fructose are in a highly concentrated solution, for example saturated or supersaturated . A cefuroxime-axetil granulate according to the present invention is also useful in the production of tablets, for example for the production of tablet cores. In another aspect, the present invention provides a tablet, for example a tablet core, for example a film-coated tablet, for example wherein the film coating comprises a film-forming polymer, a plasticizer, lubricant; for example for oral administration, which comprises cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid as active ingredient, and a pharmaceutically acceptable excipient, for example auxiliaries, for example that are useful in the process of forming tablets, for example a disintegrant, and / or binder, and / or lubricant, and / or surface activity agent, and / or filler, and / or flow aid; for example binder, and / or surface activity agent, and / or filler, and / or flow aid; for example, wherein this tablet, for example film coated, effects a dissolution of at least 60 percent (Q value) of the labeled amount of cefuroxime-axetil within 15 minutes, for example, and / or a solution of at least 75 percent (Q value) of the labeled amount of cefuroxime-axetil within 45 minutes; when a dosage form of cefuroxime-axetil is tested as stipulated in the USP <test; 711 > in a USP-2 device under conditions as less astringent as the following: 900 milliliters of 0.07N hydrochloric acid, 37 ° C, with the paddles rotating at 55 rpm. A tablet, for example a tablet core, according to the present invention, can be obtained, for example, according to a conventional method, or, for example, as follows: A granulate according to the present invention can be mixed with one or more pharmaceutically acceptable excipients, for example auxiliaries that are useful in tablets / in the tabletting process; and the granulate or mixture with pharmaceutically acceptable excipients can be compressed into tablets, for example into tablet cores, for example by a conventional method, for example optionally comprising compaction steps before being compressed. The pharmaceutically acceptable excipients in tablets / - in a tabletting process, which are those preferred in the tablets / tabletting process according to the present invention include, for example: disintegrants, eg, to accelerate the release of the active compound, such as starches, for example including modified starches, for example cross-linked, such as sodium starch glycollates, croscarmellose sodium, polyvinylpyrrolidones, for example including modified, for example crosslinked polyvinylpyrrolidones, such as polyplasdone, crospovidone; celluloses, such as sodium and calcium carboxymethylcelluloses, modified celluloses, for example crosslinked; such as AcDiSol; formaldehyde-casein compounds, for example Esma-Spreng®, defatted soybean seed extracts; preferably crosslinked Na carboxymethyl cellulose, for example AcDiSol, polyvinyl pyrrolidone, for example crosslinked, for example polyplasdone and crospovidone; formaldehyde-casein compounds, for example Esma-Spreng®; for example crosslinked Na carboxymethylcellulose, formaldehyde-casein compounds, for example formaldehyde-casein compounds; binders, for example including micro-crystalline cellulose, for example Avicel®; fillers, for example including crystalline celluloses, sugars, for example mannitol, for example Pearlitol®; lubricants, for example including talcum, Mg stearates, for example talc; - flow aids, for example including silicon dioxide, such as Aerosil®; surface active agents, for example as described above in the production of a granulate according to the present invention, preferably including sodium lauryl sulfate, for example mixed with ammonium lauryl sulfate, for example Texapon®; preferably, for example a disintegrant, and / or binder, and / or lubricant, and / or surface activity agent, and / or filler, and / or flow aid; for example binder, and / or surface activity agent, and / or filler. In a preferred method according to the present invention, the process for the production of tablets may contain additional processing data of an intermediate mixture of pharmaceutically acceptable excipients and / or cefuroxime axetil before being compressed, for example by breaking into a ta-miz. by granulating, compacting, for example a granulate according to the present invention, for example by further processing, for example through a sieve, by grinding; it can be granulated, for example compacted, mixed with one or more pharmaceutically acceptable excipients, for example that are useful in tablets / tabletting processes, the obtained mixture can be broken, for example processed through a sieve, and it can be mixed with a one or more pharmaceutically acceptable excipients, for example that are useful in tablets / in tabletting processes. The final mixture obtained can be compressed into tablets / tablet cores, for example according to a conventional method. In another aspect, the present invention provides a process for the production of a tablet, for example a tablet core, for example a film-coated tablet, for example wherein the film coating comprises a film-forming polymer, lubricant , plasticizer, dye material, and / or flavoring agent; which comprises an effective amount of cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid as an active ingredient, and a pharmaceutically acceptable excipient, for example one or more, for example, which is useful in tablets / the process of forming tablets, for example auxiliaries, which comprises compressing a granulate comprising cefuroximexetile in a non-gelatinous form upon contact with an aqueous liquid, according to the present invention, in combination with, for example, one or