Cefuroximaxetil-containing combinations

FIELD: medicine, antibiotics.

SUBSTANCE: invention relates to cephalosporin antibiotic - cefuroximaxetil that is used in treatment of bacterial infections. Invention proposes a new form of cefuroximaxetil not forming gel in contact with an aqueous solution. New form represents a solid solution of cefuroximaxetil in polymer and/or solid dispersion on adsorbent. New form of cefuroximaxetil can be used for preparing a granulate that can be used in oral pharmaceutical compositions as tablets or powder. Exclusion of gel-formation allows improving solubility of cefuroximaxetil that results to enhancing absorption of cefuroximaxetil in digestive tract.

EFFECT: improved pharmaceutical properties of combinations.

23 cl, 3 dwg, 8 tbl, 19 ex

 

The present invention relates to compositions containing β-lactam, primarily aporoximately, representing a complex 1-ecotoxicology ester of cefuroxime, which corresponds to the well-known second generation cephalosporin antibiotics, which are used, for example, for the treatment of microbial infections, are described, for example, in The Merck Index, 12th ed., 324 PP and 325, No. 2002. The active substance of aporoximately in vivo is cefuroxime, because in vivo ether carboxylic acid in position 4 of the ring system is cleaved, thereby making the free carboxylic acid and is formed cefuroxime.

Aporoximately, for example, in crystalline form or in amorphous form, may be introduced, for example, orally, for example in the form of filmtabletten, tablets or in the form of a dry powder, which, for example, may be in pure form, for example, with an aqueous solution or in the form of recovered aqueous solution, for example, water, or in the form of suspension/syrup. However, aporoximately in crystalline or amorphous form may be subjected to gelation, for example, it can form a gel-like mass upon contact with aqueous solution, for example, with water or saliva; for example, the gel can be formed on the surface of, for example, included in Galanova the form of particles cefuroxime is. Gelation, for example, the gel formation on the surface of, for example, included in Galanova the form of particles of aporoximately, can lead to poor solubility of aporoximately that as a result can lead, for example, to decrease the absorption of aporoximately the gastrointestinal tract.

In the claimed invention unexpectedly found that gelation of aporoximately, for example, gel formation on the surface of, for example, included in Galanova the form of particles of aporoximately, upon contact with aqueous solution, can be avoided, for example, to a large extent, if aporoximately upon contact with the aqueous solution is not in crystalline or amorphous form, and forms negineering form.

Without going into theory, we can assume that aporoximately forming negineering form upon contact with the aqueous solution of the present invention, can be incorporated into the polymer in the form of a molecular dispersion, which represents a solid solution of cefuroxime in the polymer; and/or in the form of a surface of a solid molecular dispersion of the adsorbent.

Naegeliana form, for example, included in Galanova form of aporoximately, for example, which does not form a gel on the surface of particles of cefuroxime in contact with the aqueous solution on the right is briteney and which is used according to the invention, includes the form of aporoximately, for example, Galanova form of aporoximately, for example, dosage form, for example, solid form, for example, a form containing as active ingredient cefuroxime, as well as pharmaceutically acceptable excipients, has a dissolution rate of the active substance at 37° in the aquatic environment, for example, acidic environment, for example acidified with hydrochloric acid, for example buffered environment, higher, or equal not below

than 5% when the pH value is about 1, for example, at pH 1, 10-15 min after the start of the experiment for the determination of solubility; and/or

than 20% at pH<0 in 25-30 min after the start of the experiment to determine the solubility, compared to the dissolution rate of the active substance at a pH of about 4, for example at pH 4.

Thus, cefuroxime, forming a gel-like form upon contact with the aqueous solution includes cefuroxime in the form of, for example, in galenical form has a dissolution rate, which is practically independent of pH, for example at pH values<0, pH 1 and pH 4.

Suitable method for determining the dissolution rate includes, for example, a method that is commonly used, for example, to determine the dissolution rate of aporoximately, for example, in dosage form, which shall be applied according to the test <711> USP (USP With The (A) using the device USP-2 at least with respect at least to the conditions specified below severity: 900 ml aqueous environment, stirring at 37°using a blade mixer with a speed of 55 rpm; determination of the average dissolution rate of at least 6 samples, containing nearly the same number of aporoximately and almost the same excipients, taken in almost the same number; the corresponding pH value, for example (approximately) pH 4, (approximately) pH 1 and pH<0. Under this definition also includes dosage forms that have passed this test in more severe conditions, such as when a smaller volume of water, lower temperature, lower speed blade mixer. Acceptable aqueous medium, which can be used to determine the dissolution rate at pH 4, includes, for example, acetate buffer (pH 4) for example, according to USP; and to determine when the value of (about) pH 1 and pH<0 includes acidified with hydrochloric acid aqueous solution with the corresponding pH value. Determination of the dissolution rate of aporoximately at a certain point in time can be carried out using a conventional method, for example using UV, IHVR.

One of the objects of the present invention is aporoximately in negineering form upon contact with aqueous solution, for example water, for example in the form of solid solution in a polymer; for example, in a mass ratio aporoximately : p is limer from 1:0.1 to 1:0.8 to. for example, from 1:0.15 to 1:0,8, such as from 1:0.15 to 1:0.6 to, for example, from 1:0.35 to 1:0.6 to, for example, from 1:0.35 to 1:0.55 to, for example, from 1:0,35 to 0,45; or in the form of surface solid dispersion on an adsorbent, for example, in a mass ratio aporoximately : adsorbent from 1:0.1 to 1:1,5; for example, from 1:0.3 to 1:1,3, preferably in the form of solid solution in a polymer.

Cefuroxime in negineering the form of, for example, the form of solid solution in a polymer or surface solid dispersion may be, for example, obtained in the following way:

the solution or suspension of cefuroxime in free form, for example, in crystalline form or in amorphous form, for example, in the form of MES or resolutional form

and polymer and/or the adsorbent can be prepared in an organic solvent, for example, in the presence of water.

The polymer includes a polymer, for example, one or more polymer (s) has (have) the ability to form solid solution of cefuroxime in the polymer, for example as indicated above for aporoximately, forming a gel-like form upon contact with aqueous solution, preferably a polymer that is soluble in the used solvent (system). The polymer preferably includes pharmaceutically acceptable polymer, for example, Homo - and copolymers, for example, Homo - and copolymer polivi is elparoladon, for example, as marketed under the trademark Kollidon®, such as homopolymer, such as povidone, cross-linked povidone, for example, crosspovidone, polyplasdone; and a copolymer of vinylpyrrolidone; polyethylene glycol, polyethylene oxide, cellulose.

Cellulose includes alkylaryl, for example, methyl-, ethyl-. propylethylene; hydroxyethylcellulose, for example, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose; hypromellose, cellulose, which, for example, chemically modified, which carries carboxyl groups as substituents, such as carboxymethylcellulose.

It is preferable polyvinylpyrrolidone, for example, marketed under the trademark Kollidon®, for example, povidone, cross-linked povidone, for example, crosspovidone or polyplasdone, copolymer of polyvinylpyrrolidone, cellulose, for example, alkylaryl, hydroxyethylcellulose, hydroxyethylmethylcellulose; for example, ethyl - and propylethylene, hydroxymethylcellulose, hydroxyethylcellulose, hypromellose, cellulose, which, for example, chemically modified, for example, which carries carboxyl groups as substituents, polyethylene oxide, crosspovidone and polyplasdone and a copolymer of polyvinylpyrrolidone.

Preferred is a copolymer of polyvinyle is rolidone, such as a copolymer of vinylpyrrolidone and vinyl acetate, for example, include N-vinyl-2-pyrrolidone and vinyl acetate, for example, for an arbitrary ratio of 60:40, for example, consisting of units of the formula

for example, marketed under the trademark Kollidon® (for example, VA64) or Plasdone® (for example, S-630).

