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WO2010123337A1 - Complexe d'enrofloxacine présentant un temps vie maximum dans du plasma de mammifères et d'oiseaux - Google Patents

Complexe d'enrofloxacine présentant un temps vie maximum dans du plasma de mammifères et d'oiseaux Download PDF

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Publication number
WO2010123337A1
WO2010123337A1 PCT/MX2009/000038 MX2009000038W WO2010123337A1 WO 2010123337 A1 WO2010123337 A1 WO 2010123337A1 MX 2009000038 W MX2009000038 W MX 2009000038W WO 2010123337 A1 WO2010123337 A1 WO 2010123337A1
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WIPO (PCT)
Prior art keywords
enr
enrofloxacin
birds
complexes
group
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Ceased
Application number
PCT/MX2009/000038
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English (en)
Spanish (es)
Inventor
LOPEZ Héctor Salvador SUMANO
Olivera Lila Gutierrez
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Weisepharm Sa De Cv
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Weisepharm Sa De Cv
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Filing date
Publication date
Application filed by Weisepharm Sa De Cv filed Critical Weisepharm Sa De Cv
Priority to PCT/MX2009/000038 priority Critical patent/WO2010123337A1/fr
Publication of WO2010123337A1 publication Critical patent/WO2010123337A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the present invention relates to the preparation and use of enrofloxacin (ENR) metal complexes, of the ENR-Mg type; ENR-Fe; ENR-Mn; ENR-Cu; ENR-Co; ENR-Ni; ENR-Ca; ENR-Zn, ENR-Cd and ENR-UO 2 , to achieve optimal oral and parenteral bioavailability by increasing the value of the maximum plasma concentration (Cmax and AUC), prolonged the time of stay and therefore the activity of the antibacterial in commercial birds , ruminants, pigs, dogs, cats, horses and other companion species and commercially exploited for meat and / or eggs such as ducks, ostriches, etc.
  • ENR enrofloxacin
  • the complexes described allow to significantly increase the oral bioavailability (F) of the antibacterial in chicken for fattening, egg-producing birds, egg-progenitor birds for the production of papillelle chicken and "grandmothers" (progenitor-producing birds), ducks, turkeys, geese, quail, ostriches and other commercial birds, as well as pigs at all stages , Dogs and cats.
  • F oral bioavailability
  • They also allow unprecedented pharmacokinetics parenterally in: sheep and goats of all ages and bovine meat or milk producers and in avian species, in dogs, in cats and horses, thus optimizing their potential effectiveness and thereby reducing to the maximum the waste of this active principle due to low F.
  • Iluorquinolones are a group of synthetic antibacterial agents used in both human and veterinary medicine for the treatment of a variety of infectious diseases. Although many of them have been synthesized, the best known in veterinary medicine include: amifloxacin, ciprofloxacin, danofloxacin, enrofloxacin, marbofloxacin, norfloxacin and sarafloxacin (Adv. Drug Delivery Reviews 54: 871-882). Others, such as premafloxacin, fleroxaci ⁇ a and difloxacin have had a less impressive income in veterinary medicine.
  • Enrichofloxacin acts in a concentration-dependent manner, exerting a rapid bactericidal effect against aerobic Gram-negative bacteria and mycoplasmas, including some that are resistant to other antibacterials and quinolones and first and second generation fluoroquinolones ⁇ Journal o / AOAC Int. 79; 397-404).
  • Enrichofloxacin is partially inactivated, less than most antibacterials, in the presence of serum, milk and other organic fluids, it acts independently of the size of the inoculum and can exert antibacterial effect at the intracellular level. (FAO. Rome 2004).
  • Enrichofloxacin acts directly by inhibiting the effect of making DNA linear and blocking the negative torsion that bacterial DNA suffers from the action of topoisomerase IV enzymes and DNA gyrase.
  • a complex is formed that causes an irreparable break in the DNA.
  • bacterial autotoxic proteins are not synthesized as in the case of nalidixic acid. Spheroplasts form quickly and the bacteria are destroyed (British Poultry ScL 49 (5) 619-624). How enrofloxacin acts on subunits A and B of topoisomerase ⁇ in addition to IV, less resistance is generated than with other quinolones (EMEA, 1999, Annex IV).
  • preventive fluoroquinolone concentrations of imitators refers to the concentrations of antibiotic required to inhibit the growth of pre-existing mimics in a bacterial population and thereby prevents the selection and emergence of resistant strains.
  • Enrichofloxacin can accumulate in phagosites and apparently stimulates them. It is eliminated mainly by renal excretion, undergoes hepatic biotransformation with partial biliary excretion (Poultry Digest 56; 18-23).
  • enrofloxacin Transepithelial removal (extrusion pumps) through the gastrointestinal wall (GI) generates high concentrations in the GI lumen.
  • enterohepatic circulation of enrofloxacin may occur.
