WO2010123337A1 - Enrofloxacin complex with maximum residence time in the plasma of mammals and birds - Google Patents

Abstract

The present invention relates to the field of veterinary medicine, in particular to antibacterial agents derived from fluoroquinolones, and in particular to a series of enrofloxacin salts such as ENR-Mg, ENR-Fe, ENR-Mn, ENR-Cu, ENR-Co, ENR-Ni, ENR-Ca_, ENR-Zn, ENR-Cd and ENR-UO_2. In this new chemical form, enrofloxacin achieves much higher bioavailability than basic enrofloxacin or hydrochloric salt, as well as increased residence time in the organisms of birds, pigs, cattle, goats, sheep, dogs, cats and horses. Said salts also lose practically all the bitter taste associated with basic enrofloxacin or the hydrochloride. Furthermore, the average retention time in all of the aforementioned species is increased, thus extending the time in which concentrations considered to be therapeutic can be obtained.

Description

 ENROFLOXACINE COMPLEXES WITH MAXIMUM RESIDENCE TIME IN PLASMA OF MAMMALS AND BIRDS

TECHNICAL FIELD OF THE INVENTION

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. 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. 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. It also minimizes the generation of resistant strains of sensitive bacteria by optimizing the relationship between pharmacokinetics / pharmacodynamics (PK / PD) of the antibacterial. In addition, the ENR-metal complexes mask the taste and therefore allow its acceptance in pigs when the administration is orally in the drinking water and avoid its rejection and salivation in cats.

BACKGROUND OF THE INVENTION

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, fleroxaciπa and difloxacin have had a less impressive income in veterinary medicine. However, the drug that revolutionized the therapeutics of bacterial diseases in veterinary medicine was and still is enrofloxacin, developed in the 80s for its exclusive use in veterinary medicine. Both in the decade of the 80 ^' s and the 90 ^' s and even to date the constant increase in the use of this antibacterial agent is evident. The reasons are: high antibacterial potency, rapid bacterial destruction in minutes regardless of the size of the inoculum and bactericidal activity with only 2-3 times the value of the minimum inhibitory concentration.

Physicochemical properties of enrofloxacin.

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).

Mechanism of action of enrofloxacin

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. In addition, with the administration of enrofloxacin a complex is formed that causes an irreparable break in the DNA. Unlike the first generation quinolones, 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 π in addition to IV, less resistance is generated than with other quinolones (EMEA, 1999, Annex IV).

The effects of enrofloxacin as a metabolic inhibitor, as a destroyer of the genetic material and of the DNA gyrase itself, are concentration dependent. Therefore, the higher the concentration, the lower the possibility that the imitating bacteria will be recovered and with this a greater antibacterial efficiency is achieved and the selection of imitators is avoided. (Current Opinion in Microbiology, 5; 472-477).

In such a way that the optimal antibacterial effect of enrofloxacin is at high concentrations (high Cmax) and for as long as possible between doses (area under the plasma enrofloxacin concentration curve vs. time, AUC, high) (The Veterinary Record 2002, 16; 350-353). It also has a post-antibiotic effect of 1 to 4 hours against S. intermedius, P. multocida, E. coli, P. aeruginosa, S. typhimurium and S. Aureus (J. ofFoodProtec. 2004, 67 (5) 980-992).

Resistance to enrofloxacin is considered to occur in approximately one in 1 x 10 ⁹ bacteria. These mutations, sometimes called slight, are sufficient to maintain infection in fluids and tissues of an individual receiving conventional doses of enrofloxacin. From this notion the term of

"preventive fluoroquinolone concentrations of imitators", which 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.