Acceptable mass ratio of aporoximately and polymers is in the range from 1:0.1 to 1:0.8 to, for example, from 1:0.15 to 1:0,8, such as from 1:0.15 to 1:0.6 to, for example, from 1:0.35 to 1:0.6 to, for example, from 1:0.35 to 1:0.55 to, for example, from 1:0.35 to 1:0,45.

Acceptable adsorbent includes, for example, pharmaceutically acceptable adsorbent, for example, one or more adsorbents possessing the ability to form surface solid dispersion with aporoximately, for example, as indicated for aporoximately, forming a gel-like form upon contact with aqueous solution, as described above, for example, a material which has the ability to communicate with other material on its surface and form a solid molecular dispersion, such as silicon dioxide, for example, colloidal silicon dioxide, such as Aerosil®, for example, Aerosil®200, preferably colloidal silicon dioxide. Preferably the adsorbent is biologically inactive.

Acceptable mass ratio is s aporoximately : the adsorbent is in the range for example, from 1:0.1 to 1:1,5, for example, from 1:0.3 to 1:1,3.

Naegeliana form of aporoximately may include both polymer and adsorbent. The preferred mass ratio aporoximately : polymer plus the adsorbent is, for example, in the range from 1:0.3 to 1:1,8, for example, from 1:0.3 to 1:0,9.

Another object of the present invention is aporoximately, forming a gel-like form upon contact with an aqueous solution comprising cefuroxime in the form of solid solution in a polymer in combination with cefuroxime in the form of a solid dispersion on an adsorbent; for example, in a mass ratio aporoximately : adsorbent from 1:0.1 to 1:1,5, for example, from 1:0.3 to 1:1,3.

Acceptable organic solvent is one or more organic solvents, for example, a solvent system in which soluble aporoximately and the polymer and in which the adsorbent is preferably insoluble or soluble only to a small extent, for example, is soluble to form a colloidal solution. In an organic solvent may be present, for example, water, for example, if the adsorbent, if present, is insoluble or only slightly soluble, for example, colloidal in water. The preferred organic solvent is only one organic rest retell or a mixture of organic solvents, for example, including water, for example, a ketone, such as acetone, alcohol, e.g. ethanol; halogenated hydrocarbons, e.g. methylene chloride. Preferred organic solvents include ketones, for example, in the presence of water, for example, approximately 30% vol. organic solvent.

The solution or suspension of aporoximately and polymer and/or adsorbent in an organic solvent, for example, in the presence of water can be obtained, for example, by heating (weak) mixture.

Aporoximately, forming a gel-like form upon contact with aqueous solution, for example, can be obtained by removing solvent from a solution or suspension which contains cefuroxime and the polymer and/or the adsorbent in an organic solvent, for example, in the presence of water, by removing the solvent, for example, evaporation of the solvent, for example, evaporating with rotary evaporator, spray drying, spray granulation, such as granulation in the fluidized bed; preferably by spray drying and granulation by spraying.

Aporoximately, forming a gel-like form upon contact with aqueous solution, for example, can be used to obtain a granulate, the granules, for example, can be used to prepare pharmaceutical compositions, for example, tablets,or powder, for example, a dry powder, for example, are suitable for oral administration compositions which comprise as active ingredient cefuroxime.

Another object of the present invention is a method of obtaining aporoximately, forming a gel-like form upon contact with aqueous solution, providing for the dissolution or suspension of aporoximately and polymer, for example, in a mass ratio aporoximately : polymer of from 1:0.1 to 1:0,8; or adsorbent, for example, in a mass ratio aporoximately : adsorbent from 1:0.1 to 1:1,5; or polymer plus adsorbent mass ratio of aporoximately : polymer plus the adsorbent from 1:0.3 to 1:1,3; in an organic solvent, for example, in the presence of water, for example, ketone, for example, in acetone; or in alcohol, such as, for example ethanol, in the presence of ketone and/or alcohol as the sole organic solvent; and removing the solvent.

Aporoximately, forming a gel-like form upon contact with aqueous solution, for example, can be used to prepare pharmaceutical compositions. The pharmaceutical composition may, for example, be prepared by a method that is usually used for the preparation of compositions in which the active substance is applied aporoximately, not brazowy gel-like form upon contact with aqueous solution, or, for example, as described in the present description method.

Another object of the present invention is a pharmaceutical composition, for example, in dosage form, for example, a solid, for example, orally, for example in the form of tablets, pills, powder (dry); comprising as active ingredient pharmaceutically effective amount of aporoximately, forming a gel-like form upon contact with aqueous solution, for example, in which the active ingredient is essentially aporoximately, for example, in a quantity which corresponds to the number of cefuroxime from 50 to 1000 mg, for example from 50 to 800 mg, for example from 100 to 600 mg, for example 125 mg, for example, 250 mg, for example 500 mg;

in combination, for example, with conventional pharmaceutically acceptable excipients, which, for example, can be used for cooking, for example, oral pharmaceutical compositions, such as compositions that are administered orally.

Found that the pharmaceutical compositions of the present invention, for example, dosage forms, including cefuroxime in negineering form upon contact with the aqueous solution of the present invention in combination with pharmaceutically acceptable excipients can meet the requirements of USP 23 (dissolution) and USP 24 (developed, the rock steps since 2000), i.e. these dosage form dissolves, for example, at least 60% (Q-value) fixed number of aporoximately for 15 min, for example, and/or at least 75% (Q-value) fixed number of aporoximately for 45 min; when the dosage form of cefuroxime evaluate test according to USP <711> the device USP-2 at least in terms of the conditions specified severity: 900 ml of 0.07 N. hydrochloric acid, 37°when the rotation speed of the blades 55 rpm

Another object of the present invention is a pharmaceutical dosage form, for example, a solid form comprising as active ingredient cefuroxime in pharmaceutically effective amounts in negineering form upon contact with the aqueous solution in combination with pharmaceutically acceptable excipients, and this dosage form provides at least 60% (Q-value) fixed number of aporoximately for 15 min, for example, and/or at least 75% (Q-value) fixed number of aporoximately for 45 min; when the dosage form of cefuroxime evaluate test according to USP <711> the device USP-2 at least in terms of specified severity: 900 ml of 0.07 N. hydrochloric acid, 37° when the rotation speed of the blades 55 rpm

It is established that ceph is roximately, not forming a gel-like form upon contact with the aqueous solution of the present invention, can be obtained in the form of a granulate, which in addition to aporoximately includes pharmaceutically acceptable excipients, for example, components that are required for the preparation of granules.

The next object of the present invention is a granulate containing cefuroxime and the polymer and/or the adsorbent, in which cefuroxime is negineering form upon contact with aqueous solution, for example, in which cefuroxime is a solid solution in a polymer and/or a surface solid dispersion on an adsorbent; and pharmaceutically acceptable excipient; for example, one or more excipients; for example, surface-active substance, for example, a carrier, for example, the sizing; for example, containing 25-95 wt.% aporoximately; 0-75 wt.%, for example, 5-75 wt.% polymer; 0-60 wt.%, for example, 5-50 wt.% adsorbent, 0-5 wt.%, for example, 0.3 to 1.5 wt.% surface-active agents; 0-50 wt.% for example, 5-50 wt.% media; and/or 0-5 wt.%, for example, 0.1 to 5 wt.% the sizing.

The granulate according to the present invention contains agglomerated or aggregated particles of the type granulate-component substance. The granulate of the present invention may for example be in the form of powder, see the Yong, granules.

The granulate of the present invention may, for example, be obtained according to the conventional method, or for example, as follows: from a solution or suspension containing cefuroxime, forming a gel-like form upon contact with aqueous solution, according to the present invention; for example, from a pre-prepared solution or suspension according to the above method of obtaining aporoximately, forming negineering form; or from a solution or suspension containing cefuroxime and the polymer and/or the adsorbent in an organic solvent, for example, in the presence of water; which contain one or more pharmaceutically acceptable excipients, for example, components of which the solvent can be removed.