more, excipients pharmaceutically acceptable, for example that are useful in the production of tablets / tabletting process, for example auxiliaries, for example a disintegrant, and / or binder, and / or lubricant, and / or surface active agent, and / or padding, and / or flow aid; for example one or more binders, and / or surface activity agents, and / or fillers; for example, and a film coating, for example in accordance with a conventional method, for example by including additional processing steps of an intermediate mixture of pharmaceutically acceptable excipients and / or cefuroxime-axetil before being compressed, for example by compacting, breaking through. from a sieve, granulating. A tablet / tablet core according to the present invention can be coated with a film coating, for example in accordance with a conventional method, for example by coating with one or more film-forming components, for example with a film-forming composition. , for example dissolved or suspended in a solvent, for example water, an organic solvent, or a mixture of water and organic solvent, preferably water, for example according to a conventional method. Preferred film coating compositions according to the present invention include, for example: film-forming polymer; for example, suitable celluloses, for example hydroxyalkyl celluloses, such as hydroxymethylpropylcellulose, methylcelluloses, for example Methocel®, polyvinylpyrrolidones, for example Kollidons®, such as Kollidon®VA64; polymethacrylates, for example Eudragit®; polyvinyl alcohols; plasticizer, for example polyethylene glycols; lubricant, for example talc; - dye material, pigment, for example Ti02, flavoring agent, preservative; preferably film-forming polymer, and / or plasticizer, and / or lubricant, and / or dyeing material, pigment, and / or flavoring agent. A film coating according to the present invention includes a film coating having a short break time, for example as described in European Patent Number EP 223365, i.e., a film coating that can serve to mask the taste bitter of the cefuroxime-axetil after its oral administration, the film coating having a thickness in which the time of rupture is less than 40 seconds when measured by a rupture test, wherein the tablet is placed in a beaker of 0.07N hydrochloric acid at 37 ° C, the rupture being measured at the time that elapses before the tablet core becomes visible to the naked eye through the broken film coating, and the core of the tablet disintegrates. tablet immediately following the breakdown of the film coating in this rupture test. The contents of the European patent number EP 223365 which relates to the film coating, for example including the examples for a film coating as claimed in the European patent number EP 223365 and the production of tablets coated with a film as claimed in European Patent Number EP 223365 are hereby incorporated by reference. Preferably, according to the present invention, a conventional film coating having a break time of 40 seconds and more is used. Because cefuroxime-axetil, for example as it is commercially available, may undergo gelatinization, for example with the consequence that the adsorption of cefuroxime axetil can be reduced from the gastrointestinal tract, for example as described herein, until the present invention, a tablet containing cefuroxime-axetil had an unconventional film coating having a very short breaking time, for example according to European Patent Number 223365, with a breaking time of less than 40 seconds under the defined conditions. A rapidly disintegrating film coating, which has a break time of less than 40 seconds, for example, may have the disadvantage that the film coating can easily be destroyed upon contact with moisture, and the film coating it loses its protective effect. Surprisingly, it has now been found that a tablet comprising cefuroxime axetil in a non-gelatinous form upon contact with an aqueous liquid can have a conventional coating that has a break time of 40 seconds and more when measured by the rupture test, as defined in European Patent Number EP 223365 and, in spite of the conventional coating, a dissolution rate according to USP 23 is maintained (for example USP 24). A tablet comprising cefuroxime axetil, which has a film coating whose break time is 40 seconds and more, for example 40 seconds to 10 minutes, for example 40 seconds to 3 minutes, determined in a break test. According to European Patent Number EP 223365, and having a dissolution rate according to USP 23 (for example, USP 24), it is new. In another aspect, the present invention provides a film-coated tablet comprising an effective amount of cefuroxime axetil as an active ingredient, and a film coating.; the breaking time of the film coating being 40 seconds and more, for example 40 seconds to 10 minutes, when measured by a rupture test where the tablet is placed in a beaker of 0.07N hydrochloric acid at 37 ° C, the break being measured as the time that elapses before the core of the tablet becomes visible to the naked eye through the broken film coating; wherein the film-coated tablet makes a solution of at least 60 percent (Q value) of the labeled amount of cefuroxime-axetil within 15 minutes, for example, and / or a solution of at least 75% by weight. percent (Q value) of the labeled amount of cefuroxime-axetil within 45 minutes; when testing a tablet coated with cefuroxime-axetil film as stipulated in the USP < 711 > in a USP-2 apparatus under at least as stringent conditions as the following: 900 milliliters of 0.7 N hydrochloric acid, 37 ° C, with the blades rotating at 55 rpm, for example including more stringent conditions, for example a lower volume of 0.07N hydrochloric acid, lower temperature, and lower speed of the paddles.