Fluorquinolones in general have an oral absorption in animals from regular to good (with the exception of ruminants and probably from horses) eg 60% in birds and 75% in dogs and a good parenteral absorption (greater than 80%). However, these figures leave room to improve this variable. The elimination half-lives fluctuate between species but in general they are from 3 hours to 10 hours and are distributed well to various tissues with values of volume of area distribution from 2 to 4 L / kg, depending on the species. 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). Possibly there is some of biotransformation in other sites such as the udder or macrophages and is also known at the level of the intestinal epithelium. The effect of first hepatic passage is approximately 7 to 20%. Common metabolic pathways of these agents including enrofloxacin are alkylation, glucuronization, oxidation, sulfoxidation, acetylation and rupture of the piperazine ring. In animals glomerular filtration occurs for the unbound fraction and also active tubular secretion (Adv. Drug Delivery Reviews, 54; 825-850), which allows high urinary concentrations to be achieved. The process of tubular secretion is sensitive to Probenecid and urinary excretion decreases in renal failure. Transepithelial removal (extrusion pumps) through the gastrointestinal wall (GI) generates high concentrations in the GI lumen. In addition, there are indications that 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 the piperazinyl segment. The pharmacokinetics 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. (J. ofFood Protec. 2004) 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 μg / mL, but no more. Scheer (Pharmacotherapy 1999, 19; 404-415) found that enrofloxacin is easily and rapidly absorbed after parenteral administration in calves, pigs, dogs, cats, chickens and turkeys, reaching maximum concentrations within 0.5 to 2 hours and again Cmax values fluctuate around 3 μg / mL. Oral absorption of enrofloxacin in cattle is poor (approximately 10%). Although the calves have the same oral absorption patterns as the monogastric species, although the parenteral route is preferred in them. If the oral route is necessary, it should be considered that the minerals present in the dairy substitutes can produce the chelation of the antimicrobial and it has been reported that hard waters reduce their F in birds. On the other hand, a temporary reduction in the density, viability and activity of rumen protozoa has been reported, with some depression of rumen metabolism, after oral administration of enrofloxacin. In cattle, enrofloxacin is widely absorbed after subcutaneous administration, with a bioavailability greater than 90%. In dairy cows they reach maximum plasma concentrations (similar both for administration by subcutaneous route, sc, and intramiscular route, im) within the first 4 hours and Cmax values reach 2.5 - 3.6 μg / mL. In one trial the bioavailability was 82% after IM administration, and 100 after sc administration. In calves the absorption is rapid, with a virtually complete systemic bioavailability, both by sc and im route. 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. The absorption via im is more slow in this species, apparently due to the irritant effect of the preparation on the injection site since enrofloxacin is diluted in KOH preparations at a pH of 10.4 or more. The bioavailability of the drug is high both in pigs subjected to fasting and in those who receive food at the time of administration. Provided that food consumption is not affected, enrofloxacin medication in the ration provides, within 2 to 4 hours, serum and tissue concentrations slightly above the MIC of certain important pathogens in these animals. However, since it is a concentration-dependent antibacterial it is preferred that this route is not used. In contrast, intramuscular administration allows rapid absorption, with a bioavailability greater than 90%.

OBJECT OF THE INVENTION

Therefore, it would be ideal for the management of large herds to have a water-soluble enrofloxacin and insipid enough that it would not be rejected by pigs and that it would achieve Cmax, AUC and F values of at least the same magnitude as when injects IM. The absorption of enrofloxacin orally in chickens achieves a bioavailability close to 60% and this translates into Tmax values of 1 - 2 and up to 3 hours and Cmax of 2 to 3 μg / mL at best when There is a bolus dose (restricting water 1 hour), purged water systems and with the best enrofloxacin given that there are notable differences in the preparations available in the market.

It has been more than two decades since a new antibacterial group for veterinary medicine is generated, although some derivatives of groups already known as tulatromycin (macrolide) and cefovecin (cephalosporin) can be highlighted. It is estimated, by the pharmaceutical industry, that to produce a novel antibacterial and at least as potent as enrofloxacin, a very high investment and a disproportionate financial risk would be required, in addition to a research period of 5 - 10 years. Obviously, this represents a high financial risk capital that has literally stopped the Veterinary Pharmaceutical Industry in advanced countries. Thus, it is unlikely that a group of antibacterials will be generated in the short or medium term that equals or exceeds the potency of enrofloxacin, used for more than two decades in Latin America and many parts of the world.

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. Additionally, there are management practices for this drug that result in low plasma concentrations (low AUC) or low Cmax. For example, 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. For example, 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. However, 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. As already mentioned, it has been postulated that 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.

BRIEF DESCRIPTION OF THE DRAWINGS

In the figures presented, the graphs of the pharmacokinetics of enrofloxacin-magnesium in pigs, birds and dogs administered orally and subsequently the kinetics in dogs, pigs and goats and cows administered by the subcutaneous route are presented.

In Figure 1, serum concentration profiles of enrofloxacin vs. are shown. Time in broiler chicken after application of enrofloxacin Mg. and of the original enrofloxacin, administered via PO at a dose of 10 mg / kg.