The solvent from the solution or suspension may be removed, for example, using the conventional method or, for example, by mixing/stirring of the solution or suspension of aporoximately, polymer and/or adsorbent and pharmaceutical excipient, for example, at elevated temperature, for example, in a vacuum; the solvent may be removed, for example using a rotary evaporator, spray drying, spray granulation, such as granulation in the fluidized bed; preferably by spray drying and granulation by spraying.

In the learn the use of media, for example, as a rule, you can use the granulation in the fluidized bed, for example, a solution of aporoximately containing polymer and/or the adsorbent, and for example, one or more pharmaceutically acceptable excipients, may be sprayed on a previously prepared liquid solid carrier, for example, this fluid may contain one or more additional pharmaceutically acceptable excipients, e.g. in solid form such as oil. The spray drying and evaporation using the rotary evaporator can, for example, be carried out according to the conventional method.

For example, pharmaceutically acceptable excipient, which is preferable to granulate according to the present invention, includes, for example, (one or more)

- surface-active substance, for example, affects the surface tension of these chemicals, for example, which lowers the surface tension of the liquid, the use of which, for example, can lead to the relief of wetting and/or facilitate emulsification solids in the liquid, and represents, for example, ionic or nonionic surfactant, a wetting agent, a substance that modifies the surface tension; that (s) as the sulfonates and sulfates of fatty KIS is now alcohols, for example, sodium dodecyl sulfate; Techarp®, which includes different types of joints obtained by washing the crude product, for example, sulfate or sulfate esters of fatty acid alcohols, such as lauryl sulfate and ammonium, for example, a mixture of sodium lauryl sulfate and ammonium, preferably sodium lauryl sulfate;

the media, for example, inert material which can be used as the core, for example, as the core of the active substance during granulation in the fluidized bed, such as the common core, for example, composed of sugar, including sugar alcohols, e.g. mannitol, which includes mannitol granules, for example, Pearlitol®, such as Pearlitol®SD 200;

- sizing, for example, talc, stearate Mg.

The granulate of aporoximately, forming a gel-like form upon contact with an aqueous solution containing one or more pharmaceutically acceptable excipients, can be obtained after removal of solvent.

For example, the granulate according to the present invention may contain, in wt.% in terms of the mass of the granulate:

aporoximately: 25-95%, for example, 30-85%;

polymer: 0-75%; if it is present, 5-75%, for example, 10-60%, in particular 15-60%; preferably 15-60%, if the granules produced by spray granulation; and preferably 25-45%, if the granulate floor is given by spray drying;

adsorbent: 0-60%, for example, 0-50%; if it is present, 5-50%;

surfactant: 0-5%, for example, 0-2,5%, for example, 0.3 to 1.5%;

media: 0-50%, for example, 0-40%, for example, 0-30%; if it is present, for example, 5-50%;

sizing: 0-5%, for example, 0-2,5%, for example, 0-1,0%; if it is present, for example, 0.1 to 1.0%, for example, 0.1 to 0.5%; and at least one pharmaceutically acceptable excipient.

Another object of the present invention is a method of obtaining a granulate in which aporoximately not form a gel-like form upon contact with aqueous solution, involving the removal of solvent from the suspension or solution containing

- aporoximately and the polymer and/or the adsorbent, having the ability to form negineering form upon contact with an aqueous solution of aporoximately; or

- aporoximately, forming a gel-like form upon contact with the aqueous solution; for example, pre-cooked, for example, according to the previously described method;

- pharmaceutically acceptable excipient; for example, one or more;

in an organic solvent, for example, in the presence of water.

Can be obtained granulate of aporoximately in negineering form, containing one or more pharmaceutically acceptable excipients, for example, which may skin is sterile for the preparation of pharmaceutical compositions for example, orally, for example, after additional processing, such as processing necessary to obtain, for example, a dry powder for oral administration, which, for example, may be in the form of a powder, or can be used for cooking suspension/syrup.

The dry powder according to the present invention can be obtained, for example, conventional methods, or, for example, as follows.

The granulate of the present invention, for example, after additional processing, e.g., sieving, grinding; can be mixed with one or more pharmaceutically acceptable excipients, for example, excipients, for example, which can be used to prepare a dry powder for oral administration. The mixing can be carried out, for example, a common method. Dry powder for oral administration may, for example, be in the form of powder, grains, granules, for example, with the desired particle size.

The resulting mixture, for example, the final mixture of powder/granules/pellets, or received intermediate mixture of powder/granules/pellets may be subjected to additional processing, for example, granulation, pressing, crushing, grinding, screening, for example, to obtain particles of any desired size, for example, using a conventional method is. Pharmaceutically acceptable excipient, which can be used to prepare a dry powder for oral administration according to the present invention includes, for example,

sugar, for example, chemically modified, for example, fructose, glucose, sucrose, sugar alcohol, for example, chemically modified,

- sweetener, for example, natural or artificial, aspartame;

- filler, including modified starches, such as starch 1500 (pre-elastometry starch);

- thickener, for example, guar flour;

- binder, for example, polyvinylpyrrolidone, cellulose;

- corrigent, preservative, surfactant, colorant;

preferably the sugar and/or sweetener, and/or filler and/or a thickening agent and/or preservative.

Another object of the present invention is a dry powder, for example, in the form of powder, grains, granules, for example, with the desired particle size, for oral administration, for example, which can be used in the form of a dry powder, for example, in combination with the aqueous solution, for example, water, for example, are suitable for the preparation of suspension/syrup, comprising as active ingredient an effective amount of cefuroxime, forming a gel-like form at stake is the act with the aqueous solution, for example, which may be recovered in an aqueous solution of, for example, water, to obtain the suspension/syrup; for example, in dosage form, for example, including the required number of aporoximately in the required amount;

and pharmaceutically acceptable excipient; for example, which can be used for the preparation of a dry powder, for example, sugar and/or sweetener, and/or filler and/or a thickening agent and/or preservative.

The dry powder according to the present invention can be prepared in the form of a pharmaceutical dosage form, for example, in the container, for example, in the package, vial, for example, which contains cefuroxime in the number corresponding to the desired number of cefuroxime, for example, in the form of a standard dose. The required number of aporoximately includes a number, which corresponds to the number of cefuroxime from 50 to 1000 mg, for example, 50-800 mg, in particular 100-800 mg, for example, 100 to 600 mg, for example, 125 mg, for example, 250 mg, for example, 500 mg standard dose.

The next object of the present invention is a dosage form containing a dry powder according to the present invention in a container, e.g. a bottle, package, for example, contains cefuroxime in the number corresponding to the desired number of cefuroxime, for example, in the form of a standard dose.

With the Hoi powder in the container, for example containing cefuroxime in the number corresponding to the desired number of cefuroxime may, for example, be in the form of suspension/syrup.

The dry powder in packets, for example, contains aporoximately of the present invention in an amount corresponding to the required number of cefuroxime, for example, from 50 to 1000 mg, for example, 50-800 mg, for example, 100-800 mg, for example, 100 to 600 mg, for example, 125 mg, for example, 250 mg, for example, 500 mg, for example, in the form of a standard dose may, for example, be in the form of a dry powder, for example, in combination with the aqueous solution, for example, water, or a suspension in an aqueous solution, for example, in water, for example, a package may contain the standard dose, indicating the amount of aqueous solution required for recovery, for example, to obtain a suspension/syrup.

The dry powder can be Packed in a bottle, for example, with a label showing what amount of an aqueous solution, for example, water must be added to the vial to obtain the required number of cefuroxime in the required amount; for example, the number of aporoximately corresponding to the number of cefuroxime from 50 to 1000 mg, for example, 50-800 mg, in particular 100-800 mg, for example, 100 to 600 mg, for example, 125 mg, for example, 250 mg, for example, 500 mg of the desired size, for example, 3-10 ml, for example, 5 ml of water races is the thief.

