Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/111—Aromatic compounds
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K40/00—Shaping or working-up of animal feeding-stuffs
  • A23K40/10—Shaping or working-up of animal feeding-stuffs by agglomeration; by granulation, e.g. making powders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the present invention relates to the preparation of orally administrable formulations of quinolone- or naphthyridonecarboxylic acids and methods of making and using the same. More specifically, the invention relates to quinolone- or naphthyridonecarboxylic acids in a solid phase dispersion, which masks their bitter taste.
• the present invention encompasses solid phase dispersion of an active ingredient of quinoloneor naphthyridonecarboxylic acid in an insoluble matrix in an effective amount to mask the taste of the active ingredient.
• a process for preparing the solid phase dispersion by admixing quinolone- or naphthyridonecarboxylic acids with an insoluble matrix to produce a solid dispersion.
• the quinolone- or naphthyridonecarboxylic acid is employed in a micronized form and more preferably in the form of fine powder, and the insoluble matrix is employed in the form of flakes or powder.
• these two components are first admixed by comminuting them by say pulverizing micronized quinolone- or naphthyridonecarboxylic acid with flakes of shellac. This is followed by further mixing and addition of water to form a hydrate, and by, say, melt mixing, and further comminuting to reduce particle size to provide the desired solid phase dispersion.
• solid dispersion is meant quinolone- or naphthyridonecarboxylic acid finely divided particles are distributed throughout the insoluble matrix.
• the solid phase dispersion in accordance with this invention provides greatly reduced quinolone- or naphthyridonecarboxylic acid. particle size. It has also been found that the dispersion provides acceptable solubility of the quinolone- or naphthyridonecarboxylic acid. It has also been found that the dispersion provides controlled release of the quinolone- or naphthyridonecarboxylic acid, which can be administered orally without any problems even to animals which will normally refuse formulations containing quinolone- or naphthyridone-carboxylic acid owing to their bitter taste. Unexpectedly, the solid phase dispersion has an outstanding acceptance when administered.
• Preferred compounds are temafloxacin, tosufloxacin, enrofloxacin, ciprofoxacin, ofloxacin, orbifloxacin, marbofloxacin, norfloxacin, benofloxacin, binfloxacin, danofloxacin, difloxacin, sarafloxacin, premafloxacin and ibafloxacin.
• Particularly preferred compounds are: enrofloxacin, danofloxacin and sarafloxacin.
• Derivatives of these active compounds include their esters such as the C.sub.1 -C.sub.4 -alkyl esters.
• Salts of these active compounds include all salts with acids forming physiologically acceptable salts. These include hydrohalic acids, sulfonic acids, carboxylic acids, amino acids, (poly)-hydroxycarboxylic acids, phosphonic acid, nitric acid and sulfuric acid.
• these are methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, dimethylolpropionic acid, hydroxyacetic acid, lactic acid, hydroxymaleic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, glutaric acid, malonic acid, adipic acid, ascorbic acid, malic acid, citric acid, tartaric acid, aminosalicyclic acid, anthranilic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, salicylic acid, phthalic acid, nicotinic acid, mandelic acid, aspartic acid, glutamic acid, gluconic acid, glucuronic acid, latobionic acid, galaturonic acid, mucic acid, phosphoric acid, nitric acid,
• alkali metal and alkaline earth metal hydroxides such as KOH, NaOH, Ca(OH).sub.2, ammonia
• basic amino acids such as arginine, lysine, choline, N-methylglucamine, ethylenediamine, mono-, di-trialkylamines, substituted amines such as,
• the insoluble matrix can be characterized as a material in which the quinolone- or naphthyridonecarboxylic acid is so embedded that it masks the taste of the quinolone- or naphthyridonecarboxylic acid and yet allows the same to be leached out and made pharmaceutically available to animals consuming the solid disperson.
• the quionolone- or naphthyridonecarboxylic acid can be made available to the target species as it dissolves in say the intestinal fluid, and is absorbed into the blood stream.
• Illustrative but non-limiting examples of the insoluble matrix can be selected from the group consisting of shellac, polyvinyl alcohol, poly (D,L-lactic-co glycolic) acid, sugars, and polyethylene glycol, which is preferably of high molecular weight.