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. DETAILED DESCRIPTION OF THE INVENTION:

The ENR-metal complexes object of the present invention are prepared following the procedure described below:

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. To this 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%.

PHARMACOCINETICS OF ENROPHLOXACINE-Mg IN COMMERCIAL BIRDS

Example: The ENRQ-MG complex was prepared according to the described procedure, which was used to exemplify the pharmacokinetics in domestic birds of the ENR metal complexes object of the present invention.

Preparation of 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.

It is allowed to dry under vacuum for approximately 6 hours, is ground at the end and sieved to the desired degree of micronization.

The product obtained was used for oral, subcutaneous and intramuscular administration in biological tests.

Considering that enrofloxacin is routinely used in broiler chicken at a dose of 10 mg / kg in drinking water, as well as the fact that pharmacokinetic data indicate that enrofloxacin works optimally, 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 +.

Material and methods

Below are the materials and methods used in studies of the pharmacokinetics of enroflaxin-Mg PO in broilers:

Resultados

Results

The results obtained for enrofloxacin-Mg orally and the comparison with the original product are presented in Figure 1 and Table 1. Table 2 shows the pharmacokinetic values obtained in the 2 groups.

Table 1. Serum profiles of enrofloxacin concentration vs. Time in Quarter Mile horses after application of enrofloxacin Mg and original enrofloxacin, administered via SC and orally at doses of 10 and 5 mg / kg.

Table 2. Pharmacokinetic values of the 2 enrofloxacin groups in broilers at doses of 10 mg / kg

Pharmacokinetics of enrofloxacin-Mg PO administered via SC and PO in dogs

Material and methods

Materials and methods are summarized as follows:

Results

The results obtained for enrofloxacin-Mg by the two routes used and the comparison with the original product are presented in Figure 2 and Table 3. Table 4 shows the pharmacokinetic values obtained in the 4 groups.

Table 3. Serum profiles of enrofloxacin concentration vs. time in dogs after application of enrofloxacin Mg. and of the original enrofloxacin, administered via SC and orally at doses of S mg / kg.

Table 4. Pharmacokinetic values of the 4 enrofloxacin groups in dogs

Pharmacokinetics of enrofloxacin-Mg PO administered via SC in horses

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.

Material and methods

Materials and methods are summarized as follows:

Results

The results obtained for enrofloxacin-Mg by the two routes used and the comparison with the original product are presented in Figure 3 and Table 5. Table 6 shows the pharmacokinetic values obtained in the 4 groups.

Table 5. Serum profiles of enrofloxacin concentration vs. horse time Quarter of NfUIa after application of enrofloxacin Mg. and of the original enrofloxacin, administered via SC and orally at doses of 10 and 5 mg / kg.

Table 6. Pharmacokinetic values of the 4 enrofloxacin groups in horses

Quarter Mile

Pharmacokinetics of enrofloxarin-Mg administered via SC in cattle

Material and methods

Materials and methods are summarized as follows.

Results

The results obtained for enrofloxacin-Mg by SC route and the comparison with the original product are presented in Figure 4 and Table 7. Table 8 shows the pharmacokinetic values obtained in the 2 groups.

Table 7. Serum profiles of enrofloxacin concentration vs. Time in Quarter Mile horses after application of Ia enrofloxacin Mg. and of the original enrofloxacin r, administered via SC and orally at doses of 10 and 10 mg / kg.

Cuadro 8 Valores farmacocinéticos de los 4 grupos de enrofloxacina en caballos

Table 8 Pharmacokinetic values of the 4 enrofloxacin groups in horses

Quarter Mile

Pharmacokinetics of enrofloxacin-Mg administered via DVf and PO in pigs

Material and methods

Materials and methods are summarized as follows.

Results

The results obtained for enrofloxacin-Mg by the two routes used and the comparison with the original product are presented in Figure 5 and Table 9. Table 10 shows the pharmacokinetic values obtained in the 4 groups. Table 9. Serum profiles of enrofloxacin concentration vs. time in pigs after application of enrofloxacin Mg. and of the original enrofloxacin, administered via IM and orally at doses of 5 and 10 mg / kg respectively.

Table 10. Pharmacokinetic values of the 4 enrofloxacin groups in pigs

Pharmacokinetics of enrofloxacin-mg administered via goats

Material and methods

Materials and methods are summarized as follows:

Results

The results obtained for enrofloxacin-Mg by SC route and the comparison with the original product are presented in Figure 6 and Table 11. Table 12 shows the pharmacokinetic values obtained in the 2 groups.