Another object of the present invention is a pharmaceutical dosage form, for example, the standard dose, including dry powder according to the present invention in the package that contains cefuroxime in the amount corresponding to the number of cefuroxime from 50 to 1000 mg, for example, 50-800 mg, in particular 100-800 mg, for example, 100 to 600 mg, for example, 125 mg, for example, 250 mg, for example, 500 mg.

And another object of the present invention is a pharmaceutical dosage form containing a dry powder according to the present invention in a bottle, and the bottle has a label that shows what amount of the aqueous solution must be added to the vial to obtain the required number of cefuroxime in the required amount; for example, the number of aporoximately corresponding to the number of cefuroxime from 50 to 1000 mg, for example, 50-800 mg, for example, 100-800 mg, for example, 100 to 600 mg, for example, 125 mg, for example, 250 mg, for example, 500 mg on the required amount of suspension/syrup, for example, 3-10 ml, for example, 5 ml of suspension/syrup.

The dry powder according to the present invention can ensure the dissolution of at least 60% (Q-value) fixed number of aporoximately for 15 min, for example, and/or at least 75% (Q-value) fixed number of aporoximately for 45 min; when the dosage form cefur is csimagefile evaluate test according to USP < 711> the device USP-2 at least in terms of specified severity: 900 ml of 0.07 N. hydrochloric acid, 37°when the rotation speed of the blades 55 rpm

The dry powder according to the present invention can be recovered by using an aqueous solution, for example, water.

Another object of the present invention is syrup/suspension for oral administration comprising (th) dry powder of the present invention, which (th) restore water solution.

According to a preferred variant implementation of the present invention is a dry powder according to the present invention containing fructose and glucose, or their mixture in such quantities that when restoring a dry powder with an aqueous solution, for example, water, for example, which contains a number of aporoximately that corresponds to the desired number of cefuroxime, for example, 50-1000 mg, for example, 50-800 mg, in particular 100-800 mg, for example, 100 to 600 mg, for example, 125 mg, for example, 250 mg, for example, 500 mg; for example, the desired size, for example, 3-10 ml, for example, 5 ml of water solution, get the suspension/syrup, in which glucose and/or fructose are highly concentrated, saturated, for example, a supersaturated solution.

Another object of the present invention is aporoximately, for example, forming a gel-like form when contact is e with an aqueous solution, in the form of a dry powder containing such a quantity of fructose and/or glucose, which is the restoration, for example, aqueous solution, for example, water, the number of aporoximately, which corresponds to the desired number of cefuroxime, for example, in the required amount, allows you to get the suspension/syrup, in which glucose and/or fructose are highly concentrated, saturated, for example, supersaturated solution;

for example, containing 3-10 ml of a highly concentrated solution, the number of aporoximately, for example, forming a gel-like form upon contact with aqueous solution, for example, corresponding 50-1000 mg of cefuroxime; and

suspension/syrup for oral administration, contain(s) an effective amount of aporoximately, for example, forming a gel-like form upon contact with aqueous solution, where glucose and/or fructose are highly concentrated, for example, a saturated or supersaturated solution.

The granulate of aporoximately of the present invention can also be used for the preparation of tablets, for example, for the preparation of core tablets.

Another object of the present invention is a tablet, for example, the core of the tablet, for example, tablets, film-coated (filmtablette), for example, where the film coating contains p is encompassi polymer, plasticizer, lubricant; for example, for oral administration, which comprises as active ingredient cefuroxime, forming a gel-like form upon contact with aqueous solution, and pharmaceutically acceptable excipient, for example, excipients, for example, which can be used in tablet/in the process of tableting, for example, baking powder, and/or binder and/or lubricant and/or surfactant and/or a filler and/or an agent that promotes fluidity; for example, a binding agent and/or surfactant, and/or filler and/or an agent that promotes fluidity; for example, where the tablet, for example, film-coated, provides a dissolution of at least 60% (Q-value) fixed number of aporoximately for 15 min, for example, and/or at least 75% (Q-value) fixed number of aporoximately for 45 min; when the dosage form of cefuroxime evaluate test according to USP <711> the device USP-2 at least in terms of specified severity: 900 ml of 0.07 N. hydrochloric acid, 37°when the rotation speed of the blades 55 rpm

Tablet, for example, the core tablet of the present invention, may, for example, be received(on) according to the conventional method or by using the following process.

The granulate according to the present invention can be mixed with one or more pharmaceutically acceptable excipients, for example, excipients, which can be used in tablets/tabletting process; and a granulate or a mixture with pharmaceutically acceptable excipients may be compressed into tablets, for example, core tablets, for example, using a conventional method, for example, providing optional stage seal at the stage of pressing.

Pharmaceutically acceptable excipients in tablets/tabletting process, which are preferred for tablets/tabletting process of the present invention include, for example,

- leavening agents, for example, to facilitate the release of the active substance, such as starches, for example, including modified starches, for example, sewn, such as matrilineality starch, croscarmellose sodium, polyvinylpyrrolidone, for example, which includes the modified polyvinylpyrrolidone for example, sewn, such as polyplasdone, crosspovidone; cellulose, such as sodium and calcium carboxymethyl cellulose, modified cellulose, for example, stitched;

such as AcDiSol; condensation products of formaldehyde-casein, for example, Esma-Spreng®, low-fat soy extracts;

preferably sshi is th Na-carboxymethylcellulose, for example, AcDiSol, polyvinylpyrrolidone, for example, sewn, for example, polyplasdone and crosspovidone; condensation products of formaldehyde-casein, for example, Esma-Spreng®; for example, crosslinked Na-carboxymethylcellulose, condensation products of formaldehyde-casein, for example, condensation products of formaldehyde - casein;

- linking agents, e.g., microcrystalline cellulose, for example, Avicel®;

- fillers, e.g., crystalline cellulose, sugar, such as mannitol, for example, Pearlitol®;

- sizing, for example, include talc, Mg stearates, for example, talc,

agent that promotes fluidity, for example, comprising silicon dioxide, such as Aerosil®,

- surfactant, such as described above to obtain a granulate according to the present invention; including, preferably sodium lauryl sulfate, for example, in a mixture with ammonium lauryl for example, Techarp®;

preferably for example, the baking powder, and/or binder and/or lubricant and/or surfactant and/or a filler and/or contribute to takuseshi agent; for example, a binding agent and/or surfactant and/or a filler.

According to a preferred method according to the present invention the process of obtaining tablets may include additional stages of processing and the intermediate mixture of pharmaceutically acceptable exipients and/or aporoximately before the seal, for example, grinding through a sieve, granulation, compaction. For example, granulates of the present invention, for example, subjected to additional processing, for example, crushed through a sieve; may be subjected to granulation, for example, condensed in a mixture with one or more pharmaceutically acceptable excipients, for example, which can be used in tablet/in the process of manufacturing tablets, the mixture may be fragmented, for example, when processing through a sieve, and mixed with one or more pharmaceutically acceptable excipients, for example, which can be used in tablets/tabletting processes. The final mixture can be compressed into tablet cores of tablets, for example, using the conventional method.

Another object of the present invention is a method of obtaining a tablet, for example, core tablets, for example, tablets, film-coated, for example, where the coating includes a film-forming polymer, a lubricant, a plasticizer, a dye and/or corrigent; which comprises as active ingredient an effective amount of cefuroxime, forming a gel-like form upon contact with aqueous solution, and pharmaceutically acceptable excipient, for example, one or more excipients, for example, which can use the taken in tablet/in the process of manufacturing tablets, for example, excipients, this method involves compressing the granulate, including cefuroxime in negineering form upon contact with the aqueous solution of the present invention, in combination, for example, with one or more pharmaceutically acceptable excipients, for example, which can be used in tablets/tabletting processes, for example, excipients, for example, baking powder, and/or binding agent, and/or sizing, and/or surface-active agent and/or filler and/or contributing to the fluidity agent, for example, one or more binding agent, and/or surface-active agent and/or filler; and for example the application of a film coating, for example, according to the conventional method, for example, including additional stages of processing the intermediate mixture of pharmaceutically acceptable excipients and/or aporoximately before pressing, for example, compaction, shredding through a sieve granulation.