  • the enrofloxacin is partially metabolized to ciprofloxacin, its main active metabolite and some of its inactive or low activity metabolites are: I) congeners of enrofloxacin 3-, 6-, and 8-hydroxylate, which have no or very low antibacterial activity ; (D) congeners 5, 6- (or 6, 8-), 5, 8-, and 7, 8-dihydroxylate, which undergo an oxidative transformation; (ID) derivatives of anthranilic acid, which directly has a cleft of the heterocyclic ring of enrofloxacin; and (TV) 1-ethylpiperazin, the congener amino-7, and disethene-enrofloxacin, which represent both the degradation molecule and the elimination of
  • enrofloxacin after intravenous injection, is ideally suited to a two-compartment model, in which it is first distributed in perfused organs and blood (rapid distribution phase) and subsequently distributed to tissues. Its apparent volumes of distribution are high, indicating an efficient distribution of enrofloxacin outside the plasma. In the liver the maximum concentrations of enrofloxacin are reached, followed by lung and kidney and the lowest in the brain. In most species, enrofloxacin lowers its concentrations below therapeutic levels in 12-24 hours and disappears completely from all the tissue after 3 days.
  • Vancutsem et al. reported that the time of appearance of the plasma concentration peak (Tmax) of enrofloxacin administered orally to horses, dogs, turkeys, chickens and fears was 0.5; 0.9; 1.4; 2.5 and 5.4 hours, respectively and the Cmax values in these species at doses of 10 mg / kg show figures that fluctuate between 2.5 and 4 ⁇ g / mL, but no more.
  • enrofloxacin In sheep, the bioavailability of enrofloxacin is low after oral administration, requiring the use of larger doses by this route to achieve therapeutic success if Cmax is considered as an important variable and should be 10 to 12 times higher than the value of the WCC. However, it is quickly and almost completely absorbed and distributed after its im injection (bioavailability greater than 85%). The maximum plasma concentration is rapidly reached and remains high for several hours, exceeding the minimum inhibitory concentrations for most pathogens. In horses, a species in which other fluorquinolones have not shown good oral absorption, enrofloxacin has a bioavailability of approximately 60%, reaching effective concentrations in plasma and tissues, even in animals not fasted.
  • ENR preparations of doubtful quality 13, 30
  • non-bioequivalent which are evidently shortening the useful life of the last antibacterial with a significant veterinary impact, have proliferated in the national and international market.
  • management practices for this drug that result in low plasma concentrations (low AUC) or low Cmax.
  • the administration of enrofloxacin in drinking water or in pig feed dosages in drinking water in commercial birds without previously restricting it; dosage of enrofloxacin in premix in this species (80); use of hard water as a vehicle in broilers (28); Pharmaceutical preparations that are far from bioequivalent in cattle.
  • Good management of enrofloxacin may increase its bioavailability.
  • the dosage of enrofloxacin in birds can be optimized and achieve maximum doses in the minimum amount of time (bolus dose) by increasing the concentration in the water tank of O l to 0.2% (without modifying the dose of 10 mg / kg); achieving bioequivalent preparations and ideally improving the bioavailability of enrofloxacin in general.
  • the best results with good handling are NOT compared with the extraordinary Cmax values achieved in birds with the ENR-metal complexes object of the present invention and the same applies to pigs in drinking water, in cats and dogs in capsules or syrups or in all species, including such and ruminants and horses and others, via im or sc
  • the pharmacokinetics for the ideal ENR should be that which achieves maximum plasma concentrations (from 10 to 12 times the MIC) at its plasma peak (Cmax) with the highest possible bioavailability (F> 100a) and ideally achieve Cmax on several occasions vg : Cmaxi, Cmax2, etc. (AUC24 / CMI> 125) That is, to achieve the modification of the pharmacokinetics of enrofloxacin to obtain the so-called "preventive enrofloxacin concentrations of mutants" and as a consequence of "maximum bactericidal efficacy".
  • the ENR-Metal complexes object of the present invention manage to overcome the indicated deficiencies.
  • the ideal Cmax and AUC values are: Cmax (maximum plasma concentration)> 12 times the MIC (minimum inhibitory concentration in the laboratory or AUC (area under the plasma enrofloxacin concentration vs. time curve) / MIC> 125 ..
  • the enrofloxacin-metal complexes disclosed in the present application achieve higher values by up to 230 % in bioavailability and up to 80% higher in Cmax.
  • Figure 2 shows the serum concentration profiles of enrofloxacin vs. time in dogs after application of enrofloxacin Mg. and of the original enrofloxacin, administered via SC and orally at doses of 5 mg / kg.