Table 11. Serum profiles of enrofloxacin concentration vs. time in Creole goats after application of enrofloxacin Mg. and of the original enrofloxacin, administered via SC 10 mg / kg.

Table 12. Pharmacokinetic values of the 12 enrofloxacin groups in goats

Pharmacokinetics of enrofloxacin-Mg administered via SC in sheep

Material and methods

Materials and methods are summarized as follows:

Results

The results obtained for enrofloxacin-Mg by SC route and the comparison with the original product are presented in Figure 7 and Table 13. Table 14 shows the pharmacokinetic values obtained in the 2 groups.

Table 13. Serum profiles of enrofloxacin concentration vs. time in Creole sheep after application of enrofloxacin Mg. and of the original enrofloxacin, administered via SC 10 mg / kg.

Table 14. Pharmacokinetic values of the 2 enrofloxacin groups in Creole sheep

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.

Claims

Once our invention has been sufficiently described, it is considered as a novelty and therefore claimed as exclusive property, the content of the following claims: 1. Process for obtaining enrofloxacin metal complexes with maximum residence time in plasma of mammals and birds, where said procedure is characterized by the following steps: a) 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⁺ ; b) add 5 times the enrofloxacin weight of double-distilled deionized water; c) stir until a milky suspension is obtained. d) quickly add 3 times the enrofloxacin weight of a strong inorganic acid, selected from the group of phosphoric, nitric, sulfuric, sulfhydric, hydrofluoric, hydrochloric, hydrobromic, iodhydric and the like, preferably from the acids of the halogen group and more preferably 35% hydrochloric acid; e) adjust the pH of the mixture to approximately 3; f) stir for approximately 3 hours to homogenize the suspension formed; filter and dry under vacuum; g) mix with anhydrous ethyl alcohol under stirring, filter and wash twice with anhydrous acetone; h) filter and dry under vacuum for 6 hours; i) the dry solid is pulverized and micronized. 2. The process according to claim 1, characterized in that an enrofloxacin metal complexes selected from the group consisting of: ENR-Mg; ENR-Fe; ENR-Mn; ENR-Cu; ENR-Co; ENR-Ni; ENR-Ca; ENR-Zn, ENR-Cd and ENR-UO ₂ 3. The process according to claim 1 characterized in that the inorganic acid used is 35% hydrochloric acid. 4. The process according to claim 1, characterized in that the inorganic salts of Mg ²⁺ , Fe ²⁺ , Co ²⁺ , Ni ²⁺ , Zn ²⁺ , Mn ²⁺ , Cu ²⁺ , Ca ²⁺ , Cd ²⁺ and UO ₂ ²⁺ , are selected from the group consisting of hydroxides, sulfates, chlorides, oxides, phosphates, nitrates and the like. 5 - The process according to claim 1, characterized in that the yield is 70 to 90% of the enrofloxacin metal complex. 6 - A metal enrofloxacin complex selected from the group consisting of ENR-Mg; ENR-Fe; ENR-Mn; ENR-Cu; ENR-Co; ENR-Ni; ENR-Ca; ENR-Zn, ENR-Cd and ENR-UO _2, characterized in that it is prepared according to the method described in any one of claims 1 to 5. 7. The use of the enrofloxacin complexes of claim 6, characterized in that they allow to achieve optimum bioavailability by increasing the value of the maximum plasma concentration (Cmax), prolonged the residence time and consequently the antibacterial activity in commercial, ruminant birds, pigs, dogs, cats, horses and other company species and commercially exploited for meat and / or eggs such as ducks, ostriches, among others. 8. The use of the enrofloxacin complexes of claim 7, characterized in that the variable Cmax is 10 to 12 times greater than the MIC value of the pathogen and that AUC / CMI is greater 120 for large bacteria - and 30 to 50 for Gram +. 9. The use of the enrofloxacin complexes of claim 6, characterized in that the ENR-metal complexes mask the taste and therefore allow its acceptance in pigs when the administration is orally in the drinking water and prevents their rejection and Salivation in cats. 10. The use of enrofloxacin complexes for the preparation of medications that allow a maximum residence time in plasma of mammals and birds, where these medications are made for oral, subcutaneous and intramuscular administration