A tablet/core tablet of the present invention can be applied film coating, for example, using a conventional method, for example, by coating with one or more film-forming components, for example, by using a film-forming composition, for example, Rast is orenday or suspended in the solvent, for example, water, an organic solvent or a mixture of water and an organic solvent, preferably in water, for example, according to the conventional method.

Preferred compositions for film coating of the present invention include, for example,

- film-forming polymer; for example, suitable cellulose, for example, hydroxyethylcellulose, such as hydroxymethylcellulose, methyl cellulose, for example, Methocel®, polyvinylpyrrolidone, for example, kollidon, such as Kollidon®VA64; polymethacrylates, for example, Eudragit®; polyvinyl alcohols;

a plasticizer, such as polyethylene glycols;

- sizing, for example, talc;

- dye, pigment, for example, TiO2corrigent, preservative, preferably film-forming polymer, and/or a plasticizer and/or lubricant and/or a dye, pigment, and/or corrigent.

Film coating according to the present invention includes a film coating with a short time of destruction, for example, described in EP 223365, i.e. the film coating, which may serve to mask the bitter taste of cefuroxime oral introduction, the film coating is of such a thickness at which it can be destroyed in less than 40 in the evaluation using the test to assess the destruction, according to which the tablet is placed in helices the third glass of 0.07 N. hydrochloric acid and stands at 37°and assess the destruction of time that has passed before, when the core of the tablet becomes visible to the naked eye through the ruined film coating, and the tablet core is destroyed immediately after the destruction of the film coating in the test, which will assess the destruction. The content of EP 223365 related to film coating, for example, including examples of film coating described in the claims of the EP 223365, and obtain film-coated tablets, stated in EP 223365 included in the present description by reference.

According to the present invention, it is preferable to use a conventional film coating, the destruction of which 40 or more.

Because aporoximately, for example, in the form of marketed product may be subjected to gelation, for example, that can lead to reduced adsorption of aporoximately from the gastrointestinal tract, for example, as indicated in the present description, before the creation of the present invention containing cefuroxime tablet, as a rule, had an unusual film coating having a very short time of destruction, for example, according to EP 223365, the destruction of which was less than 40 in certain conditions. For example, the disadvantage of rapidly disintegrating film coating is, the time of destruction is less than 40, may be the fact that the film coating can easily collapse upon contact with moisture and film coating loses its protective effect.

In the claimed invention unexpectedly found that tablet, including cefuroxime, forming a gel-like form upon contact with aqueous solution, may have a normal floor, the destruction of which is 40 or more when measured by a test, by definition, destruction, described in EP 223365, and save despite the use of conventional coating dissolution rate corresponding to the requirements of USP 23 (e.g., USP 24). Tablet, including cefuroxime, which has a film coating, collapsing in 40 seconds or more, for example, from 40 s to 10 min, for example, from 40 s to 3 min, when measured by the test to assess the destruction, according to EP 223365, and having a dissolution rate that corresponds to the requirements of USP 23 (e.g., USP 24), is new.

The next object of the present invention is a tablet with a film coating, comprising as active ingredient an effective amount of cefuroxime and film coating, and the destruction of the film coating is 40 or more, for example, from 40 s to 10 min, when measured by the test to assess israsena, according to which the tablet is placed in a chemical glass 0,07 N. hydrochloric acid, stands at 37°assess the destruction of time that has passed before, when the core of the tablet becomes visible to the naked eye through the ruined film coating; the tablet with a film coating provides a dissolution of at least 60% (Q-value) fixed number of aporoximately for 15 min, for example, and/or at least 75% (Q-value) fixed number of aporoximately for 45 min; when containing cefuroxime tablet with a film coating evaluate test according to USP <711> the device USP-2 at least in terms of specified severity: 900 ml of 0.07 N. hydrochloric acid, 37°when the rotation speed of the blades 55 rpm, for example, including more stringent conditions, for example, less 0,07 N. hydrochloric acid, lower temperature, lower speed blade mixer.

And another object of the present invention is the application of a film coating for the preparation of tablets with a film coating, comprising as active ingredient an effective amount of cefuroxime and providing for the dissolution of at least 60% (Q-value) fixed number of aporoximately for 15 min, for example, and/or less than the least 75% (Q-value) fixed number of aporoximately for 45 min; when containing cefuroxime tablet with a film coating evaluate test according to USP <711> the device USP-2 at least in terms of specified severity: 900 ml of 0.07 N. hydrochloric acid, 37°when the rotation speed of the blades 55 rpm, for example, including more stringent conditions, for example, less 0,07 N. hydrochloric acid, lower temperature, lower speed blade mixer; and the destruction of the film coating is 40 or more, for example, from 40 s to 10 min, in the evaluation using the test to assess the destruction, according to which the tablet is placed in a chemical glass 0,07 N. hydrochloric acid stands at 37°assess the destruction of time that has passed before, when the core of the tablet becomes visible to the naked eye through the ruined film coating.

Tablet with a film coating, as a rule, protected from moisture film coating. So, the tablet with a film coating of the present invention, the time of destruction which is 40 or more when evaluated using the above test to assess the destruction, does not require sealing in order to protect from moisture in packaging for pharmaceutical compositions, whereas the tablet, the time of the destruction of a film coating which is less than 40, may be the AGCO destroyed upon contact with moisture and should be sealed for protection against moisture in the packaging. Packaging for pharmaceutical compositions comprising cefuroxime in packaging with no protection against moisture, is new.

The next object of the present invention is a packaging for pharmaceutical compositions, for example, a container such as a vial, containing as active substance of cefuroxime in the form of film-coated tablets comprising an effective amount of cefuroxime, and this package is not sealed to protect from moisture and tablet with a film coating is not sealed to protect from moisture.

Tablet with a film coating of the present invention may contain as active substance cefuroxime in an amount which corresponds to from 50 to 1000 mg of cefuroxime, which preferably corresponds to 500, 250 or 125 mg of cefuroxime.

It is known that marketed cefuroxime in tablet form and in the form of a dry powder, when they contain the same number of aporoximately not characterized by almost the same speed of dissolution according to USP, i.e. tablet with a film coating, and dry powder are not completely interchangeable despite the same number of aporoximately, for example, tablet, including, for example, aporoximately in number which corresponds, for example, 125 m is cefuroxime, cannot be simply replaced by a dry powder containing cefuroxime in number, which corresponds to 125 mg of cefuroxime, due to their different speeds of dissolution, i.e. different biological availability. It is also known that the dry powder, comprising cefuroxime, does not meet the requirements of USP 23 in respect of dissolution, and has a dissolution rate of the active substance, other than one that meets the requirements of USP 23.

When creating inventions unexpected found that as a tablet with a film coating, and dry powder with an equal amount of aporoximately, forming a gel-like form upon contact with the aqueous solution of the present invention have almost the same rate of dissolution according to USP and therefore are completely interchangeable.

Another object of the present invention is the use of aporoximately for the preparation of tablets with a film coating, the dissolution rate which meets the requirements of USP 23, and for the preparation of a dry powder, the rate of dissolution which meets the requirements of USP 23, where the tablet film coating contains the same effective number of aporoximately, as a dry powder, for example, dry powder and tablet with a film coating are what I biologically equivalent oral forms of administration of cefuroxime.

