GRANULES AND VETERINARY COMPOSITIONS COMPRISING A WATER-SOLUBLE COMPLEX OF FLUMEQUINE

Abstract: The invention relates to granules comprising a water-soluble complex of flumequine formed with polyvinyl pyrrolidone, an amino acid monomer or polymer containing basic group(s) or urea. These granules are prepared according to the invention by admixing flumequine with one of the above complexing agents and optionally with a granulation aid and subjecting the mixture to wet granulation. The invention also relates to veterinary compositions prepared from the above granules.

Description: GRΛKULϊSS AITD COϊijPOSITlJϊϊo COIJPAIJIIJG A " .ATi_Iv- The invention relates to granules comprising a water- soluble complex of flume ruine, as .veil as to a process for the pre par it ion of such granules. The invention also relates to veterinary compositions produced from the granules according to the invention. _iS known, flumequine (S, 7-dihydro-9-f luoro- - me hyl - -l-oxo-lH,5H--bcn.so-quinolysine-2-carboxylic acid) is an effective antimicrobial agent, highly active against various microorganisms, such as Aeromonas, ^scherichia coli, Pro- teus, Klebsiella, Salmonella and Ihiterobacter species (D HO. 2,264,163). Flumequine is, however, only εpairingly soluble in water, which renders difficult to convert it into pharma¬ ceutical and veterinary compositions and also restricts its therapeutic use. According to French patent lϊo . 2,453 » 647 these, dif iculties are overcome. by converting flumequine into pharmaceutical compositions in admixture with sodium carbonate; thus the resulting compositions comprise flu¬ mequine as its water-soluble sodium salt. According to the cited reference a water-soluble powder mixture comprising 3-10.5 ,- by weight of flume uine can be prepared by admix¬ ing flumequine with sodium carbonate and lactose. Over these powders additional pharmaceutical compositions, such as tablets, injcctable aqueous suspensions and ointments, are also mentioned in the cited reference; these composi- tions are prepared by methods conventionally applied in pharmacotechnolog • ϊ/e have found that these known compositions do not meet all the requirements of pharmaceutical and veterinary use. The 3θlid and se isolid compositions, such as powder mixtures and ointments, are liable to segregation, which impairs the security of dosing. Considerable disadvantages arise from the alkaline nature of the compositions. This alkalinity renders the compositions les3 stable, and re- stricts both their fields of use and their compatibility with other active agents. Thus e.g. alkaline compositions are less suitable for injection purposes, may cause re- pellency when mixed into drinking water, and cannot be com¬ bined with proteins, enzymes and other alkali-sensitive substances. Our investigations have shown that these dis¬ advantages cannot be overcome by utilizing other salts of flumequine, either. How we have found that the disadvantages outlined above can be eliminated completely when flumequine is ad- mixed with polyvinyl pyrrolidine, an amino acid monomer or polymer comprising basic group(s) or urea and optionally • Λ-ith a known pharmacoteehnological granulation aid, and the resulting mixture is granulated in wet state. Under such conditions flumequine forms a complex with the poly- vinyl pyrrolidine, amino acid monomer or polymer or urea present. The resulting complex is highly water-soluble and forms a neutral aqueous solution. Owing to their neutral ¬ ity, these complexes are much more suitable for injection or oral administration than the known alkaline flumequine salts, and can be combined unrestrictedly with alkali- sensitive substances. The granulation technique applied according to the invention ensures, on one hand, the homogeneity of the admixed components, and, on the other hand, provides the flumequine complex as a product easy to handle and particularly suitable for processing into a veterinary composition. Thus the invention relates to granules comprising a water-soluble complex of flumequine formed with poly- vinyl pyrrolidone, an amino acid monomer or polymer con¬ taining basic group(s) or urea. These granules are prepared according to the in¬ vention as follows: flumequine is admixed with 5-55 ,-~ by weight, calculated for the weight of flumequine, of poly- vinyl pyrrolidone or an amino acid monomer or polymer containing basic group(s) or with 20-100 . by weight, calculated or the weight ox flumequine, of urea, and op¬ tionally with a known pharmacotcchnological granulation aid, and the mixture is subjected to wet granulation. In these granules flumequine is present as its complex formed with the complexing agent applied, i.e. with polyvinyl pyrrolidone, an amino acid monomer or poly¬ mer containing basic grouρ(s) or urea. These complexes are new compounds, ' ..'hen the mixture to be granulated con- tains the complexing