In another aspect, the present invention provides the use of a film coating in the manufacture of a film coated tablet comprising an effective amount of cefuroxime axetil as an active ingredient, and effecting a dissolution of at least 60 percent ( Q value) of the labeled amount of cefuroxime-axetil within 15 minutes, for example, and / or a solution of at least 75 percent (Q value) of the labeled amount of cefuroxime-axetil within 45 minutes, under conditions at least as astringent as the following: 900 milliliters of hydrochloric acid 0.07N, 37 ° C, with the blades rotating at 55 rpm, for example including more astringent conditions, for example a lower volume of hydrochloric acid 0.07N, a lower temperature, lower speed of the paddles; when a tablet coated with cefuroxime-axetil film is tested as stipulated in the USP < 711 > in a USP-2 apparatus, comprising the break time of the film coating of 40 seconds and more, for example 40 seconds to 10 minutes, when measured by a rupture test, wherein the film coated tablet is placed in a beaker with 0.07N hydrochloric acid at 37 ° C, the break time being measured as the time that elapses before the tablet core becomes visible to the naked eye through the coating of broken film. A tablet having a conventional film coating is normally protected from moisture by film coating. Accordingly, a film-coated tablet according to the present invention, having a break time of 40 seconds and more in a break test as described above, does not need to be sealed against moisture attack in a packaging for a composition pharmaceutical, while a tablet that has a rupture time less than 40 seconds, can be easily destroyed on contact with moisture, and must be sealed against moisture in a package. A package for a pharmaceutical composition comprising cefuroxime-axetil in a package lacking seal against moisture attack is new. In another aspect, the present invention provides an em-pack for a pharmaceutical composition, for example a container, such as a bottle, comprising cefuroxime axetil as an active ingredient in the form of film-coated tablets, which comprises an amount effective cefuroxime-axetil, which comprises a package that has no seal against moisture attack, and film-coated tablets lack seal against moisture attack. A film coated tablet according to the present invention may comprise cefuroxime axetil in an amount corresponding to 50 to 1000 milligrams of cefuroxime as an active ingredient, preferably corresponding to 500 milligrams, 250 milligrams, or 125 milligrams of cefuroxime. It is known that cefuroxime axetil commercially available in the form of a tablet and in the form of a dry powder, both comprising the same amount of cefuroxime axetil, do not have substantially the same dissolution rates according to USP, ie, a film coated tablet and a dry powder are not directly interchangeable, despite containing the same amount of cefuroxime axetil, for example a tablet comprising, for example, cefuroxime axetil in an amount corresponding to, for example, 125 milligrams of cefuroxime, can not be directly replaced by a dry powder comprising cefuroxime-axetil in an amount corresponding to 125 milligrams of cefuroxime, due to the different dissolution rates, that is, to the different bioavailability. It is also known that a dry powder comprising cefuroxime-axetil does not meet the dissolution requirements of USP 23, but has a dissolution rate of the active ingredient that is different from the requirements of USP 23. It was now surprisingly found that a coated tablet film and a dry powder, both comprising the same amount of cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid according to the present invention, both have substantially the same dissolution rate according to USP, and therefore, are directly interchangeable. In another aspect, the present invention provides the use of cefuroxime axetil in the manufacture of a film coated tablet, having a dissolution rate according to USP 23, and in the production of a dry powder having a dissolution rate according to USP 23, wherein the film-coated tablet contains the same effective amount of cefuroxime-axetil as the dried powder, for example, the dry powder and the film-coated tablet are bioequivalent oral forms of cefuroxime administration. It is known that the absorption and bioavailability of any particular active therapeutic agent, for example a drug, can be affected by numerous factors when dosed orally. These factors include the presence of food in the gastrointestinal tract / stomach. If the bioavailability of a drug is affected beyond a certain point due to the presence of food in the gastrointestinal tract / stomach, the drug is said to exhibit a "food effect". It has long been known that cefuroxime axetil in oral forms that are commercially available, for example in an amorphous form in oral dry tablets and powder, and crystalline cefuroxime axetil, exhibit a food effect, for example, cefuroxime axetil has a better bioavailability after oral administration of a mammal after food consumption, than a mammal in the fasted state. Consequently, the administration of commercially available cefuroximexetil is recommended after the consumption of food. This food effect of cefuroxime-axetil is described as possibly due to the different pH conditions in the stomach in the fasted state (around a pH of 1 and lower), and in the presence of food (around a pH of 4). It was now found that the rate of dissolution of cefuroxime-axetil from commercially available pharmaceutical compositions, wherein cefuroxime-axetil is in an amorphous form, depends on the pH; for example, the release of cefuroxime axetil from the formulation at 37 ° C, is considerably reduced to a pH of 1, compared to the solution at a pH of 4, while, surprisingly, the release of the compound cefuroxime axetil active in a pharmaceutical composition according to the present invention, is practically independent of the pH, for example as shown in Figures 1 to 3. Figure 1 shows the pH dependence of the dissolution rate of the cefuroxime axetil in a 500 milligram film-coated tablet commercially available under the trade name Zinnat® at a pH of 1, at a pH < 0, and at a pH of 4 to 37 ° C in percentage of dissolution of the labeled amount of cefuroxime-axetil in a defined period of time (in minutes). From Figure 1, for example, it is evident that the rate of dissolution of cefuroxime axetil in a commercially available film-coated tablet at 37 ° C in an aqueous medium, for example acid, for example acid with acid hydrochloric, for example regulated, is lower: than 5 percent at a pH of about 1, for example at a pH of 1 after 10 to 15 minutes from the start of the dissolution test; and / or that 20 percent at a pH < 0 after 25 to 30 minutes from the start of the dissolution test, than the rate of dissolution of the cefuroxime-axetil at a pH of about 4, for example at a pH of 4.