It is known that the absorption and bioavailability of any specific active therapeutic agent, for example, medicines, in his oral introduction can be influenced by numerous factors. Such factors include the presence of food in the gastrointestinal tract/stomach. If the bioavailability of drugs after a certain point is affected by the presence of food in the gastrointestinal tract/stomach, then we say that the drug is sensitive to the impact of food". It has long been known that cefuroxime in forms for oral administration, which are sold, for example, in amorphous form in tablets or in the form of dry powders for oral administration, and in the form of crystals that are sensitive to the impact of food", for example, cefuroxime has better bioavailability when taken orally doing the mammal after eating than when the mammal is in a hungry state. Therefore, the introduction of going on sale of aporoximately recommended after a meal. This sensitivity to food aporoximately, as you know, has a positive effect on its activity due to differences in pH values in the stomach of a hungry state (pH value of about 1 and below) and Pris the accordance of food (pH about 4). It is now known that the dissolution rate of aporoximately on the market of pharmaceutical compositions, in which cefuroxime is in amorphous form, depends on pH; for example, the release of aporoximately from the composition at 37°With significantly reduced at pH 1 in comparison with dissolution at pH 4, whereas in the claimed invention unexpectedly found that the release of the active substance of aporoximately when using the pharmaceutical compositions of the present invention practically does not depend on pH value, for example, as is evident from figure 1-3.

Figure 1 shows the dependence of the dissolution rate of aporoximately from pH to 500-milligrammes tablet with a film coating, which is sold under the trademark Zinnat® at pH 1, pH<0 and pH 4 at 37°expressed as% of dissolving a fixed amount of aporoximately in a certain period of time (in min). From figure 1, for example, it is evident that the dissolution rate of aporoximately when using the marketed tablets film-coated at 37°in the aquatic environment, for example, acidic, for example, acidified with hydrochloric acid, for example, buffered, is

than 5% when the pH value is about 1, for example, at pH 1, 10-15 min after the achala test for determination of solubility; and/or

than 20% at pH<0 in 25-30 min after the start of the test to determine the solubility,

compared with the dissolution rate of aporoximately at pH about 4, for example, at pH 4.

Figure 2 shows the dependence of the dissolution rate of aporoximately from pH to 500-milligrammes tablet with a film coating of the present invention, i.e. containing cefuroxime, forming a gel-like form upon contact with aqueous solution, such as that obtained according to example 13 of the present description, at pH 1, pH<0 and pH 4 at 37°expressed as % of dissolving a fixed amount of aporoximately for a certain period of time (in min). From figure 2, for example, it is evident that the dissolution rate of aporoximately when using the tablet with a film coating of the present invention at 37°in the aquatic environment, for example, acidic, for example, acidified with hydrochloric acid, for example, buffered, equal to or not less than

than 5% when the pH value is about 1, for example, at pH 1, 10-15 min after the start of the test to determine the solubility; and/or

than 20% at pH<0 in 25-30 min after the start of the test to determine the solubility,

compared with the dissolution rate of aporoximately at pH about 4, for example, at pH 4.

Figure 3 shows the dependence with whom oresti dissolution of aporoximately from pH values

- to 500-milligrammes tablet with a film coating of the present invention, i.e. containing cefuroxime, forming a gel-like form upon contact with aqueous solution, such as that obtained according to example 13 of the present description (declare pill)

- to 500-milligrammes tablet with a film coating, which is obtained according to example 19 of the present description, and contains amorphous cefuroxime, for example, marketed, instead of aporoximately, forming a gel-like form, by replacing the granulation phase And normal phase mixing (prototype), at pH<0 at 37°expressed as % of dissolving a fixed amount of aporoximately in a certain period of time (in minutes).

From figure 3, for example, it is evident that the dissolution rate of amorphous cefuroxime differs from the rate of dissolution of aporoximately, forming a gel-like form upon contact with aqueous solution.

The dissolution rate of aporoximately, as can be seen from figures 1 to 3, preferably may be determined according to the test USP <711>, as will be described in more detail below.

Since, as a rule, the pH value increases in the stomach in the presence of food to about pH 4 compared to pH value of about 1 and below in the hungry condition, probably sensibility is the impact of food aporoximately is a consequence of the dependence on the pH value of the dissolution rate of amorphous cefuroxime in the marketed form.

On the other hand, in the claimed invention unexpectedly found that the dissolution rate of aporoximately, forming a gel-like form of the present invention, for example, in the form of tablets or granules, practically does not depend on pH. Thus, tablet or granulate, including cefuroxime, forming a gel-like form, the present invention can be imposed regardless of whether the mammal is full or is in the hungry state, for example, for aporoximately of the present invention is not typical adverse effects of food.

The use of aporoximately for the preparation of oral dosage forms, which is not typical adverse effects of food, is new.

The next object of the present invention is the use of aporoximately for the preparation of oral dosage forms, e.g. tablets or dry powder or suspension/syrup for oral administration, which is not typical adverse effects of food, for the treatment of microbial, e.g. bacterial infection, for example, a mammal, whereby this dosage form dissolves, for example, at least 60% (Q-value) fixed number of aporoximately for 15 min, for example, and/or the least about 75% (Q-value) fixed number of aporoximately for 45 min; when dosed form of aporoximately evaluate test according to USP <711> the device USP-2 at least in terms of specified severity: 900 ml of 0.07 N. hydrochloric acid, 37°when the rotation speed of the blades 55 rpm; for example, including more stringent conditions, for example, less 0,07 N. hydrochloric acid, lower temperature, lower speed blade mixer; for example, when the mammal is a human.

The next object of the present invention is an oral dosage form of cefuroxime having the form of a tablet, for example, film-coated, for example, with conventional film coating, which is administered to a mammal, in the hungry state, and for which there is a common adverse effect of food, comprising an effective amount of cefuroxime and pharmaceutically acceptable excipients, for example, leavening agents and/or binders and/or fillers and/or lubricant and/or an agent that promotes fluidity, and/or surfactant, and this dosage form provides a dissolution, for example, at least 60% (Q-value) fixed number of aporoximately for 15 min, for example, and/or at least 75% (Q-value) fixed number of aporoximately for the tion 45 min; when dosed form of aporoximately evaluate test according to USP <711> the device USP-2 at least in terms of specified severity: 900 ml of 0.07 N. hydrochloric acid, 37°when the rotation speed of the blades 55 rpm; for example, including more stringent conditions, for example, less 0,07 N. hydrochloric acid, lower temperature, lower speed blade mixer; for example, when the mammal is a human.

And another object of the present invention is an oral dosage form comprising as active ingredient cefuroxime in the form of a dry powder or in suspension/syrup, which is administered to a mammal, in the hungry state, and for which there is a common adverse effect of food, comprising an effective amount of cefuroxime and one or more pharmaceutically acceptable excipients, sugar and/or sweetener, and/or filler and/or a thickening agent and/or preservative, for example, this dry powder provides dissolving, for example, at least 60% (Q-value) a fixed number of aporoximately for 15 min, for example, and/or at least 75% (Q-value) fixed number of aporoximately for 45 min; when the dosage form of cefuroxime assess the societal test according to USP < 711> the device USP-2 at least in terms of specified severity: 900 ml of 0.07 N. hydrochloric acid, 37°when the rotation speed of the blades 55 rpm; for example, including more stringent conditions, for example, smaller volume 0,n. hydrochloric acid, lower temperature, lower speed blade mixer; for example, when the mammal is a human.

And another object of the present invention are methods for producing granules comprising aporoximately, in which the active substance cefuroxime is present in activated form, which means that he has no tendency to form a gel upon contact with an aqueous medium, characterized in that the granulation is carried out with the addition of polymer or insoluble adsorbent.

The following examples illustrate the present invention.

Examples 1-13

Stage A. obtaining a granulate. including peroxidases. not forming a gel-like form upon contact with aqueous solution, and the other components are listed in table 1 and table 2.

The number of aporoximately in table 1 and table 2 (mg/tablet) is indicated in terms of the appropriate number of cefuroxime, which represents the number of the active substance in vivo, since in vivo ether carboxylic acid in position 4 of the ring is istemi cleaved, released a free carboxylic acid and is formed cefuroxime.