• shellac especially in form of flakes.
• Suitable excipients, carriers and/or auxiliaries which are preferably organic or inorganic inert solid substances can be formulated with the solid phase dispersion.
• Inorganic and organic substances may be used in this capacity.
• inorganic substances are: common salt, carbonates (for example, calcium carbonic), hydrogencarbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide and phosphates.
• organic substances are sugar and optionally their derivatives, polyethylene glycols, paraffins, and fatty acids.
• a carrier As a carrier, one can use a mixture of the substances mentioned in addition to cellulose and its derivatives, starches (for examples corn, rice, potato, tapioca, or wheat starch), foodstuffs and feeds such as, for example milk powder, animal meal, ground and bruised grain.
• Other carriers which in addition have the property of binding water can be employed.
• Example thereof are carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, chitin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl ether and acid anhydrides, polyethylene glycols, waxes, colloidal silicas or mixtures of the substances and classes of substances mentioned.
• Auxiliaries such as preservatives, antioxidants, photostabilizers, colorants, absorption-promoting substances, disintegration-promoting substances, binders or lubricants and stabilizers may be used.
• the method according to the invention comprises mixing the individual components. Any convenient mixer, including high intensity mixers having chopping devices can be employed. The following is a non-limiting description of a method of preparation.
• the components can be mixed together and passed through a cone-mill with a sieve size of 1.0-8.0 mm at 500 to 800 rpm, to give a fine homogeneous powder.
• a cone-mill with a sieve size of 1.0-8.0 mm at 500 to 800 rpm, to give a fine homogeneous powder.
• micronized quinolone- or naphthyridonecarboxylic acid and shellac flakes are mixed.
• the resulting mixture is heated until it melts and flows, typically at about 125 to 135° C.
• the mixture is then extruded or poured as a sheet and cooled rapidly to give a solid wherein the quinolone- or naphthyridonecarboxylic acid is dispersed or dissolved in the solid matrix of the shellac.
• the solid is then reduced in size by means of a mill to give particles between 20 to 100 mesh sizes depending on the intended use.
• the particles can be mixed with a suitable excipient to give an end product.
• the excipients, carriers or auxiliaries can be charged initially in a conventional mixer and mixed.
• the quinolone- or naphthyridonecarboxylic acid embedded in the insoluble matrix is added.
• the thus-obtained mixture is then admixed using mixers including high intensity mixers having chopping devices.
• the ratio of quinolone- or naphthyridonecarboxylic acid to the insoluble matrix in the solid dispersion prepared according to this invention is about 1:0.5 to 10, preferably 1:2 to 8, more preferably 1:5.
• solid dispersion can be extruded or pelletized or in powdered form.
• the formulations according to the invention can be applied dry on food pellets.
• suitable binders for example, vegetable, animal or synthetic oils, fats, fatty acids, fatty alcohols, waxes and gelatine.
• the formulations prepared according to the invention can, inter alia, also be filled into capsules, the capsule wall being made of hard or soft gelatin.
• the capsule can, if appropriate, be entericcoated.
• the formulations prepared by the process according to the invention can be used as such or in a formulation adapted to the prophylaxis or therapy of diseases in humans or target animals, in particular the treatment of bacterial infections. They are especially suitable for use in the fields of geriatrics and pediatrics or in veterinary practice in taste-sensitive animals, such as, for example, cats and pigs.
• the invention provides a process for improving animal “uptake” of the quinolone- or naphthyridonecarboxylic acid by animals, by providing it in a solid dispersion of an insoluble matrix, such as shellac.