Figure 2 shows the pH dependency of the dissolution rate of cefuroxime axetil in a 500 milligram film-coated tablet according to the present invention, ie, comprising cefuroxime axetil in a non-gelatinous form upon contact with an aqueous liquid, for example prepared according to example 13 of the present application, at a pH of 1, at a pH < 0, and at a pH of 4 to 37 ° C, in percentage of dissolution of the labeled amount of cefuroxime-axetil in a defined period of time (in minutes). From Figure 2, for example, it is evident that the rate of dissolution of the cefuroxime axetil in a film-coated tablet according to the present invention at 37 ° C in an aqueous medium, for example acid, for example acid with hydrochloric acid, for example regulated, is equal or not lower: - than 5 percent at a pH of about 1, for example at a pH of 1 after 10 to 15 minutes from the start of the dissolution test; and / or that 20 percent at a pH < 0 after 25 to 30 minutes from the start of the dissolution test, - that the rate of dissolution of cefuroxime-axetil at a pH of about 4, for example at a pH of 4. Figure 3 shows the dependence on the pH of the dissolution rate of cefuroxime-axetil, of a film-coated tablet of 500 milligrams in accordance with the present invention, ie, comprising cefuroxime-axetil in a non-gelatinous form upon contact with a aqueous liquid, prepared according to Example 13 of the present application (invention); and a film-coated tablet of 500 milligrams according to Example 19 of the present application, comprising cefuroxime-axetil amorphous, for example as commercially available, in place of cefuroxime-axetil in a non-gelatinous form, replacing the granulation step A by a conventional mixing step (Prior Art), at a pH < 0 to 37 ° C in percentage of dissolution of the labeled amount of cefuroxime-axetil in a defined period of time (in minutes). From Figure 3, for example, it is evident that the rate of dissolution of amorphous cefuroxime axetil is different than the dissolution rate of cefuroxime axetil in a non-gelatinous form upon contact with an aqueous liquid. The rate of dissolution of cefuroxime-axetil as shown in Figures 1 to 3, preferably can be determined as stipulated in the USP < 711 > , which is described in more detail above. Because the pH normally increases in the stomach in the presence of food until around a pH of 4, compared to a pH of around 1 and lower in the fasting state, it is believed that the food effect of cefuroxime- axetil is due to the pH dependent dissolution rate of amorphous cefuroxime axetil in a form as is commercially available. On the other hand, it was surprisingly found that the rate of dissolution of cefuroxime-axetil in a non-gelatinous form according to the present invention, for example in the form of a tablet or a granulate, is practically independent of pH. Accordingly, a tablet or a granulate comprising cefuroxime axetil in a non-gelatinous form according to the present invention can be administered independently of whether a mammal has eaten or is fasting, for example cefuroxime axetil according to the present invention. invention does not exhibit an adverse food effect. The use of cefuroxime-axetil in the manufacture of an oral dosage form that does not exhibit an adverse food effect is new. In another aspect, the present invention provides the use of cefuroxime axetil in the manufacture of an oral dosage form, for example a tablet or a dry powder or a suspension / syrup for oral administration, which does not exhibit an adverse food effect, in the treatment of a microbial infection, for example bacterial, in a mammal, for example, and wherein