Table 1
ComponentExample No./quantity of the component in the examples given in mg/tablet
No. 12345678
Icefuroxime in terms of cefuroxime250125500500250250250250
IIKollidon®VA 64122,5-70-121,576121,5-
IIIsodium lauryl sulfate31,56632,53-
IVAerosil®-60-66--250100
VKollidon®-------
VImannitol, for example, Pearlitol®150768690100---
VIItalc----1,5---

Table 2
ComponentExample No./quantity of the component in the examples given in mg/tablet
No. 9101112131415
Icefuroxime in terms of cefuroxime125500500500500250125
IIKollidon®VA 64-243243243243121,560,8
IIIsodium lauryl sulfate-666631,5
IVAerosil®--- - - 
vKollidon®25150--- - 
VImannitol, for example, Pearlitol®-200200200-- 
VIItalc-2-- - 

The General process used in examples 1-5 and 10-12

Liquid comprising solid components VI and VII, are listed in tables 1 and 2 (if they are present in the corresponding example in table 1 and table 2), in the granulator with the fluidized bed process (by spraying) a solution/suspension components I-IV listed in table 1 and table 2 (if present in the respective examples are shown in table 1 and table 2). As a solvent in examples 1-5 using acetone, as in examples 10-12 mixture of acetone : water (approximately 7:1). The obtained dry granulate is passed through a sieve (e.g., 210, 250, 500, 630 μm) or crushed.

The General process used in examples 6 and 13-15

Solution components I, II and III, are presented in tables 1 and 2 (if they are in conformity with the plans example shown in table 1 and table 2), granularit in the spray dryer. As the solvent in example 6 use acetone, as in examples 13-15 mixture of acetone : water (approximately 7:1). Get the dry granulate.

The General process used in example 7

Component IV, are shown in table 2, hydrate solution (in the form of portions of components I, II and III, are shown in table 2, in acetone and the resulting mixture granularit under stirring and then the mixture is dried. The obtained dry granulate is passed through a sieve (500 μm) and after sieving crushed.

The General process used in examples 8 and 9

From a solution/suspension components I, IV and V are presented in table 2 (if they are present in the corresponding example in table 2), the solvent is evaporated using a rotary evaporator. In example 8 as the solvent used ethanol as in example 9 methylene chloride. The obtained dry granulate is passed through a sieve after sieving crushed.

B. the mixture for tabletting comprising a granulate. containing cefuroxime, forming a gel-like form upon contact with aqueous solution, and the other components shown in tables 4 and 5

Table 4
ComponentP the emer NQ/quantity of the component in the examples given in mg/tablet
No. 12345678
VIIIAc-Di-Sol37,520-140302040-
IXCrosspovidone, Polyplasdone37,520125-30204065
Xtalc12,561081010108
XIAerosil®211116111515159,5
XIIsodium lauryl sulfate74985778,5
XIIIMg-stearate52,5884,54,555
XIVSa-carboxymethylcellulose--25- ----
XVmicrocrystalline cellulose--304860306024
XVIEsma-Spreng®--------

No. 12345678
XVIImannitol, for example, Peariitol®--------
Table 5
ComponentExample No./quantity of the component in the examples given in mg/tablet
No. 9101112131415
VIIIAc-Di-Sol25-80801507638
IX Crosspovidone, Polyplasdone13808080402010
Xtalc64030301473,5
XIAerosil®1040333336189
XIIsodium lauryl sulfate3,51414141261,5
XIIIMg-stearate2,5201515842
XIVSa-carboxymethylcellulose-------
XVmicrocrystalline cellulose-121--30157,5
XVIEsma-Spreng®-808080 -
XVIImannitol, for example, Peariitol®----904522,5

The General process used in examples 1-4, 7-9

The granulate obtained in stage A, is mixed with components VIII - XIII shown in table 4 and table 5 (if they are present in the corresponding example in table 4 and table 5), and the resulting mixture is pressed into tablets.

The General process used in example 5 and example 6

The granulate obtained in stage A, is mixed with component XV and condense and the resulting compaction of the product is passed through a sieve and mix with the components VIII, IX, X, XI, XII and XIII. The resulting mixture is pressed into tablets.

Components VIII, IX, X, XI, XII, XIII and XV table 4 (if they are present in the corresponding example in the table).

The General process applicable in example 10

The granulate obtained in stage A, is mixed with the components of the XV and is taken as 30 mg/tablet component XI. The resulting mixture is compacted and the resulting compaction of the product is passed through a sieve with mesh size of 1.00 mm and the resulting granules are mixed with component X, is taken as 10 mg/tablet component XI, and components XIII, XII, IX and XVI. who received the mixture is pressed into tablets.

Components IX, XI, XII, XIII, XV and XVI are presented table 5.

The General process used in examples 11 and 12

The granulate obtained in stage A, is mixed with a component of the XVI and is taken as 30 mg/tablet component XI. The resulting mixture is compacted, the resulting sealing product is passed through a sieve with mesh size of 630 μm and the resulting granules are mixed with the component VIII, taken at the rate of 3 mg/tablet component XI, and with components X, XIII, XII, IX and XVI. The resulting mixture is pressed into tablets.

Components VIII, IX, X, XI, XII, XIII and XVI are presented in table 5.

The General process used in example 13

The granulate obtained in stage A, is mixed with taken as 110 mg/tablet ingredient VIII, is taken as 30 mg/tablet component XI and taken at a rate of 5 mg/tablet ingredient XIII. The resulting mixture is compacted, the resulting sealing product is passed through a sieve with mesh size of 630 μm and the resulting granules are mixed with taken as 40 mg/tablet ingredient VIII, is taken as 6 mg/tablet component XI, taken at the rate of 3 mg/tablet ingredient XIII and with components X, XII, IX, XV and XVII. The resulting mixture is pressed into tablets.

Components VIII, IX, X, XI, XII, XIII, XV and XVII are presented in table 5.

The General process used in examples 14 and 15

Taken as 55 mg/tablet (27,5 mg/t is bletso) component VIII, 15 mg/tablet (7.5 mg/tablet) component XI and 2.5 mg/tablet (1.2 mg/tablet) component XIII mixed with the granules obtained in stage A. the resulting mixture is compacted and the resulting compaction of the product is passed through a sieve with mesh size of 630 μm. The resulting granules are mixed with taken 21 mg/tablet (10.5 mg/tablet) component VIII, taken at the rate of 3 mg/pill (1.5 mg/tablet) component XI and 1.5 mg component XIII and components IX, X, XI, XII, XV and XVII. The resulting mixture is pressed into tablets.

Components VIII, IX, X, XI, XII, XIII, XV and XVII are presented in table 5.

C. Obtaining tablets film-coated tablets obtained in stage B, which includes components for coverage, are presented in table 6 and table 7.

Table 6
ComponentExample No./quantity of the component in the examples given in mg/tablet
No. 12345678
XVIIIhydroxypropylmethyl-lulose, for example, Methocel®6565to 59.6to 59.665656565
XIXPolietileno-Col®600010109,29,210101010
XXTio3202018,318,320202020
XXItalc554,64,65555
XXIIKollidon®VA64--8,38,3----

Table 7
ComponentExample No./quantity of the component in the examples given in mg/tablet
No. 9101112131415
XVIIIthe hypromellose, for example, Methocel®59,136,853,653,653,652,254,5
XIXThe glycol®60009,1 ----4,3-
XXTio218,231,619,619,619,617,418,2
XXItalc4,531,626,826,826,826,127,3
XXIIKollidon®VA649,1------

The General process used in examples 1-15

Components of the XVIII-XXII shown in table 6 and table 7 (if they are present in the corresponding example in table 6 and table 7), dissolved or suspended in water and the tablets obtained in stage B, the applied film coating using the prepared suspension. Dried tablets are film-coated.

The thickness of the coating is such that the time of destruction film-coated tablets, for example, determined according to the test described in EP 233365 and described in this description, averaged from 1 to 2, for example, about 1.5 minutes

The time of dissolution of the active substance from the tablets obtained in examples 1-15, meets the requirements of USP 23 (and USP 24, which is relagen and entered into force since 2000).