agent in excess related to the stoi- chiomctrically required value, this excess serves as a carrier. Λmino acid monomers or polymers containing basic grouρ(s), utilized as complexing agents, are amino acids which contain ovπr the -I-H-.group characteristic of such compounds at least one further nitrogen-contain¬ ing basic group, such as one additional amino group, too. Examples of these amino acids are lysine and arginine. The term "an amino acid polymer containing basic group(s)" refers to oligomεrs and polymers formed from these amino acids by peptide bonds. The mass to be granulated may also contain one or more known pharmacotecnnologieal granulation aid. These granulation aids may be substances for inhibiting adhesion and substances for improving distribution. Examples of the substances for inhibiting adhesion are silicon di¬ oxides with high specific surface area (such as Aerosil) and magnesium εtcarate. As substances for improving distri¬ bution pharmaceutically acceptable water-soluble neutral p rticulatc solids can be applied, characteristic repre¬ sentatives of which are sugars (such as lactose and glu¬ cose) and pol saC-charides (such as various starch types). In the presence of granulation aids the mass to be gra¬ nulated is more easy to homogenise, granulation can bo per- formed more simply, and granules with more even particle size are formed. It is preferred to use a granulation aid particularly if polyvinyl pyrrolidone or a basic amino acid polymer is applied as complexing agent. If a gra¬ nulation aid is also present in the mass to be granulated, its amount may be e.g. 1-100 ,J by weight, calculated for the weight of flumequine. Granules are prepared according to the invention by any of the wet granulation methods well known in phar- macotcchnology. Pharmaceutically acceptable inorganic or organic liquids, such as water or an alcohol, can be utilised as granulating liquids. According to a preferred method the total amount or a part of the complexing agent and/or of the granulation aid is admixed to the mass to be granulated as a solution formed with the granulating liquid. The mass to be granulated may have typically e.g. one of the following compositions: a) 10 - 20 parts by weight of flumequine 0.1 - 1 part by weight of erosil 0.5 - 2 parts by weight of polyvinyl pyrrolidone b) 10 - 20 parts by weight of flumequine 0.1 - 1 part by weight of Aerosi1 2 - 4 parts by weight of lactose 0.5 - 2 parts by weight of polyvinyl pyrrolidone c ) 10 - 20 parts by weight of flumequine 0.5 - 5 parts by weight of lysine d) 10 - 20 parts by weight oi flumequine 3 - 20 parts by weight of urea c ) 10 - 20 parts by weight of flumequine 0.1 - 2 parts by weight of starch 0.5 - 5 parts by 'weight of polylysine The granules according to the invention may be applied directly for veterinary purposes, e.g. they can be dissolved in the drinking water of cni -ls. If desired, however, the granules according to the invention can be converted into veterinary compositions, such as powder mixtures, tablets, capsules, injectuble composi- ionε etc., by conv antiona1 piia u.cot chno1ogicsi o era- tions, utilizing conventional veterinary carriers, dilu¬ ents and/or other auxiliary agents (such as sur actants). uc veterinary compositions can be applied to advantage e.g. for individual treatment or for the treatment of a smaller population. The invention also relates to such veterinary compositions as well as to their preparation. The veterinary compositionc according to the inven¬ tion may also comprise adjuvants. Preferred representatives of adjuvants are bactoriolytic enzymes which facilitate flumequine to reach its point of attack, i.e. to reach the infecting microorganism. The known veterinary compo¬ sitions comprising flumequine as its alkaline salt cannot be combined with such cn ymes which arc characteristic re resentatives of alkali-sensitive substances. As adjuvant e.g. lysosi c or an acid addition salt thereof can be applied. The veterinary compositions according to the invention may comprise an adjuvant generally in an amount ox 0.5-10 ,J by ,, * eight, preferably 1-3 , ~ by weight, cal¬ culated for the weight of the composition. It has been found, unexpectedly, that the gra¬ nules and veterinary compositions according to the inven¬ tion, which comprise flumequine as its water-soluble complex, exjrt more favourable therapeutical effects than the respective known compositions which comprise flumequine as its salt administered- on the same therap¬ eutic level. Thus according to the invention flumequine can not only be converted into a water-soluble form which is easy to handle and can be applied to advantage in pharmacotcchnological operations, but the biological value of the active agent can be improved, too. The invention is elucidated in detail by the aid of the following non-limiting Examples. Example I Granules