this dosage form effects a dissolution of at least 60 percent (Q value) of the labeled amount of cefuroxime-axetil within 15 minutes, for example, and / or a dissolution of at least 75 percent (Q value) of the labeled amount of cefuroxime-axetil within 45 minutes; when a dosage form of cefuroxime-axetil is tested as stipulated in the USP < 711 > in a USP-2 device under at least as stringent conditions as the following: 900 milliliters of hydrochloric acid 0.07N, 37 ° C, with the paddles rotating at 55 rpm; for example including more astringent conditions, for example a lower volume of hydrochloric acid 0.07N, a lower temperature, a lower speed of the paddles, for example where this mammal is a human being. In another aspect, the present invention provides an oral dosage form of cefuroxime axetil which is in the form of a tablet, for example film coated, e.g. conventionally film coated, which can be administered to a fasted mammal. , and which does not exhibit an adverse food effect, which comprises an effective amount of cefuroxime-axetil and pharmaceutically acceptable excipients, for example disintegrant, and / or binder, and / or filler, and / or lubricant, and / or adjuvant flow, and / or surface activity agent, and this dosage form effects a dissolution of at least 60 percent (Q value) of the labeled amount of cefuroxime-axetil within 15 minutes, for example, and / or a solution at least 75 percent (Q value) of the labeled amount of cefuroxime-axetil within 45 minutes; when a dosage form of cefuroxime-axetil is tested as stipulated in the USP < 711 > in a USP-2 device under at least as stringent conditions as the following: 900 milliliters of hydrochloric acid 0.07N, 37 ° C, with the paddles rotating at 55 rpm; for example including more astringent conditions, for example a lower vo-lumen of 0.07N hydrochloric acid, a lower temperature, a lower velocity of the vanes; for example, where this mammal is a human being. In another aspect, the present invention provides an oral dosage form containing cefuroxime axetil as an active ingredient, which is in the form of a dry powder, or which is in the form of a suspension / syrup, and which can be administered to a mammal that is fasting, and that does not exhibit an adverse food effect, which comprises an effective amount of cefuroxime-axetil, and one or more pharmaceutically acceptable excipients, sugar, and / or sweetener, and / or filler , and / or thickener, and / or preservative, for example the dry powder effects a dissolution of at least 60 percent (Q value) of the labeled amount of cefuroxime-axetil within 15 minutes, for example, and / or a dissolution of at least 75 percent (Q value) of the labeled amount of cefuroxime-axetil within 45 minutes; when a dosage form of cefuroxime-axetil is tested as stipulated in the USP < 711 > in a USP-2 apparatus, under conditions at least as stringent as the following: 900 milliliters of hydrochloric acid 0.07N 37 ° C, with the blades rotating at 55 rpm, for example including more stringent conditions, for example a lower volume of 0.07N hydrochloric acid, lower temperature, lower speed of the paddles; for example where this mammal is a human being. In another aspect, the present invention provides processes, for the production of granules comprising cefuroxime-axetil, wherein the active ingredient of cefuroxime-axetil is present in an activated form, such that it no longer has a tendency to form a gel when in contact with an aqueous medium, characterized in that the granulation is carried out with the addition of a polymer or an insoluble adsorbent. The following examples illustrate the present invention.