Examples 16-19

Obtaining a dry powder for oral administration, comprising aporoximately. not forming a gel-like form upon contact with aqueous solution, which can be used for cooking suspension/syrup

The overall process

The granules obtained according to example 1, step a and example 2, stage a or example 13, step A, either without treatment or after compaction and pass through a sieve with mesh size of 630 μm, are mixed to a homogeneous state with components XXIII-XXX, is presented in table 8 (if they are present in the corresponding example in table 8).

Get the mixture in the form of a dry powder, which can be used for oral administration of cefuroxime.

The obtained homogeneous mixture or

- treated water, getting the suspension/syrup for oral administration in an amount such that the 5 ml of the recovered suspension contained a number of aporoximately corresponding to 125, 250 or 500 mg of cefuroxime;

- put in a bottle, for example, has a label, which shows how the amount of aqueous solution is necessary to obtain 125, 250 or 500 mg of cefuroxime 5 ml suspension/syrup for oral administration; or

- placed in the package in such quantity that one package contained a number of aporoximately corresponding to 125, 25 or 500 mg of cefuroxime.

Table 8
ComponentExample No/quantity of the component in the examples given in mg/tablet
No. 161718
 the granulate obtained according to stages a, examples 1, 2 or 13289,81)579,62)1208,13)
XXIIIglucose7001500500
XXIVfructose120015003500
XXVaspartame151510
XXVIstrawberry corrigent404040
XXVIIcaramel corrigent404050
XXVIIIsucrose200010002200
XXIXguar flour1515-
XXXstarch type Starch®1500400400-
1): corresponds to 125 mg CE is Proxima

2): corresponds to 250 mg of cefuroxime

3): corresponds to 500 mg of cefuroxime

Example 19

Comparative analysis

They use the same components as shown in example 13, stage A, stage B and stage, in such quantities, as listed in table 2, table 4 and table 6.

Mix aporoximately (amorphous), KollidonVA64, mannitol, Esma-Spreng® and 6 mg of sodium lauryl. The mixture is compacted and the resulting compaction of the product is passed through a sieve with mesh size of 1.00 mm, the Resulting granulate is mixed with polyplasdone, Ac-Di-Sol, microcrystalline cellulose, talc, Mg-stearate and the remaining part of lauryl sodium and pressed.

On the pill cause a film coating according to the process described in example 13, step C.

The obtained data on the dissolution rate of the film-coated tablets are shown in figure 3.

1. Form of aporoximately, not forming a gel upon contact with aqueous solution, characterized in that cefuroxime is in the form of solid solution in a polymer and/or in the form of a solid dispersion on an adsorbent.

2. Form of aporoximately according to claim 1, in which cefuroxime is in the form of solid solution in a polymer.

3. Form of aporoximately according to claim 2, where the mass ratio aporoximately:poly the EP is in the range from 1:0.1 to 1:0.8 to.

4. Form of aporoximately according to claim 1, in which cefuroxime is in the form of a solid dispersion on an adsorbent.

5. Form of aporoximately according to claim 1, including cefuroxime in the form of solid solution in a polymer in combination with cefuroxime in the form of a solid dispersion on an adsorbent.

6. Granulate comprising cefuroxime in the form, not forming a gel upon contact with aqueous solution, characterized in that cefuroxime is in the form of solid solution in a polymer and/or in the form of a solid dispersion on an adsorbent, and pharmaceutically acceptable excipient.

7. Pharmaceutical composition for treating microbial infections comprising as an active ingredient pharmaceutically effective amount of cefuroxime in the form of solid solution in a polymer and/or in the form of a solid dispersion on an adsorbent, in combination with a pharmaceutically acceptable excipient.

8. The pharmaceutical composition according to claim 7 in the form of a pharmaceutical dosage form, where the dosage form provides a dissolution of at least 60% (Q-value) fixed number of aporoximately for 15 min and/or at least 75% (Q-value) fixed number of aporoximately for 45 min, when dosed form of aporoximately evaluate test according to USP <711> in the mouth is oiste USP-2 at least in terms of specified severity: 900 ml of 0.07 N. hydrochloric acid, 37°when the rotation speed of the blades 55 rpm

9. The composition according to claim 7, where the pharmaceutical composition is a dry powder for oral administration.

10. The composition according to claim 9, comprising a dry powder containing an effective amount of aporoximately placed in the container.

11. The composition according to claim 7, where the pharmaceutical composition is a syrup/suspension for oral administration, comprising a dry powder according to any one of PP and 10, which restores the water solution.

12. The composition according to claim 11, where the pharmaceutical composition is a suspension/syrup for oral administration, comprising(a) an effective amount of cefuroxime, where glucose and/or fructose is in a saturated or supersaturated solution.

13. The composition according to claim 7, where the pharmaceutical composition is a tablet for oral administration.

14. The composition according to item 13, which is a tablet with a film coating (filmtablette).

15. Filmtablette, comprising as active substance cefuroxime in the form, not forming a gel upon contact with the aqueous solution according to any one of claims 1 to 5, and having a film coating, and the destruction of the film coating is 40 or more when measured by the test to assess the destruction, according to which the tablet is placed in a chemical is a mini glass of 0.07 N. hydrochloric acid and incubated at 37°To assess the destruction of time that has passed before, when the core of the tablet becomes visible to the naked eye through the ruined film coating; where filmtablette provides a dissolution of at least 60% (Q-value) fixed number of aporoximately for 15 min and/or at least 75% (Q-value) fixed number of aporoximately for 45 min; when containing cefuroxime filmtablette evaluate test according to USP <711> the device USP-2 at least in terms of specified severity: 900 ml of 0.07 N. hydrochloric acid, 37°when the rotation speed of the blades 55 rpm

16. A method of producing a tablet according to any one of p-15, which comprises as active ingredient an effective amount of cefuroxime in the form, not forming a gel upon contact with aqueous solution, involving the pressing of the granules of aporoximately according to claim 6 in a mixture with one or more pharmaceutically acceptable excipients, and optionally applying a film coating.

17. The method of obtaining the shape of aporoximately, not forming a gel upon contact with the aqueous solution according to any one of claims 1 to 5, providing for the dissolution or suspension of aporoximately and polymer, which has the ability to form negatives is lebresne solid with cefuroxime, and/or media that has the ability to form surface solid dispersion with cefuroxime in an organic solvent, and removing the solvent.

18. A method of obtaining a granulate according to claim 6, in which cefuroxime is in form, not forming a gel upon contact with aqueous solution, involving the removal of solvent from the suspension or solution containing cefuroxime and the polymer and/or the adsorbent, which have the ability to form negineering form of aporoximately when in contact with aqueous solution; or cefuroxime in the form, not forming a gel upon contact with the aqueous solution; and pharmaceutically acceptable excipient, for example, one or more, in an organic solvent optionally in the presence of water.

19. Oral dosage form of cefuroxime, which is administered to a mammal, in the hungry state, and for which there is a common adverse effect of food, comprising an effective amount of cefuroxime in the form, not forming a gel upon contact with the aqueous solution according to any one of claims 1 to 5, and pharmaceutically acceptable excipient.

20. Oral dosage form of cefuroxime according to claim 19, presented in the form of a dry powder or in suspension/syrup.

21. Oral dotiruemymi of aporoximately according to claim 19, presented in the form of tablets.

22. Oral dosage form according to any one of p-21, which provides a dissolution of at least 60% (Q-value) fixed number of aporoximately for 15 min and/or at least 75% (Q-value) fixed number of aporoximately for 45 min; when the dosage form of cefuroxime evaluate test according to USP <711> the device USP-2 at least in terms of specified severity: 900 ml of 0.07 N. hydrochloric acid, 37°when the rotation speed of the blades 55 rpm

23. A method of obtaining a granulate according to claim 6, including cefuroxime, characterized in that the granulation is carried out with the addition of polymer or insoluble adsorbent.



 

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