are prepared from the following components Flumequine 15.15 k£ Aerosil 200 0.50 kg Polyvinyl pyrrolidone 1.00 kg Lactose 2.50 kg The half of polyvinyl pyrrolidine is added to the pre -homogenized mixture of the further components as a 20 ,J by weight ethanol solution. The granules are prepared by fluidisation technique. Exam le 2 The granules prepared according to Example 1 are homogenized in a drum with 129.35 kg of lactose. A powder mixture suitable for veterinary purposes is obtained. lϋxamole 3 Granules are prepared as described in Example 1 from the following components: Plumequine 10.00 kg * Λeroεil 200 0.20 kg Polyvinyl pyrrolidone 1.00 kg Lactose 2.00 kg -xamplo 4 One proceeds as described in Example 1 with the difference that water is used as granulating liquid and the granules are prepared from the following components: flumequine 10.0 kg Urea 7.0 kg Example 5 One proceeds as described in ixample 1 with the difference that an aqueous gel of potato starch is U3θd as granulating liquid and the granules are prepared from the following components: Plumeσuine 10.0 kg Lysine 2.0 kg Potato starch 0.3 kg Example 6 Comparative biological tests were performed on 120 weeks old Tetra-3 broiler cocks. The animals were infected artificially with Salmonella typhimurium. ' . ' hen the symptoms of infection became observable the animals were divided into three equal groups, and the individual groups were kept separately in cages of 20 ani uls/m . The individual groups were treated as follows: Group I: untreated control Group II: 5 days' treatment with a composition according to rench patent Ho. 2,453,647 comprising flu¬ mequine as its sodium salt, at a therapeutic level of 12 g/kg Group III: 5 days' treatment with a composition according to Example 2 at a therapeutic level of 10 mg/kg The results were evaluated at the end of the 5th day. The following results were obtained: Group I Group II Group II Mortality in 5 clays ! 5 ■ -- 12.5 , >J Diarrhoeal day s re¬ lated to Group I ,0 3

Claims: What we claim is : 1. Granules comprising a water-soluble complex of flumequine formed with polyviny l pyrrolidone , an amino acid monomer or polymer containing basic group (s ) or urea . 2. Granules as claimed in claim 1, in which the water-soluble complex of flumequine is formed with poly¬ vinyl pyrrolidone. 3. A process for the preparation of granules accor - ing to claim 1, in which flumequine is admixed with 5-55 ,- * by weight, calculated for the weight of flumequine, of polyvinyl pyrrolidone or an amino acid monomer or polymer containing basic group(s) or with 20-100 by weight, calculated for the weight of flumequine, of urea, ana optionally with a known pharmacotechnological granule- tion aid, and the mixture is subjected to wet granulation. 4. A process as claimed in claim 3, in which gra¬ nulation is performed in the presence of 1-100 >a by weight, calculated for the weight of flumequine, of a conventional pharmacotechnological granulation aid. . Λ process as claimed in claim 4, in which gra¬ nulation is performed in the presence of 7-50 ,-ό by- weight, calculated for the weight of flumequine, of poly¬ vinyl pyrrolidone. 6. A process as claimed in any of claims 3 to 5, in which a silicon dioxide with high specific surface area and/or a sugar is applied as granulation aid. 7. A veterinary composition which comprises gra¬ nules comprising a water-soluble complex of flumequine formed with polyvinyl pyrrolidone, an amino acid monomer or polymer containing basic group(s) or urea, together with a conventional veterinary diluent or carrier and op¬ tionally with an adjuvant. 8. A veterinary composition as claimed in claim 7 » which comprises granules comprising a water-soluble complex of flumequine formed with polyvinyl pyrrolidone 9. A veterinary composition as claimed in claim 7 or 3, which comprises lysoεiue or an acid addition salt thereof as adjuvant in an amount of 0.5-10 /J by weight calculated for the weight of the composition. 10. A process for the preparation of a veterinary composition as claimed in claim 7, in which the granules prepared as claimed in claim 3 ^ e converted into c- ve- terinary composition by a kπo..n pharmacotechnological operation in combination with conventional veterinary diluent or carrier and optionally with an adjuvant. 11. A process as claimed in claim 10, in ..hich granules prepared as claimed in claim 5 ^rε applied. 12. A proccs . as claimed in claim 10 or 11, in which lysosime or on acid addition salt thereof is applied as adjuvant in an amount of 0.5-10 ,J by weight calculated for the weight of the composition.

Inventors: BENDE ZOLTAN, HASZMANN-MARTON ANDREA, HUTAS ISTVAN, NAGY LASZLO, PRIBEK FERENC, BENDE, ZOLTAN, HASZMANN-MARTON, ANDREA, HUTAS, ISTVAN, NAGY, LASZLO, PRIBEK, FERENC
Applicants: REANAL FINOMVEGYSZERGYAR
Application year: 1992
Main classification: A61K9
IPC codes: A61K9, A61K31