  • Figure 3 shows the serum concentration profiles of enrofloxacin vs. Time in horses Quarter Mile after application of enrofloxacin Mg. and of the original enrofloxacin, administered via SC and orally at doses of 10 and 5 mg / kg.
  • Figure 4 shows the concentration profiles of enrofloxacin vs. time in cattle after application of enrofloxacin Mg. and of the original enrofloxacin, administered via SC at a dose of 10 mg / kg.
  • Figure 5 shows the concentration profiles of enrofloxacin vs. time in pigs after application of enrofloxacin Mg and original enrofloxacin, administered via IM and orally at doses of 5 and 10 mg / kg respectively.
  • Figure 6 shows the concentration profiles of enrofloxacin vs. time in goats after the application of enrofloxacin Mg. and of the pioneer reference enrofloxacin, administered via SC at a dose of 10 mg / kg.
  • Figure 7 shows the concentration profiles of enrofloxacin vs. time in sheep after application of enrofloxacin Mg. and of the original enrofloxacin, administered via SC at a dose of 10 mg / kg.
  • the ENR-metal complexes object of the present invention are prepared following the procedure described below:
  • enrofloxacin To a previously defined amount of enrofloxacin is added 30 to 35% by weight of an inorganic salt of the group of metals consisting of Mg 2+ , Fe 2+ , Co 2+ , Ni 2+ , Zn 2+ , Mn 2+ , Cu 2+ , Ca 2+ , Cd 2+ and UO 2 2+ , and add 5 times the enrofloxacin weight of double-distilled water. Shake until you get a milky suspension.
  • the enrofloxacin weight of a strong inorganic acid is rapidly added 3 times, selected from the group of phosphoric, nitric, sulfuric, hydrogen sulfide, hydrofluoric, hydrochloric, hydrobromic, iodhydric and the like, preferably of the halogen acids and more preferably 35% hydrochloric acid, adjusting the pH of the mixture to approximately 3, stir for approximately 3 hours to homogenize the suspension formed.
  • Filter and dry in vacuo the solid obtained is mixed with anhydrous ethyl alcohol under stirring, filtered and washed twice with anhydrous acetone, filtered and dried under vacuum for 6 hours. Once the solid is dry, it is pulverized and micronized. The yield is between 70-90%.
  • ENR-Mg 10 g of quality enrofloxacin was mixed with 3 g of anhydrous magnesium hydroxide, mixed in a beaker with 50 mL of double-distilled deionized water. Stir until a milky-looking suspension is obtained. 30 mL of 35% HCl are quickly added and the pH is adjusted to 3. It was stirred for about 3 hours, obtaining a homogeneous suspension without lumps, a little yellowish-white and slightly pearly. It is filtered in a paper filter on a porcelain filter and in Kitazato Flask to vacuum until it dries. The powder-stone obtained is washed with 50 mL of ethyl alcohol only once by pouring it into a beaker using magnetic stirring. It is dried again as in the previous step and the powder-stone obtained is washed with anhydrous acetone twice with 50 mL pouring it into a beaker using magnetic stirring and vacuum drying.
  • the product obtained was used for oral, subcutaneous and intramuscular administration in biological tests.
  • the Cmax variable is required to be 10 12 times greater than the MIC value of the pathogen involved and that AUC / MIC is greater than 120 for Gram bacteria - and 30 to 50 for Gram +.
  • Enrichofloxacin is not commonly used in horses, although substantial evidence has been accumulated to be able to indicate it for 3-5 days in a row in adults of this species without any side effects. However, it is still contraindicated in foals because their joints can be affected by the demineralization of joint surfaces and deforming arthritis. Therefore, the pharmacokinetics PO of enrofloxacin-Mg in horses is presented here.
  • ENR metal complexes with Fe 2+ , Co 2+ , Ni 2+ , Zn 2+ , Mn 2+ , Cu 2+ , Ca 2+ , Cd 2+ and UO 2 2+ can easily be prepared by a technician With knowledge in the field of chemistry following the procedure described here, in the same way, you can apply them following the description of the described invention, obtaining the same or similar results.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine de la médecine vétérinaire, plus particulièrement, les anti-bactériens dérivés des fluorquinolones, plus particulièrement, une série sels d'enrofloxacine du type ENR-Mg; ENR-Fe; ENR-Mn; ENR-Cu; ENR-Co; ENR-Ni; ENR-Ca; ENR-Zn, ENR-Cd et ENR-UO2; avec cette nouvelle forme chimique l'enrofloxacine atteint une biodisponibilité largement supérieure à celle de l'enrofloxacine base ou du sel de chlorhydrate et on obtient une prolongation de sa présence dans l'organisme des oiseaux, des porcs, des bovins, des caprins, des ovins, des canidés, des félidés et des chevaux. En outre, ces sels perdent pratiquement la totalité de leur goût amer caractéristique de l'enrofloxacine base ou du chlorhydrate. Ainsi, l'augmentation du temps moyen de rétention et, de ce fait, du temps durant lequel on obtient des concentrations thérapeutiques est prolongé dans toutes les espèces mentionnées.
PCT/MX2009/000038 2009-04-24 2009-04-24 Complexe d'enrofloxacine présentant un temps vie maximum dans du plasma de mammifères et d'oiseaux Ceased WO2010123337A1 (fr)