• the dispersions and formulations thereof are active against microorganisms pathogenic to humans and animals. These microorganisms include:
• Spirochaetaceae for example, Treponema, Leptospira and Borrelia
• Micrococcaceae for example, staphylococci of biotype A-F and St. hyicus
• Streptococcacease for example, Streptococcus uberis . Str. Equi. Str. agalactiae, Str. dysgalactiae and streptococci of the Lancefield groups A-N
• Pseudomonaceae for example, Pseudomonas malei , Ps. cepacia, Ps. aeruginosa, Ps. maltophilia
• Brucella such as Brucella abort
• B. melitensis B. suis
• Bordetella such as Bordetella bronchiseptica , Moraxella, Acinetobacter
• Enterobacteriaceae for example, Salmonella of the types B-E, Shigella, E. coli , Klebsiella, Proteus, Citrobacter, Edwardsiella, Haemophilus, Providencia and Yersina
• Vibronaceae for example, Bribrio such as Vibrio chloerae
• Pasteurella such as Pasteurella multocia , Aeromonas, Actinobacillus and Streptobacillus
• Bacteroidaceae for example, Bacteroides, Fusobacterium
• Bacillaceae for example, Bacillus, Closteridium types A-D, such as Clostridium perfringens
• Lactobacillaceae and also anaerobic cocci such as, for example, Peptostreptococci and Peptococci
• Coryneform bacteria for example, Corynebacterium pyogenes .
• Mycobacteriaceae for example, Mycobacterium bovis, M. avium , and M. tuberculosis .
• Actinomyceae for example, Actinomyces bovis and A. israelii .
• Nocardiaceae for example, Norcardia facinica and N. asteroides
• Bartonellaceae for example, Baronella
• Chlamydiaceae for example, Chlamydia psittaci
• Mycoplasmataceae for example, Mycoplasma mycoides, M. agalactiae and M. gallisepticum
• Microorganisms pathogenic to humans and animals can cause disease symptoms in mono- or mixed infections of the following animal organ systems: lungs and intratracheal lumen, digestive systems such as stomach and intestine, breast and udder, genital system such as uterus, soft tissue such as skin, muscles, nails, claws, hoofs, active and passive locomotive system such as bones, muscles, sinews, joints and urogenital system such as kidney, urethra, ureter, nervous system, ears, eyes and gills.
• the formulations are used to fight bacterial diseases in humans and animals.
• the animals include: mammals, such as, for example, cattle, horses, pigs, sheep, goats, dogs, cats, camels, animals such as mink, chinchilla, zoo animals and laboratory animals such as, for example, mice and rats; birds, such as, for examples, geese, chickens, turkeys, ducks, pigeons, aviary birds, laboratory birds, such as, for example, parrots and budgerigars; reptiles, such as, for example, crocodiles, snakes, frogs; crustaceans, such as, for example, Penaeidae; for example P. monodon, crabs, lobsters.
• mammals such as, for example, cattle, horses, pigs, sheep, goats, dogs, cats, camels, animals such as mink, chinchilla, zoo animals and laboratory animals such as, for example, mice and rats
• birds such as,
• the bacterial diseases of animals include: swine dysentery, spirochactosis in fowl, leptospirosis in cattle, swine, horses, dogs: Campylobacter-induced enteritis in cattle; Campylobacter-induced abortion in sheep and swine; Campylobacter-induced hepatitis in chicken, infections of the skin; pyoderma in dogs, otitis externa; mastitis in cattle, sheep and goats; streptococcal mastitas, streptococcal infections of the horse, of pigs and other kinds of animals; pneumococcal infections of the calf, and of other kinds of animals; glanders; conjunctivitis; enteritis; pneumonia; brucellosis in cattle, sheep, swine; stropic rhinitis of swine; salmonellosis in cattle, horses, sheep, chicken and other kinds of animals; septicemia; Escherichia coli infections

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Polymers & Plastics (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Food Science & Technology (AREA)
• Zoology (AREA)
• Animal Husbandry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Fodder In General (AREA)

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• 2001
  • 2001-01-24 US US09/768,657 patent/US20020122824A1/en not_active Abandoned
• 2002
  • 2002-01-18 MX MXPA03006089A patent/MXPA03006089A/es active IP Right Grant
  • 2002-01-18 EP EP02709141A patent/EP1355629B1/de not_active Expired - Lifetime
  • 2002-01-18 DE DE60229106T patent/DE60229106D1/de not_active Expired - Lifetime
  • 2002-01-18 WO PCT/US2002/001895 patent/WO2002058669A1/en not_active Application Discontinuation
  • 2002-01-18 CA CA2435414A patent/CA2435414C/en not_active Expired - Fee Related
• 2004
  • 2004-04-30 US US10/835,804 patent/US7112336B2/en not_active Expired - Fee Related

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