Examples 1 to 13 Step A. Preparation of a granulate comprising cefuroxime axetil in a non-gelatinous form upon contact with an aqueous liquid, and other components as indicated in Table 1 and Table 2. The amount of cefuroxime-axetil in Table 1 and Table 2 (in milligrams per tablet) is indicated in the corresponding amount of cefuroxime which is the active amount in vivo, because the carboxylic ester in position 4 of the ring system is removed in vivo, the carboxylic acid is released, and the cefuroxime compound is formed.

TABLE 1 General procedure in Examples I to 5 and 10 to 12 A fluid of the solid components VI and VII as stipulated in Tables 1 and 2 (if present in the corresponding Example according to Table 1 and Table 1) 2) in a fluidized bed granulator, treated (sprayed) with a solution / suspension of components I to IV as stipulated in Table 1 and Table 2 (if present in the corresponding Example in accordance with the Table 1 and Table 2). As the solvent, acetone is used in Examples 1 to 5, and a mixture of acetone: water (about 7: 1) in Examples 10 to 12. The dry granulate obtained is processed through a screen (for example, 210). mieras, 250 microns, 500 microns, 630 microns), or grinds. General procedure in Examples 6 and 13 to 15 A solution of components I, II, and III, as stipulated in Table 1 and Table 2 (if present in the corresponding Example in accordance with Table 1 and with Table 2) is granulated in a spray dryer. As a solvent, acetone is used in Example 6, and a mixture of acetone: water (about 7: 1) in Examples 13 to 15. A dry granulate is obtained. General procedure in Example 7 Component IV as stipulated in Table 2, is moistened with a solution of components I, II, and III as stipulated in Table 2, in acetone, in portions, and the mixture obtained is granulate with mixture, and the obtained mixture is dried. The dry granulate obtained is processed through a sieve (500 microns), and is milled after being processed into a sieve. General procedure in Examples 8 and 9 From a solution / suspension of components I, IV, and V, as stipulated in Table 2 (if present in the corresponding Example according to Table 2), the solvent it is evaporated in a rotary evaporator. In Example 8 ethanol is used, and in Example 9 methylene chloride is used as a solvent. The dried granulate obtained is processed through a sieve and milled after being processed in the sieve. B. Production of a tabletting mixture, comprising a granulate comprising cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid, and - other components as indicated in Table 4 and Table . TABLE 4 TABLE 5 General procedure in Examples 1 to 4, 7 to 9 The granulate obtained in Step A is mixed with components VIII to XIII as stipulated in Table 4 and Table 5 (if present in the corresponding Example in accordance with Table 4 and Table 5), and the obtained mixture is compressed into tablets. General procedure in Example 5 and in Example 6 The granulate obtained in Step A is mixed with component XV and compressed, the tablet obtained is processed through a screen and mixed with components VIII, IX, X, XI, XII and XIII. The obtained mixture is compressed into tablets. The components VIII, IX, X, XI, XII, XIII and XV are as stipulated in Table 4 (if they are present in the corresponding Example according to Table 4). General procedure in Example 10 The granulate obtained in Step A is mixed with components XV and 30 milligrams / tablet of component XI. The obtained mixture is compacted, and the obtained tablet is processed through a 1.00 millimeter sieve, and the granules obtained are mixed with the X component., 10 milligrams / tablet of component XI, and components XIII, XII, IX, and XVI. The obtained mixture is compressed into tablets. The components IX, XI, XII, XIII, XV and XVI are as stipulated in Table 5. General procedure in Examples 11 and 12 The granulate obtained in Step A is mixed with component XVI and 30 milligrams / tablet of the component XI. The obtained mixture is compacted, and the tablet obtained is processed through a sieve of 630 microns, and the obtained granules are mixed with component VIII, 3 milligrams / tablet of component XI and components X, XIII, XII, IX, and XVI. The obtained mixture is compressed into tablets. Components VIII, IX, X, XI, XII, XIII, and XVI are as stipulated in Table 5. General procedure in Example 13 The granulate obtained in Step A is mixed with 110 milligrams / tablet of component VIII, milligrams / tablet of component XI, and 5 milligrams / tablet of component XIII. The obtained mixture is compacted, and the tablet obtained is processed through a 630 micron sieve, and the obtained granules are mixed with 40 milligrams / tablet of component VIII, 6 milligrams / tablet of component XI 3 milligrams / tablet of the component XIII, and with the components X, XII, IX, XV and XVII. The obtained mixture is compressed into tablets. Components VIII, IX, X, XI, XII, XIII, XV and XVII are as stipulated in Table 5. General procedure in Examples 14 and 15 55 milligrams / tablet (27.5 milligrams / tablet) of component VIII, 15 milligrams / tablet (7.5 milligrams / tablet) of component XI, and 2.5 milligrams / tablet (1.2 milligrams / tablet) of component XIII, are mixed with the granulate obtained in Step A. The obtained mixture is compacted, and the tablet obtained it is processed through a sieve of 630 microns. The obtained granules are mixed with 21 milligrams / - tablet (10.5 milligrams / tablet) of component VIII, 3 milligrams / tablet (1.5 milligrams / tablet) of component XI, and 1.5 milligrams of component XIII, and with components IX, X, XI, XII, XV and XVII. The obtained mixture is compressed into tablets. Components VIII, IX, X, XI, XII, XIII, XV and XVII are as stipulated in Table 5. C. Production of film coated tablets from the tablets produced in Step B comprising the coating components as indicated in Table 6 and Table 7 TABLE 6 TABLE 7 General Procedure of Examples 1 to 15 Components XVIII to XXII as stipulated in Table 6 and Table 7 (if present in accordance with Table 6 and Table 7 in the corresponding Example) are dissolved or suspended , respectively, in water, and the tablets obtained in Step B are film coated with the obtained suspension. The film-coated tablets are dried. The thickness of a coating is such that the breaking time of the film coated tablets, for example determined as described in European Patent No. EP 233365, and as described herein above, is on average 1 to 2 , for example around 1.5 minutes. The dissolution of the active component from the tablets obtained according to Examples 1 to 15 complies with the requirements of USP 23 (and USP 24, which is provided and assumed to be in force since 2000).