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PCT/MX2009/000038 WO2010123337A1 (fr) 2009-04-24 2009-04-24 Complexe d'enrofloxacine présentant un temps vie maximum dans du plasma de mammifères et d'oiseaux

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PCT/MX2009/000038 WO2010123337A1 (fr) 2009-04-24 2009-04-24 Complexe d'enrofloxacine présentant un temps vie maximum dans du plasma de mammifères et d'oiseaux

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015088305A1 (fr) * 2013-12-11 2015-06-18 Universidad Nacional Autónoma de México Complexe recristallisé de chlorhydrate d'enrofloxacine dihydraté et son procédé d'obtention
EP2992884A4 (fr) * 2013-05-03 2016-06-22 Guangzhou Insighter Biotechnology Co Ltd Utilisation de sel d'enrofloxacine dans la préparation d'une préparation orale pour porcs

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070197548A1 (en) * 2006-02-17 2007-08-23 Murthy Yerramilli V S Fluoroquinolone compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070197548A1 (en) * 2006-02-17 2007-08-23 Murthy Yerramilli V S Fluoroquinolone compositions

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EFTHIMIADOU, E. K. ET AL.: "Mononuclear metal complexes of the second-generation quinolone antibacterial agent enrofloxacin: Synthesis, structure, antibacterial activity and interaction with DNA", POLYHEDRON, vol. 27, 2008, pages 1729 - 1738, XP022586713, DOI: doi:10.1016/j.poly.2008.02.006 *
EFTHIMIADOU, E. K. ET AL.: "Neutral and cationic mononuclear copper(II) complexes with enrofloxacin: Structure and biological activity", JOURNAL OF INORGANIC BIOCHEMISTRY, vol. 100, 2006, pages 1378 - 1388, XP025038293, DOI: doi:10.1016/j.jinorgbio.2006.03.013 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2992884A4 (fr) * 2013-05-03 2016-06-22 Guangzhou Insighter Biotechnology Co Ltd Utilisation de sel d'enrofloxacine dans la préparation d'une préparation orale pour porcs
WO2015088305A1 (fr) * 2013-12-11 2015-06-18 Universidad Nacional Autónoma de México Complexe recristallisé de chlorhydrate d'enrofloxacine dihydraté et son procédé d'obtention

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