Examples 16 to 19 Production of an oral dry powder comprising cefuroximexetile in a non-gelatinous form upon contact with an aqueous liquid, suitable for the production of a suspension / arabic. General Procedure A granulate obtained according to Example 1, Step A, or according to Example 2, Step A, or according to Example 13, Step A, either as such, or after compaction and processing through a 630 micron sieve, is mixed with components XXIII to XXX as stipulated in Table 8 (if present in accordance with Table 8 in the corresponding example) to homogeneity. A mixture is obtained in the form of a dry powder which can be used in the oral administration of cefuroxime axetil.

The obtained homogenous mixture: is treated with water to form an oral suspension / syrup, in an amount such that 5 milliliters of a reconstituted suspension contains an amount of cefuroxime-axetil corresponding to 125, 250, or 500 milligrams of cefuroxime; is filled into a bottle, for example having a mark indicating the necessary amount of aqueous liquid to obtain 125, 250, or 500 milligrams of cefuroxime in 5 milliliters of oral suspension / syrup; or it is filled into small envelopes in such an amount that a small envelope contains an amount of cefuroxime-axetil corresponding to 125, 250, or 500 milligrams of cefuroxime. : corresponding to 125 milligrams of cefuroxime. 2): corresponding to 250 milligrams of cefuroxime. 3): corresponding to 500 milligrams of cefuroxime.

Use 19 Comparison The components are, for Example 13, Step A, Step B, and Step C, in the same amounts as listed in Table 2, Table 4, and Table 6. Cefuroxime-axetil (amorphous) KollidonVA64, mannitol, Esma-Spreng® and 6 milligrams of sodium lauryl sulfate are mixed. The mixture is compacted, and the obtained tablet is processed through a 1.00 millimeter sieve. The obtained granulate is mixed with polyplasdone, Ac-Di-Sol, microcrystalline cellulose, talc, Mg stearate, and the rest of sodium lauryl sulfate, and compressed. The tablets are coated with film as described in Example 13C. The dissolution rate of the obtained film-coated tablets is shown in Figure 3.

Claims (26)

1. -Cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid.

2. Cefuroxime-axetil in the form of a solid solution in a polymer.

3. Cefuroxime axetil according to claim 2, wherein the weight ratio of the cefuroxime axetil: polymer is from 1: 0.15 to 1:06.

4. Cefuroxime axetil in the form of a solid dispersion on an adsorbent.

5. Cefuroxime axetil in a non-gelatinous form upon contact with an aqueous liquid, comprising cefuroxime axetil in the form of a solid solution in a polymer, in combination with cefuroxime axetil in the form of a solid dispersion on an adsorbent.

6. A granulate comprising cefuroxime axetil and a polymer and / or an adsorbent, wherein the cefuroxime axetil is in a non-gelatinous form upon contact with an aqueous liquid, and a pharmaceutically acceptable excipient.

7. A pharmaceutical composition comprising a pharmaceutically effective amount of cefuroxime axetil in a non-gelatinous form upon contact with an aqueous liquid as an active ingredient, in combination with a pharmaceutically acceptable excipient.

8. A pharmaceutical composition according to claim 7, in the form of a pharmaceutical dosage form wherein this dosage form effects a dissolution of at least 60 percent (Q value) of the labeled amount of cefuroxime-axetil within 15 minutes, and / or a solution of at least 75 percent (Q value) of Xa labeled amount of cefuroxime-axetil within 45 minutes; when a dosage form of cefuroxime-axetil is tested as stipulated in the USP < 711 > in a USP-2 device, under conditions as less astringent as the following: 900 milliliters of hydrochloric acid 0.07N 37 ° C, with the paddles rotating at 55 rpm.

9. A dry powder for oral administration, which comprises an effective amount of cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid as an active ingredient, and a pharmaceutically acceptable excipient.

10. A dry powder according to claim 9 in a container, containing cefuroxime-axetil in an amount corresponding to a desired amount of cefuroxime.

11. A syrup / suspension for oral administration, comprising a dry powder according to any of claims 9 to 10, which is reconstituted with an aqueous liquid.

12. A suspension / syrup according to the oral administration, comprising an effective amount of cefuro-xima-axetil, wherein the glucose and / or fructose are in a highly concentrated solution.

13. A tablet for oral administration, which comprises an effective amount of cefuroxime axetil in a non-gelatinous form upon contact with an aqueous liquid as an active ingredient, and a pharmaceutically acceptable excipient.

14. A tablet according to claim 13, which is coated with film.

15. A film-coated tablet, which comprises cefuroxime axetil as an active ingredient, and a film coating, the film coating breaking time being 40 seconds and more when measured by a rupture test, wherein the The tablet is placed in a beaker of 0.07N hydrochloric acid at 37 ° C, the rupture being measured as the time that elapses before the tablet core becomes visible to the naked eye through the broken film coating.; wherein the film-coated tablet effects a dissolution of at least 60 percent (Q value) of the labeled amount of cefuroxime-axetil within 15 minutes, and / or a solution of at least 75 percent (Q value) of the labeled amount of cefuroxime-axetil within 45 minutes; when testing a tablet coated with cefuroxime-axetil film as stipulated in the USP < 711 > in a USP-2 device under conditions as less astringent as the following: 900 milliliters of hydrochloric acid 0.07N, 37 ° C, with the paddles rotating at 55 rpm.

16. A package for a pharmaceutical composition comprising cefuroxime axetil as an active ingredient in the form of film-coated tablets comprising an effective amount of. .. cefuroxime axetil, which comprises that the package has no seal against the attack of moisture, and film-coated tablets lack seal against moisture attack.

17. A process for the production of a tablet according to any of claims 13 to 15, comprising an effective amount of cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid as an active ingredient, which comprises compressing a cefuroxime-axetil granulate and a polymer and / or an adsorbent, wherein the cefuroxime-axetil is in a non-gelatinous form upon contact with an aqueous liquid, and one or more pharmaceutically acceptable excipients blended with one or more pharmaceutically acceptable excipients, and if desired, a film coating.

18. A process for the production of cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid, which comprises dissolving or suspending cefuroxime-axetil and a polymer that can form a non-gelatinous solid together with cefuroxime-axetil and / or a vehicle that can form a solid surface dispersion with cefuroxime-axetil in an organic solvent, and remove the solvent.

19. A process for the production of a granulate, wherein the cefuroxime-axetil is in a non-gelatinous form upon contact with an aqueous liquid, which comprises removing the solvent from a suspension or solution containing: - cefuroxime-axetil and a polymer and / or an adsorbent which can form a non-gelatinous form upon contact with an aqueous liquid with cefuroxime-axetil; or cefuroxime-axetil in a non-gelatinous form upon contact with an aqueous liquid; and a pharmaceutically acceptable excipient; for example one or more; in an organic solvent, if desired in the presence of water.

20. The use of cefuroxime-axetil in the manufacture of a film-coated tablet having a dissolution rate in accordance with USP 23, and in the production of a dry powder having a dissolution rate according to USP 23, in where the film-coated tablet contains the same effective amount of cefuroxime-axetil as the dried powder.

21. The use of cefuroxime-axetil in the manufacture of an oral dosage form that does not exhibit an adverse food effect in the treatment of microbial diseases in a mammal.

22. The use according to claim 21, wherein: this dosage form effects a dissolution of at least 60 percent (Q value) of the labeled amount of cefuroxime-axetil within 15 minutes, and / or a dissolution at least 75 percent (Q value) of the amount labeled cefuroxime-axetil within 45 minutes; when a dosage form of cefuroxime-axetil is tested as stipulated in the USP < 711 > in a USP-2 device, under conditions as less astringent as the following: 900 milliliters of 0.07N hydrochloric acid at 37 ° C, with the blades rotating at 55 rpm.

23. An oral dosage form of cefuroxime axetil, which is in the form of a tablet that can be administered to a mammal that is in the fasted state, and which exhibits no adverse food effect, which comprises a quantity Effectiveness of cefuroxime-axetil, and a pharmaceutically acceptable excipient.

24. An oral dosage form of cefuroxime axetil which is in the form of a dry powder, or which is in the form of a suspension / syrup, and which can be administered to a mammal in the fasting state. , and which exhibits no adverse food effect, which comprises an effective amount of cefuroxime-axetil, and a pharmaceutically acceptable excipient.

25. An oral dosage form according to any of claims 23 to 24, which effects a resolution of at least 60 percent (Q value) of the labeled amount of cefuroxime-axetil within 15 minutes. , and / or a dissolution of at least 75 percent (Q value) of the labeled amount of cefuroxime-axetil within 45 minutes; when a dosage form of cefuroxime-axetil is tested as stipulated in the USP < 711 > in a USP-2 device, under conditions as less astringent as the following: 900 milliliters of hydrochloric acid 0.07N 37 ° C, with the paddles rotating at 55 rpm.

26. A process for the production of granules comprising cefuroxime-axetil, wherein the active ingredient of cefuroxime-axetil is present in an activated form, such that it no longer has a tendency to form a gel when in contact with a medium aqueous, characterized in that the granulation is carried out with the addition of a polymer or an insoluble adsorbent.